AMPH
Amphiphysin [AMPH1]
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Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D (SKF 82958) or D (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D (SKF 83566) or D (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Behavior, Animal
- Central Nervous System Stimulants
- Dopamine Agonists
- Dopamine Antagonists
- Male
- Motor Activity
- Neurons
- Prefrontal Cortex
- Rats
- Receptors, Dopamine D1
- Receptors, Dopamine D2
- Stereotyped Behavior
Keywords
- Adolescent
- D(1)receptor
- D(2)receptor
- Development
- Locomotor activity
- Sensitization
Amphetamines (AMPH) are psychostimulants widely used for therapy as well as for recreational purposes. Previous results of our group showed that AMPH exposure in pregnant rats induces physiological and behavioral changes in the offspring at prepubertal and postpubertal ages. In addition, several reports have shown that AMPH are capable of modifying the morphology of neurons in some regions of the limbic system. These modifications can cause some psychiatric conditions. However, it is still unclear if there are changes to behavioral and morphological levels when low doses of AMPH are administered at a juvenile age. The aim of this study was to assess the effect of AMPH administration (1mg/kg) in Sprague-Dawley rats (postnatal day, PD21-PD35) on locomotor activity in a novel environment and compare the neuronal morphology of limbic system areas at three different ages: prepubertal (PD 36), pubertal (PD50) and postpubertal (PD 62). We found that AMPH altered locomotor activity in the prepubertal group, but did not have an effect on the other two age groups. The Golgi-Cox staining method was used to describe the neural morphology of five limbic regions: (Layers 3 and 5) the medial prefrontal cortex (mPFC), the dorsal and ventral hippocampus, the nucleus accumbens and the amygdala, showing that AMPH induced changes at pubertal ages in arborization and spine density of these neurons, but interestingly these changes did not persist at postpubertal ages. Our findings suggest that even early-life AMPH exposure does not induce long-term behavioral and morphological changes, however it causes alterations at pubertal ages in the limbic system networks, a stage of life strongly associated with the development of substance abuse behaviors.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Central Nervous System Stimulants
- Dendritic Spines
- Female
- Limbic System
- Male
- Motor Activity
- Neurons
- Rats
- Rats, Sprague-Dawley
- Sexual Maturation
Keywords
- Attention deficit hyperactive disorder
- Basolateral amygdala
- Hippocampus
- Juvenile rats
- Medial prefrontal cortex
- Nucleus accumbens
- d-Amphetamine
Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD(BOLD)) in younger and older adults during a working memory task (letter n-back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD(BOLD) levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD(BOLD) and reaction time means (RT(mean)) and SDs (RT(SD)). Older adults who received AMPH in the first session tended to improve in RT(mean) and RT(SD) when SD(BOLD) was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD(BOLD) decreased (for RT(mean)) or no effect at all (for RT(SD)). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics.
MeSH Terms
- Adult
- Aged
- Aging
- Brain
- Dextroamphetamine
- Dopamine
- Double-Blind Method
- Female
- Functional Neuroimaging
- Humans
- Least-Squares Analysis
- Magnetic Resonance Imaging
- Male
- Memory, Short-Term
- Middle Aged
- Models, Neurological
- Models, Psychological
- Multivariate Analysis
- Young Adult
Keywords
- aging
- brain signal variability
- dopamine
- fMRI
- working memory
The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Central Nervous System Stimulants
- Cocaine
- Dose-Response Relationship, Drug
- Female
- Injections, Intraperitoneal
- Locomotion
- Male
- Methamphetamine
- Methylphenidate
- Mice
- Mice, Inbred C57BL
- Motor Activity
- Sex Factors
- Time Factors
Keywords
- Addiction
- Adolescence
- Cross-sensitization
- Mice
- Psychostimulants
- Sex-specific effects
Drug use typically begins during adolescence, which is a period of ongoing neurobiological development that may confer heightened vulnerability to develop drug dependence. Previously, our lab has shown that amphetamine (AMPH)-induced deficits in a medial prefrontal cortex (mPFC)-sensitive working memory task are greater in rats exposed to the drug during adolescence compared to adulthood. Here, we examine potential age-dependent effects of AMPH exposure on behavioral flexibility tasks that are sensitive to disruptions in mPFC and orbitofrontal cortex (OFC) function. Male Sprague-Dawley rats were injected (i.p.) with saline or 3mg/kg AMPH every other day between postnatal days (PNDs) 27-45 and PNDs 85-103. Starting around PND 125, rats were tested in an attentional set-shifting task and a subset of those was then tested in an operant strategy shifting task. Following completion of the operant task, rats were challenged with 3mg/kg AMPH and monitored in open field chambers. Our results demonstrate that AMPH-exposed rats were faster to acquire simple and compound discriminations, but were impaired during the first stimulus-reward reversal when compared to controls. In the operant strategy shifting task, adolescent-exposed rats shifted more rapidly between strategies and completed reversals faster than adult-exposed and control rats, respectively. The final AMPH challenge revealed evidence for sensitization in drug pre-exposed rats, with adult-exposed animals exhibiting the most significant effects. Together, these results suggest that AMPH induces long-lasting changes in behavioral flexibility that are at least partially dependent on age of exposure and may be due to adaptations in OFC function.
MeSH Terms
- Adaptation, Physiological
- Aging
- Amphetamine
- Analysis of Variance
- Animals
- Animals, Newborn
- Attention
- Central Nervous System Stimulants
- Conditioning, Operant
- Discrimination, Psychological
- Exploratory Behavior
- Food Deprivation
- Male
- Motor Activity
- Odorants
- Rats
- Rats, Sprague-Dawley
Keywords
- Adolescence
- Amphetamine
- Behavioral flexibility
- Prefrontal cortex
Social interaction can serve as a natural reward that attenuates drug reward in rats; however, it is unknown if age or housing conditions alter the choice between social interaction and drug. Individually- and pair-housed adolescent and adult male rats were tested using conditioned place preference (CPP) in separate experiments in which: (1) social interaction was conditioned against no social interaction; (2) amphetamine (AMPH; 1mg/kg, s.c.) was conditioned against saline; or (3) social interaction was conditioned against AMPH. Social interaction CPP was obtained only in individually-housed adolescents, whereas AMPH CPP was obtained in both individually-housed adolescents and adults; however, the effect of AMPH was not statistically significant in pair-housed adults. When allowed to choose concurrently between compartments paired with either social interaction or AMPH, individually-housed adolescents preferred the compartment paired with social interaction, whereas pair-housed adolescents preferred the compartment paired with AMPH. Regardless of housing condition, adults showed a similar preference for the compartments paired with either social interaction or AMPH. Although some caution is needed in interpreting cross-experiment comparisons, the overall results suggest that individually-housed adolescents were most sensitive to the rewarding effect of social interaction, and this hypersensitivity to social reward effectively competed with AMPH reward.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Choice Behavior
- Conditioning, Psychological
- Housing, Animal
- Interpersonal Relations
- Male
- Rats
- Rats, Sprague-Dawley
Cognitive dysfunction is a hallmark of chronic psychostimulant misuse. Adolescents may have heightened risk of developing drug-induced deficits because their brains are already undergoing widespread changes in anatomy and function as a normal part of development. To address this hypothesis, we performed two sets of experiments where adolescent and young adult rats were pre-exposed to saline or amphetamine (1 or 3mg/kg) and subsequently tested in a prefrontal cortex (PFC)-sensitive working memory task. A total of ten injections of AMPH or saline (in control rats) were given every other day over the course of 19 days. After rats reached adulthood (>90 days old), cognitive performance was assessed using operant-based delayed matching-to-position (DMTP) and delayed nonmatching-to-position (DNMTP) tasks. DNMTP was also assessed following challenges with amphetamine (0.3-1.25mg/kg), and ketamine (5.0-10mg/kg). In experiment one, we also measured the locomotor response following the first and tenth pre-exposure to amphetamine and after an amphetamine challenge given at the conclusion of operant testing. Compared to adult-exposed groups, adolescents were less sensitive to the psychomotor effects of amphetamine. However, they were more vulnerable to exposure-induced cognitive impairments. For example, adolescent-exposed rats displayed delay-dependent deficits in accuracy, increased sensitivity to proactive interference, and required more training to reach criterion. Drug challenges produced deficits in DNMTP performance, but these were not dependent on pre-exposure group. These studies demonstrate age of exposure-dependent effects of amphetamine on cognition in a PFC-sensitive task, suggesting a heightened sensitivity of adolescents to amphetamine-induced neuroplasticity.
MeSH Terms
- Aging
- Amphetamine
- Analysis of Variance
- Animals
- Central Nervous System Stimulants
- Conditioning, Operant
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Excitatory Amino Acid Antagonists
- Female
- Food Deprivation
- Ketamine
- Male
- Memory, Short-Term
- Motor Activity
- Rats
- Rats, Sprague-Dawley
- Reinforcement Schedule
Repeated administration of the indirect dopamine receptor agonist amphetamine (AMPH) produces robust locomotor sensitization and additional behavioral abnormalities. Accumulating evidence suggests that the developmental timing of drug exposure can critically influence this effect. The present study compared the consequences of withdrawal from repeated AMPH exposure in adolescence and adulthood on information processing and locomotor sensitization in C57BL/6 mice. Animals were injected daily with AMPH (1 or 2.5 mg/kg) or vehicle on 7 consecutive days starting either from postnatal day 35 to 42, or from postnatal day 70 to 77, following which they were given a 4 week withdrawal period before behavioral and pharmacological testing commenced. We found that withdrawal from the higher dose of AMPH (2.5 mg/kg/day) given either in adolescence or adulthood similarly disrupted selective associative learning as measured by the latent inhibition paradigm. None of the AMPH withdrawal groups displayed alterations in sensorimotor gating in the form of prepulse inhibition. Withdrawal from adult AMPH exposure at both doses induced marked locomotor sensitization, whereas adolescent pre-treatment with the higher (2.5 mg/kg/day) but not lower (1 mg/kg/day) dose of AMPH potentiated the locomotor-enhancing effects of acute AMPH re-challenge. Our study suggests that withdrawal from repeated AMPH exposure in adolescence and adulthood has similar consequences on selective associative learning, but the two manipulations differ with respect to their efficacy to induce long-term locomotor sensitization to the drug. The latter finding supports the hypothesis that the precise developmental timing determines, at least in part, the impact on long-term dopamine-associated sensitization processes.
MeSH Terms
- Age Factors
- Aging
- Amphetamine
- Animals
- Association Learning
- Central Nervous System Sensitization
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Immobility Response, Tonic
- Male
- Mice
- Motor Activity
- Neural Inhibition
- Reflex, Startle
- Substance Withdrawal Syndrome
Netrin-1 guidance cues contribute to amphetamine-induced plasticity of the adult mesocorticolimbic dopamine system in rodents. The netrin-1 receptor, deleted in colorectal cancer (DCC), is upregulated by repeated amphetamine treatment selectively in the ventral tegmental area (VTA) of adult rats and wild-type mice. Furthermore, adult dcc heterozygous mice fail to show amphetamine-induced increases in VTA DCC expression and do not develop sensitization to this drug. The effects of netrin-1 receptor signaling on mesocorticolimbic dopamine system function change across development. However, the effects of AMPH on DCC receptor regulation and behavioral sensitization before puberty have not been determined. Here we examined whether (1) repeated amphetamine treatment would also alter DCC expression in juvenile rats and wild-type mice, and (2) dcc heterozygotes treated with amphetamine during the juvenile period (PND 22-32) would develop behavioral sensitization to this drug. Repeated amphetamine downregulates DCC expression selectively in the VTA of juvenile rodents. Moreover, the behavioral phenotype of adult dcc heterozygous mice is not present before puberty and is abolished by amphetamine treatment during the juvenile period. Remarkably, adult dcc heterozygotes pretreated with amphetamine as juveniles no longer exhibit reduced DCC expression in the VTA compared to wild-type controls. Our results indicate that netrin-1 receptor signaling may be a key factor in determining individual differences in vulnerability to the behaviorally sensitizing effects of amphetamine at different ages. Moreover, they suggest that the juvenile period marks a window of vulnerability during which exposure to stimulant drugs can reverse the behavioral phenotype of adult dcc heterozygous mice.
MeSH Terms
- Aging
- Amphetamine
- Amphetamine-Related Disorders
- Animals
- Behavior, Animal
- Blotting, Western
- DCC Receptor
- Down-Regulation
- Gene-Environment Interaction
- Heterozygote
- Male
- Mice
- Motor Activity
- Netrin Receptors
- Rats
- Rats, Wistar
- Receptors, Cell Surface
- Tumor Suppressor Proteins
- Up-Regulation
- Ventral Tegmental Area
Adolescence is a critical age for addiction formation as a large percentage of pathological drug-seeking behaviors manifest during this time. The extent to which the neurotoxic effects of drugs of abuse influence subsequent drug seeking behaviors and impulsivity is an understudied area of research. Methamphetamine (METH) is a widely abused drug that produces locomotor responses ranging from behavioral sensitization to tolerance, both of which are behaviors that may relate to risk of abuse. Here we investigated the effects of age, genotype, METH dose, including a neurotoxic dose, and METH metabolism on open-field activity (OFA) to gain insight into the complex disease of drug abuse. C57Bl/6 (B6), DBA/2 (D2), and 129S6SvEv/Tac (129) mouse strains were administered saline or either a high dose (4×5 mg/kg in 2 h intervals for 2 days) or low dose (2×1 mg/kg in 24 h intervals) METH pretreatment during adolescence (post natal day (PND) 40) or early adulthood (PND 80) followed by behavioral testing with a METH (1 mg/kg) or saline challenge 40 days later. Striatal concentrations of METH and AMPH were also determined. Significant findings include: 1) METH pretreated adolescent B6 mice displayed significant sensitization for horizontal locomotion due to high dose METH pretreatment; 2) METH pretreated B6 adults showed significant tolerance for the vertical activity measure caused by low dose METH pretreatment; 3) METH pretreated adult D2 mice exhibited significant sensitization for vertical activity induced by low dose METH pretreatment, and 4) 129 mice metabolized METH significantly faster than the B6 and D2 mice, but METH pretreatment did not alter metabolism. No significant behavioral responses to either METH pretreatment dose were observed for the D2 adolescent studies or either 129 age group. Our results highlight the importance of the interactions of age, strain and METH dose on locomotor behavioral outcomes.
MeSH Terms
- Adolescent
- Aging
- Animals
- Dose-Response Relationship, Drug
- Drug-Seeking Behavior
- Genotype
- Humans
- Illicit Drugs
- Male
- Methamphetamine
- Mice
- Mice, 129 Strain
- Mice, Inbred A
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Models, Animal
- Motor Activity
- Species Specificity
Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet.
MeSH Terms
- Aging
- Amphetamine
- Analysis of Variance
- Animals
- Behavior, Animal
- Blood Glucose
- Central Nervous System Stimulants
- Corticosterone
- Exploratory Behavior
- Food Deprivation
- Habituation, Psychophysiologic
- Male
- Motor Activity
- Rats
- Rats, Wistar
Psychostimulant drugs are widely used in children for the treatment of attention-deficit/hyperactivity disorder. Recent animal studies have suggested that exposure to these agents in early life could be detrimental to brain development. Here, for the first time, the effect of methylphenidate (MPH) and D-amphetamine (AMPH) on the expression of two key genes for neuronal development and plasticity, brain-derived neurotrophic factor (bdnf) and the effector immediate early gene activity-regulated, cytoskeletal-associated protein (Arc), was examined in both juvenile and adult rats. Both MPH [2 mg/kg, intraperitoneal (i.p.)] and AMPH (0.5 mg/kg, i.p.) induced marked decreases of bdnf mRNA in hippocampal and cortical brain regions of juveniles, whereas effects in adults were significantly less (hippocampus) or opposite (frontal cortex). In comparison, Arc mRNA was decreased (hippocampus and parietal cortex), largely unaffected (frontal cortex) or increased (striatum) in juveniles, whereas in adults, Arc mRNA increased in most brain regions. MPH-induced locomotion was also measured, and showed a much smaller increase in juveniles than in adults. In summary, our data show that the effects of MPH and AMPH on expression of the neurodevelopmentally important genes, bdnf and Arc, differ markedly in juvenile and adult rats, with juveniles showing evidence of brain region-specific decreases in both genes. These age-dependent effects on gene expression may be linked with the reported long-term harmful effects of psychostimulants in animal models.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Brain
- Brain-Derived Neurotrophic Factor
- Central Nervous System Stimulants
- Cytoskeletal Proteins
- Down-Regulation
- Gene Expression Regulation
- Genes, Immediate-Early
- Male
- Methamphetamine
- Nerve Tissue Proteins
- Rats
- Rats, Sprague-Dawley
Effects of post-implantation time on potassium (K )- versus D-amphetamine (D-AMPH)-evoked striatal dopamine (DA) overflow were measured using microdialysis in freely moving young and aged Fischer 344 rats. In one group, samples were collected on the day of probe insertion (Day 1 group). In a second group, samples were collected 24 h after probe insertion (Day 2 group). While analyses revealed no significant differences between the two age groups, the 100 mM K stimulus evoked a significantly greater amount of DA overflow in the Day 1 group compared to the Day 2 group. The decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) produced by K stimulation was not influenced by post-implantation time. The effect of the 250 microM D-AMPH stimulus on DA overflow did not differ between the Day 1 and Day 2 groups, nor did the decrease in DOPAC that accompanied D-AMPH stimulation. These results support the hypothesis that under some stimulus conditions, post-implantation time is an important variable in microdialysis studies.
MeSH Terms
- 3,4-Dihydroxyphenylacetic Acid
- Aging
- Animals
- Dextroamphetamine
- Dopamine
- Extracellular Space
- Microdialysis
- Neostriatum
- Neural Pathways
- Potassium
- Rats
- Rats, Inbred F344
- Reaction Time
- Substantia Nigra
Changes in locomotor and stereotypic activities induced by an i.p. injection of either ( )-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cycloheptan-5,10-imine maleate (dizocilpine or MK-801; 0.3 mg/kg) or D-amphetamine sulfate (AMPH; 1.5 mg/kg) were studied in male Mill Hill hooded rats of different age. The following age groups of animals were considered: 28-30 postnatal day (PND)-old rats (peripubertal), 48-50 PND-old (pubertal), 3-month-old (adults), 12-month-old (middle-aged) and 24-month-old (aged). The motor response was measured by an automated animal activity measuring system. The obtained results showed that: (1) in contrast to AMPH, MK-801 induced more pronounced increases of both locomotor and stereotypic activities in peripubertal and pubertal than in adult and aged rats; (2) AMPH induced the same locomotor and stereotypic activity increase in pubertal, adult and middle-aged rats; (3) both AMPH and MK-801 led to a senescence-related decrease of motor activity. These data suggest that the balance of the glutamatergic and dopaminergic systems changes during aging. Such a change is important in understanding schizophrenia and the motor system decline observed in the later stages of life.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Animals, Newborn
- Central Nervous System Stimulants
- Dizocilpine Maleate
- Male
- Motor Activity
- Rats
- Receptors, N-Methyl-D-Aspartate
- Stereotyped Behavior
- Time Factors
In order to measure the effects of different concentrations of D-amphetamine (D-AMPH) infusions on striatal dopamine (DA) overflow in young versus aged rats, and to determine the influence of preceding infusions on subsequent stimuli, two microdialysis studies were conducted. In the first study, D-AMPH (100, 200, and 2000 microM) was infused in ascending order of concentration, while in the second study the order of administration was reversed. The order of administration significantly affected DA overflow and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC). Generally, DA overflow was greater for a given concentration when it was administered first in a sequence than when it was administered later in a sequence. The two age groups did not differ on measures of DA overflow. The order of administration also significantly influenced the effect of D-AMPH on extracellular DOPAC, as the D-AMPH-related decreases in DOPAC were greater for a concentration when it was administered earlier versus later in the sequence. This effect was greater in the young rats than in the aged rats. D-AMPH also resulted in diminished levels of DOPAC in the aged rats compared to the young rats. These results suggest that between-groups studies may be more appropriate for determining the effects of different concentrations of D-AMPH on striatal DA overflow. They also demonstrate that while some measures of stimulus-evoked DA overflow may not differ between young and aged F344 rats, extracellular regulation of striatal DA (as measured by changes in DOPAC) may be altered. These alterations may contribute to age-related decreases in motor function.
MeSH Terms
- 3,4-Dihydroxyphenylacetic Acid
- Aging
- Animals
- Central Nervous System Stimulants
- Chromatography, High Pressure Liquid
- Corpus Striatum
- Dextroamphetamine
- Dopamine
- Extracellular Space
- Male
- Microdialysis
- Rats
Selective breeding has been used to develop the alcohol-preferring (P) and -nonpreferring (NP) rats, with the P rat having lower CNS levels of dopamine (DA) and reduced DA innervation in the nucleus accumbens compared with the NP rat. The acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR are experimental behaviors altered by DA agonists. We examined whether functional differences in amphetamine (AMPH)-modified ASR and PPI exist between P and NP rats. AMPH [0.0 (saline), 1.0, 2.0, or 4.0 mg/kg] was injected 15 min prior to placement into a startle apparatus. After a 5-min habituation period, rats were given approximately twelve 95-, 105-, or 115-dB white-noise burst (ASR) and PPI trials. As adults, P rats were sensitive to AMPH potentiation of the ASR to a greater extent than NP rats. During adolescence, P and NP rats had similar levels of AMPH-potentiated ASR. As adults, NP rats displayed potentiated, rather than disrupted, PPI at the 1.0-mg/kg dose, whereas P rats displayed the expected disrupted PPI at the 4.0-mg/kg dose. As adolescents, NP rats did not display significant differences in PPI after AMPH, whereas P rats displayed dose-dependent disruption of PPI, which was significant at the 4.0-mg/kg dose. The limited effect of AMPH on increasing the ASR and the presence of AMPH-potentiated PPI at the lowest dose in the adult NP rat suggests reduced functioning of the interactions between DA circuits and the neurocircuitry mediating the ASR and PPI, compared with P rats. However, the neurocircuitry mediating PPI does not appear to be fully developed in the adolescent NP rat. The present findings also indicate that lower levels of DA content and immunoreactive fibers in the P rat may not reflect reduced DA neuronal activity, because the P rat displayed AMPH-potentiated ASR, and, at the highest dose, AMPH disruption of PPI during both adulthood and adolescence.
MeSH Terms
- Acoustic Stimulation
- Aging
- Alcohol Drinking
- Amphetamine
- Animals
- Central Nervous System Stimulants
- Dopamine
- Dopamine Uptake Inhibitors
- Dose-Response Relationship, Drug
- Female
- Rats
- Reflex, Startle
Individual differences in coping with novelty and in the response to psychoactive drugs have been related to early life events, such as the age of weaning. Outbred CD-1 mice underwent a precocious (postnatal day (pnd) 15, Wean-15 group), regular (pnd 21, Wean-21 group), or delayed (pnd 27, Wean-27 group) weaning, and were tested as adults (pnd > 60). In Experiment 1, animals underwent a treatment history with d-amphetamine (AMPH 0, 1, or 5 mg/kg once/day for three days) in a familiar environment. On testing day, mice were challenged with SAL or a standard 1 mg/kg AMPH dose (to evaluate acute drug effects and sensitization), and placed in the familiar environment. As expected, regular Wean-21 animals showed an AMPH-induced hyperactivity and a profile of conditioned locomotion, whereas the same dosage failed to induce any change in Wean-15 and Wean-27 groups. Levels of spontaneous novelty seeking were particularly elevated for Wean-27 mice, when compared with the other weaning groups. In Experiment 2, pairing of AMPH administration (0, 1, 2, 3.3, or 5 mg/kg once/day for three days) with a distinct environment produced a classical conditioned place preference. The magnitude of the preference profile was significantly more marked for Wean-15 mice, when compared with the other two weaning groups. Both experiments also provided evidence that the development of sensitization was particularly evident in Wean-27 mice. In summary, delayed weaning was associated in adult mice with both elevated levels of novelty seeking and increased sensitization to drug effects. Conversely, animals weaned precociously were much more responsive to AMPH-induced incentive conditioning. These results appear relevant to the issue of early experiences as possible risk factors for a number of psychiatric disorders in humans, including the abuse of drugs.
MeSH Terms
- Aging
- Amphetamine
- Amphetamine-Related Disorders
- Animals
- Animals, Newborn
- Behavior, Animal
- Conditioning, Psychological
- Dose-Response Relationship, Drug
- Exploratory Behavior
- Female
- Male
- Maternal Behavior
- Mice
- Motor Activity
- Weaning
To determine whether the dopamine D(2) receptor plays a crucial role in chemically acquired sensitivity to drugs of abuse like amphetamine (AMPH) after an exposure to aryloxoalkanoic compounds, we examined in the present work the impact of AMPH (10 mg/kg, i.p.) on the dopaminergic D(2)-like receptors. Rats were exposed to 2,4-D 70 mg/kg/day from gestation day (GD) 16 to postnatal day (PND) 23. After weaning, the pups were assigned to one of the two subgroups: T1 (fed with untreated diet until PND 90) and T2 (maintained with 2,4-D diet until PND 90). After that, an acute challenge with AMPH was administered to each animal. Rats were sacrificed at 0, 5, 24, 72, and 168 h after AMPH, and membranes of striatum (CPu), prefrontal cortex (PfC), hippocampus (H), and cerebellum (Ce) were obtained. Binding studies employing [(3)H]nemonapride showed that AMPH caused an increase in DA D(2)-like receptors of all brain areas between 5 and 24 h after the treatment, with a reduction to the basal levels one week later. The AMPH challenge to (T1 and T2) 2,4-D-exposed rats showed an alteration on receptor density depending on brain area and on sex, more than on the 2,4-D exposure time. This D(2)-like receptor density increase could explain the exacerbated behaviors of the 2,4-D-exposed and amphetamine-challenged animals, as previously observed by us. The withdrawal of 2,4-D did not produce a real reversion to basal levels of D(2)-like receptors, indicating that herbicide exposure during the preweanling period caused a sensitization and a stable DA D(2)-like receptor increase that was elicited when the system was challenged with this dopaminergic drug.
MeSH Terms
- 2,4-Dichlorophenoxyacetic Acid
- Aging
- Amphetamine
- Animals
- Benzamides
- Brain
- Dopamine Antagonists
- Female
- Male
- Maternal Exposure
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
- Rats, Wistar
- Receptors, Dopamine D2
- Tissue Distribution
Although final brain size and the number of available neurons and axons appear to be established early in infancy, plasticity of the brain continues during adolescence through an integrated process of overproduction and elimination of synapses and receptors. In addition, hormonal levels change dramatically during this period, as a result of the onset of puberty. This age-specific condition has been suggested to serve as a permissive factor for the emergence of a number of early-onset neuropsychiatric disorders, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and perhaps substance abuse. However, relatively few investigations have focused on animal models of this developmental phase. The periadolescent rodent (similar30-45-day-old), has been proposed as a useful model. Periadolescent rats and mice are generally associated with a peculiar behavioral profile, consisting of basal hyperactivity, high attraction towards novel stimuli and a marked involvement in affiliative and playful behaviors. Moreover, a unique profile of psychopharmacological responsivity characterizes rodents around this age. Recent experiments by our group investigated age-related discontinuities in the response of the hypothalamic-pituitary-adrenal axis (HPA) to both stress and psychostimulants. The latter are often administered as therapeutic drugs to children with ADHD, which have been also associated with an impaired response to stress and abnormalities in HPA axis function. Indeed, an altered functioning of the HPA axis has been proposed as a possible risk factor and a potential marker for such a behavioral vulnerability. Animals were studied at adulthood (> pnd 70) or during periadolescence. Experiment I characterized basal corticosterone (CORT) levels in naive mice kept undisturbed in standard social conditions from weaning to sacrifice. Periadolescent male mice showed higher basal CORT levels than adult subjects, suggesting that the set up of the HPA axis is physiologically elevated during adolescence. In experiment II, we investigated age-related differences in the response to both acute and chronic stress conditions. Periadolescent and adult mice were housed either in a standard (three animals per cage) or in a crowding condition (nine animals per cage). The latter has been indeed reported to potentiate the subsequent reaction to acute stress in adult rodents. At the end of this period and following 24 h individual housing, mice were injected with either saline (SAL) or a standard amphetamine (AMPH) dose (2 mg/kg), and faced with a mild acute psychological stress, namely removal of sawdust from the home cage. Important sex differences emerged in animals of the two ages. Periadolescent females showed a reduced CORT response to acute stress. Within the adult male group, the chronic crowding condition produced a prominent potentiation of CORT response to the acute stress challenge. Conversely, this profile was not evidenced in periadolescents. These results indicate a strong role for gender and social variables in the response of periadolescent subjects to the various aspects of stress. As for AMPH effects, in the absence of significant changes in adult subjects, the drug produced a marked CORT release in periadolescent mice. A better understanding of neuroendocrine-related AMPH effects as a function of social and environmental risk factors during adolescence, might deepen our knowledge on the neurobiological bases of genetically determined neuropsichiatric disorders and possibly improve the therapeutical efficacy of psychostimulant drugs.
MeSH Terms
- Acute Disease
- Aging
- Amphetamine
- Animals
- Central Nervous System Stimulants
- Chronic Disease
- Corticosterone
- Crowding
- Female
- Male
- Mice
- Sex Characteristics
- Stress, Psychological
In order to study age-related differences in striatal electrophysiological activity in freely-moving animals, multi-wire electrode arrays were chronically implanted in the striatum of young (6-8 months) and aged (24-26 months) Fischer 344 rats. After recording baseline activity, d-amphetamine (D-AMPH; 1.0 mg/kg) and apomorphine (APO; 0.5 mg/kg) were administered to the two age groups. For both the D-AMPH and APO series, the percentage of striatal neurons that increased firing rates as a result of the DA agonists was 19% higher in the old animals than in the young animals. In addition, D-AMPH increased the firing rates of D-AMPH-excited neurons to a greater extent in the old animals than in the young animals. While the rate-increasing effects of APO did not differ significantly as a function of age, its effects were slightly greater in the old animals as well. These results suggest that age-related decreases in nigrostriatal DA function may result in alterations in the way in which the striatum integrates corticostriatal and nigrostriatal inputs to influence motor function.
MeSH Terms
- Aging
- Animals
- Apomorphine
- Dextroamphetamine
- Dopamine Agonists
- Dopamine Uptake Inhibitors
- Electrodes, Implanted
- Electrophysiology
- Male
- Neostriatum
- Neurons
- Rats
- Rats, Inbred F344
The objective of this study was to determine whether functional differences exist in amphetamine-induced locomotor activity between alcohol-naive alcohol-preferring (P) and -nonpreferring (NP) rats during postnatal development and during adulthood. Using a between-subjects design, 20- and 28-day-old P and NP rats (male and female counterbalanced, n=11-16/line) were habituated for 30 min in a photocell activity field. Each rat received subcutaneous injections of saline or 0.3, 0.6 or 1.2 mg/kg d-amphetamine (AMPH) and were then tested for an additional 30 min. Because of age and line differences in basal locomotor activity, total activity counts during the 30-min postdrug period were standardized using Z-score transformations. In the 20- and 28-day-old rats, dose-dependent locomotor activity increases after AMPH injections were obtained at both ages, although activity levels were greater in the 20-day-old pups. The 20-day-old female NP rats showed greater AMPH-induced increases in locomotor activity than P rats, whereas at 28 days of age, male NP rats showed greater activity levels than P rats to AMPH. For the adult P and NP rats (n=8/line/gender), a within-subject design was used. In the adults, the NP line had higher locomotor activity than the P line following AMPH injection, and male rats were activated more by AMPH than female rats. The results suggest that functioning of the DA system in the adult P line is reduced compared to the adult NP line, and this line difference is also observed to some degree at an early postweaning developmental period.
MeSH Terms
- Aging
- Alcohol Drinking
- Amphetamine
- Animals
- Dopamine Uptake Inhibitors
- Dose-Response Relationship, Drug
- Female
- Male
- Motor Activity
- Rats
- Rats, Wistar
- Sex Factors
- Species Specificity
Effects of amphetamine on the production of 50-kHz ultrasonic calls were studied. Calls were emitted spontaneously or were induced by an intrahypothalamic-preoptic injection of glutamate. Sonographic analysis of recorded calls revealed that they were within the 35-70-kHz sound frequency range reported for the 50-kHz call type. Systemic amphetamine (AMPH, 2 mg/kg) significantly increased the number of spontaneously emitted 50-kHz calls and the effect of AMPH was dose-dependent. Low dose of intracerebral glutamate (17 microg) had no additive effect on the number of AMPH-induced calls. Higher dose of intracerebral glutamate alone (34 microg) significantly increased the number of 50-kHz calls, which was completely reversed by systemic application of haloperidol (2 mg/kg), a dopamine antagonist. The results suggest that glutamate-induced or spontaneously occurring 50-kHz calls in adult rats are dependent upon dopaminergic transmission. It is postulated that this type of calls may be indicative of dopamine mediated affective state in adult rats.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Brain
- Dopamine
- Dopamine Antagonists
- Dopamine Uptake Inhibitors
- Glutamic Acid
- Haloperidol
- Injections, Intraventricular
- Male
- Rats
- Rats, Wistar
- Ultrasonics
- Vocalization, Animal
The neurobiological and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants. Periadolescent (33-43 days) and adult (>70 days) Sprague-Dawley rats underwent a 3-day treatment history with D-amphetamine (AMPH) at 0, 2, or 10 mg/kg (once a day). After a short 5-day-long withdrawal interval, freely moving animals were challenged with a 2-mg/kg AMPH dose and their behavior as well as in vivo intrastriatum dopamine (DA) release in the CNS were assessed. Microdialysis data indicated that AMPH-history periadolescent rats showed a prominent sensitization of AMPH-stimulated DA release, whereas no such change was found in adult subjects. As expected, acute AMPH administration strongly reduced time spent lying still and increased levels of cage exploration in animals of both ages. A treatment history of high AMPH dosage was associated with a marked sensitization of the exploratory behavior in adults, whereas it induced a quite opposite profile in periadolescents. The latter group only was also characterized by a compulsive involvement in the stereotyped head-bobbing response. These results indicate that differently from adults, marked alterations in neurobiological target mechanisms are observed in rats around periadolescence as a consequence of a quite mild regimen of intermittent AMPH exposure. Thus, a neurobiological substrate for an age-related increased vulnerability towards the addictive risks of these drugs is suggested.
MeSH Terms
- 3,4-Dihydroxyphenylacetic Acid
- Aging
- Animals
- Behavior, Animal
- Body Weight
- Brain Chemistry
- Caudate Nucleus
- Chromatography, High Pressure Liquid
- Dextroamphetamine
- Dopamine
- Dopamine Uptake Inhibitors
- Dose-Response Relationship, Drug
- Exploratory Behavior
- Female
- Homovanillic Acid
- Microdialysis
- Neostriatum
- Pregnancy
- Putamen
- Rats
- Rats, Sprague-Dawley
- Stereotyped Behavior
The psychostimulant D-amphetamine (AMPH) increases generalised activity in adult subjects, while exerting a paradoxical "calming effect" in children with Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal models have been developed to characterise the neurobiological basis of this AMPH action. In this line, the present review summarises recent work on the effects of AMPH on behavioural and physiological parameters in developing mice with a special emphasis on the role of gender and environmental risk factors. Behavioural and neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their relation to changes in the environment, represented by social stimuli, were studied in infant CD-1 mouse pups of both sexes at three different developmental ages (3, 8, or 18 postnatal (pnd) days). Mouse pups were assessed either in baseline condition or following 24 h maternal deprivation. AMPH exerted a paradoxical effect on CORT secretion only in maternally deprived subjects while affecting behaviour mainly in deprived female subjects, which showed a generalised shift to the left in the dose-response curve to this drug. Unwanted perseverative motor effects and possible dependence states represent side effects of AMPH administration. Further knowledge on these aspects comes from another set of studies where a shortened conditioned place preference (CPP) paradigm was employed to assess the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in developing mice on 14-17, 21-24, and 28-31 pnd. Data indicate that AMPH-CPP develops early, mice being able, already at two weeks of age, to acquire a place preference that relies on adult-like sensory, motor, and associative capacities. AMPH-CPP appears earlier in females, compared to males. A detailed analysis of acute D-amphetamine effects evidenced that the drug produces a dose-dependent increase in locomotor activity and in several responses (including stereotypes). These effects appear much larger at both post weaning stages than in preweanlings and are significantly more pronounced in females than in males. Overall these data suggest that AMPH action is dependent on the baseline level of activity and indicate a strong role of gender in the effects of this drug measured early on during development, with females showing greater sensitivity to this drug. A better understanding of AMPH action during the early ontogenetic phases, particularly its interaction with environmental factors, might extend our knowledge on the neurobiological basis of AD/HD, possibly improving the clinical efficacy of psychostimulant drugs.
MeSH Terms
- Aging
- Animals
- Attention Deficit Disorder with Hyperactivity
- Central Nervous System Stimulants
- Dextroamphetamine
- Environment
- Female
- Male
- Mice
- Risk Factors
- Sex Characteristics
Adolescence is associated with an increased risk of developing drug abuse/dependence. During this ontogenetic phase, brain and hormonal systems are still undergoing crucial maturational rearrangements, which take place together with significant modifications in psychosocial development. However, the neurohormonal and behavioral facets of adolescence have been poorly investigated in relation to the vulnerability to psychostimulants such as MDMA ("Ecstasy") and amphetamine (AMPH). Novelty-seeking, a temperamental/behavioral trait that is typical of this age period, might substantially contribute to both psychological and psychobiological vulnerability. In humans, an elevated score of novelty-sensation seeking and a derangement of monoaminergic function were both associated with late adolescence MDMA users compared to controls. In animal models of periadolescence, the search for novel stimuli and sensations actually shares a common neurobiological substrate (the reward-related brain mesolimbic pathways) with psychostimulants. The present review summarises recent work in mice, which indicates that periadolescent subjects are characterized by an unbalanced and "extremes-oriented" behavior and by elevated novelty-seeking compared to adults. Repeated and intermittent administration of cocaine or AMPH was associated with the development of a prominent locomotor sensitization in periadolescents, which failed to exhibit the marked sensitization of the stereotyped behavioral syndrome--possibly associated with poor welfare--that was typical of adults. A unique profile of integrated behavioral and physiological hyporesponsivity to both forced novelty and acute AMPH administration during periadolescence was also found. As a whole, these results, together with previous work on this topic, suggest that periadolescents may be more "protected" from AMPH-related aversive properties, and perhaps more vulnerable to the experience of internal states of reward, than older animals. Thus, the present animal model of adolescence seems to represent a reliable and useful method for the investigation of vulnerability to a variety of habit-forming agents or emotional experiences whose positive reinforcing properties may rely on common neurobiological substrates. A deeper understanding of psychostimulant effects during adolescence on the complex interaction between genetic, neurobiologic, psychosocial, and environmental factors will lead to earlier and more effective prevention and treatment.
MeSH Terms
- Adolescent
- Aging
- Animals
- Central Nervous System Stimulants
- Exploratory Behavior
- Humans
- Risk Factors
- Substance-Related Disorders
It has been reported that post-natal day (PD) 30-40 rats respond differently to the behavioral effects of dopaminergic drugs when compared to younger or older rats. In this study, the behavioral effects of amphetamine (AMPH) on motor behavior and the effects of dopaminergic drugs on striatal acetylcholine (ACh) release were evaluated in periadolescent (PD35) and adult rats. AMPH increased dopamine (DA)-mediated motor behaviors (locomotor activity and stereotypy) in periadolescent and adult rats; however, these responses were of a lesser magnitude in periadolescent rats. In adult rats, cocaine and nomifensine inhibited ACh overflow in a dose-dependent manner. In periadolescent rats, ACh overflow was maximally inhibited at a lower drug concentration (5 microM) than in adult rats (10 microM) signifying increased sensitivity in these rats. Apomorphine inhibited ACh overflow in a dose-dependent fashion in slices from adult rats. In contrast, apomorphine did not consistently inhibit ACh overflow in striatal slices prepared from periadolescent rats. Collectively, the results of this study demonstrate behavioral subsensitivity to AMPH in periadolescent rats. Examination of the effects of DA reuptake blockers on DA modulation of striatal cholinergic neurons failed to reveal a corresponding subsensitivity. In fact, ACh release was more sensitive to DA reuptake blockers in periadolescent rats. This latter finding suggests that undisclosed factors override dopaminergic modulation of striatal neurons in the mediation of behavior in periadolescent rats. We propose that during periadolescence, DA transmission is transiently elevated. This results in post-synaptic supersensitivity of cholinergic receptors and consequently induces behavioral subsensitivity when challenged with dopaminergic drugs. Increased cholinergic tone may mediate behavioral subsensitivity despite drug-induced elevations in DA.
MeSH Terms
- Acetylcholine
- Aging
- Amphetamine
- Animals
- Apomorphine
- Behavior, Animal
- Cocaine
- Corpus Striatum
- Dopamine Agents
- Dopamine Agonists
- Dopamine Uptake Inhibitors
- Drug Resistance
- Grooming
- Habituation, Psychophysiologic
- In Vitro Techniques
- Male
- Motor Activity
- Nomifensine
- Rats
- Rats, Long-Evans
- Stereotyped Behavior
This study was designed to examine the effects of d-amphetamine (D-AMPH) and D1- and D2-selective dopaminergic drugs on the concentration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid (KYNA) in the striatum of developing and adult rats. At all ages, KYNA levels were significantly reduced 1 h after the systemic administration of D-AMPH (5 mg/kg). SKF 38393 (5 mg/kg) and quinpirole (2 mg/kg) also caused a rapid decrease in striatal KYNA, but only in postnatal day (PND) 7 and 14 rats. All these effects were readily prevented by specific dopamine receptor antagonists. The possible functional significance of the reduction in KYNA levels was tested in PND 14 animals. When pretreated with D-AMPH (5 mg/kg), these rats showed markedly increased vulnerability to an intrastriatal injection of the excitotoxin NMDA. These data suggest that KYNA plays a role as a mediator of dopamine-glutamate interactions in the rat striatum.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Corpus Striatum
- Dextroamphetamine
- Dopamine
- Dopamine Agents
- Dopamine Antagonists
- Excitatory Amino Acid Agonists
- Haloperidol
- Injections
- Kynurenic Acid
- Ligands
- Male
- N-Methylaspartate
- Rats
- Rats, Sprague-Dawley
- Receptors, Dopamine D1
- Receptors, Dopamine D2
Induction of the immediate-early gene c-fos by the stimulants cocaine and amphetamine (AMPH) was analyzed by Fos immunocytochemistry at different ages in the brains of prenatally cocaine-treated and control rats. Cocaine and AMPH induced c-fos in patches of striatal neurons during the first postnatal week, and thereafter produced a progressively more homogeneous pattern that was more dense medially. Quantification of Fos-immunoreactive cells in older rats revealed differences related to sex and prenatal cocaine treatment. Both cocaine and AMPH produced dose-dependent increases in the number of Fos-immunoreactive cells in striatum. Prenatal cocaine exposure resulted in increased Fos in males in response to AMPH (2 mg/kg) at P18 and cocaine (10 mg/kg) at 1-2 months. In females, prenatal cocaine treatment resulted in a reduced response to cocaine at 1-2 months. Increased c-fos induction was observed in control females compared to control males in response to low doses of stimulants; no such sex difference was observed in prenatally cocaine-treated rats. The dopamine D1 antagonist SCH23390 blocked cocaine-mediated c-fos induction in all groups. The NMDA antagonist MK-801 blocked cocaine-mediated c-fos induction in the medial striatum. In females only, MK-801 pretreatment resulted in a dramatic increase in the number of Fos-immunoreactive cells in lateral striatum. These findings indicate differences in the neural basis of c-fos induction in males and females, and changes in stimulant-mediated c-fos induction resulting from prenatal cocaine exposure.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Benzazepines
- Cocaine
- Corpus Striatum
- Dopamine Antagonists
- Dopamine Uptake Inhibitors
- Excitatory Amino Acid Antagonists
- Female
- Nerve Tissue Proteins
- Pregnancy
- Prenatal Exposure Delayed Effects
- Proto-Oncogene Proteins c-fos
- Rats
- Rats, Sprague-Dawley
- Sex Characteristics
- Stimulation, Chemical
Individual differences arise from both genetic and epigenetic factors. The aim of this study was to test whether pups raised in distinct socio-sexual conditions would show different behavioural and neuroendocrine responses to d-amphetamine (AMPH) administration upon placement in a novel environment. This issue was addressed by testing infant CD-1 mouse pups of both sexes at three different developmental ages [3, 8, or 18 postnatal (PND) days]. These pups were raised from birth in all-male, all-female, or mixed-sex litters. AMPH effects were assessed as a function of the hypothalamic-pituitary-adrenal (HPA) axis activational state using litters that were either maternally deprived for 24 h (DEP) or normally kept with the dam (NDEP). A concomitant maternal behaviour score carried out on selected postpartum days showed that mothers taking care of all-male litters were more often involved in Active nursing than those rearing the mixed-sex ones, whereas the latter were found more often Laying still out of the nest. Basal and stress-induced corticosterone (CORT) secretion was increased in unisexually reared pups following maternal deprivation, an effect limited to PND 3. In general, neuroendocrine and behavioural responses to AMPH were found to be dissociated and were affected by sexual segregation only in conjunction with maternal deprivation. On PND 3, AMPH injection (1 or 3 mg/kg, i.p.) decreased CORT secretion in deprived unisexually reared subjects without affecting their behaviour. As a whole, behavioural changes due to unisexual rearing were limited to female subjects. On PND 8, unisexually reared females showed, upon maternal deprivation, a generalized shift to the left in the dose-response curve to AMPH for Crossing behaviour, while on PND 18 AMPH-induced stereotypies were considerably reduced in sexually segregated females, especially following maternal deprivation. Thus, maternal deprivation appeared to "sensitize" the monoaminergic system to an AMPH challenge. The individual behavioural and neuroendocrine profiles shown in response to a stressful challenge suggest that changes in social stimulation early during development might produce subtle shifts in the function of selected central monoaminergic systems.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Body Weight
- Central Nervous System Stimulants
- Corticosterone
- Dextroamphetamine
- Dose-Response Relationship, Drug
- Female
- Individuality
- Male
- Maternal Behavior
- Mice
- Neurosecretory Systems
- Sex Characteristics
The effect of neonatal hippocampal lesions on behavioral sensitivity to amphetamine (AMPH) and dopamine (DA) release in the nucleus accumbens (NAc) were examined. The ventral hippocampus was damaged bilaterally by ibotenic acid on postnatal day 7 (PD7). Spontaneous exploration and AMPH-stimulated locomotor activity were examined on postnatal day 35 (PD35) and day 56 (PD56). Extracellular DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were sampled using in vivo microdialysis while simultaneously AMPH-stimulated locomotion was examined in freely moving rats on PD56. Spontaneous exploration increased in rats with hippocampal lesions relative to controls on PD56 but not PD35. AMPH (0, 0.187, 0.375, 0.75, 1.5, and 3 mg/kg) enhanced locomotion dose-dependently in both control and lesioned groups. Locomotor activity was higher in lesioned rats than controls following AMPH at the dose of 0.75 mg/kg on PD35 and at the doses of 1.5 and 3.0 mg/kg on PD56. The basal level of DA in the NAc was not different between the hippocampal and control groups. AMPH (1.5 mg/kg) induced hyperlocomotion in lesioned rats relative to controls. DA release in the NAc for both groups was enhanced following injections of AMPH. However, neonatal hippocampal lesions had no further enhancement on AMPH-stimulated release of DA as compared to the control group. The levels of DOPAC and HVA in the NAc were altered by AMPH but not lesions. The level of 5-HIAA was not influenced by either lesions or AMPH. The results of neonatal lesion-induced hyperlocomotion suggest that an emergence of behavioral hyperresponsiveness to AMPH was dependent on an interaction of lesions, age of examination, and dose of the drug. A dissociation between the effect of AMPH on lesion-enhanced hyperlocomotion and a lack of a lesion-enhanced DA release in the NAc suggest that presynaptic release of DA had no major contribution to lesion-enhanced DA transmission in the mesolimbic DA system.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Behavior, Animal
- Brain Chemistry
- Central Nervous System Stimulants
- Dextroamphetamine
- Dopamine
- Dopamine Agents
- Environment
- Exploratory Behavior
- Female
- Hippocampus
- Microdialysis
- Motor Activity
- Nucleus Accumbens
- Pregnancy
- Rats
- Rats, Sprague-Dawley
Pregnant albino rats received 2 IP injections, spaced by 4 h, of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline, on gestational day (GD) 8. During adulthood, male rats prenatally exposed to alcohol exhibited an increased stereotyped behavioral response to 12 mg/kg of amphetamine (AMPH) or 1 mg/kg of apomorphine (APO), whereas the stereotypy induced by 6 mg/kg of AMPH showed no difference between control and experimental animals. Also, the hypoactivity response elicited by small doses of APO was not significantly affected by the prenatal treatment with alcohol. Analysis of dopaminergic function in the striatum and nucleus accumbens demonstrated no change on dopamine (DA) levels in both structures in alcohol pre-exposed 55- and 180-day-old rats. A reduction in striatum 3-4 dihydroxyphenylacetic acid levels was observed at both ages. These results indicate that an acute intoxication with alcohol on GD 8 induces a long-lasting decrease in striatal but not in nucleus accumbens DA metabolism. As a consequence, a lower striatal DA release might produce a compensatory supersensitivity of postsynaptic DA sites. This interpretation is consistent and correlates with behavioral results.
MeSH Terms
- 3,4-Dihydroxyphenylacetic Acid
- Aging
- Alcoholic Intoxication
- Amphetamine
- Animals
- Apomorphine
- Corpus Striatum
- Dopamine
- Dose-Response Relationship, Drug
- Female
- Gestational Age
- Male
- Motor Activity
- Nucleus Accumbens
- Pregnancy
- Prenatal Exposure Delayed Effects
- Rats
- Rats, Wistar
- Stereotyped Behavior
- Synapses
The effects of life-long dietary restriction on rotational behavior and stereotypy induced by intrastriatally administered dopamine-excitatory (dopamine, DA; amphetamine, AMPH) or cholinergic inhibitory (atropine, AT) agents were examined in rats. Three groups of male Wistar rats were used; mature ad lib (YAL, 6 month), old ad lib (OAL 24 month), and old restricted animals (OR). OR animals were fed and fasted on alternate days from weaning. Each rat was unilaterally lesioned in the left substantia nigra with 6-hydroxydopamine and a cannula was implanted in the right caudate nucleus. Several doses of each drug [AT (0, 1, 7, micrograms) DA (0, 5, 50 micrograms), and AMPH (0, 2, 5, 5, 10 micrograms)] were given randomly (1 dose/day with 1 week between drugs). All doses of a particular drug were given before the next drug regimen was started. A combination of AMPH (25 micrograms) and AT (1 microgram) was also administered in one injection at the completion of all other regimens. Results showed that OR animals responded as well as YAL animals and far better than OAL animals following AMPH, DA, or low doses of AT. However, both the high dose of AT and the combined dose of AMPH-AT seemed to suppress responding in OR animals. Neither AT alone or AMPH-AT combinations had effects in OAL animals. Results are discussed in terms of the possible specificity of effects of dietary restriction on striatal functioning and behavior in senescence.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Body Weight
- Corpus Striatum
- Diet
- Dopamine
- Grooming
- Humans
- Male
- Motor Activity
- Rats
- Rats, Inbred Strains
- Stereotyped Behavior
The effects of chronic prolactin administration on amphetamine or dopamine (DA) induced rotational behavior was examined in mature (6 month) and senescent (24 month) Wistar rats which were unilaterally lesioned in the left substantia nigra with 6-hydroxydopamine. Prolactin (150 ng/hr) was administered for 7 days via subcutaneously implanted Alzet minipumps. Amphetamine (AMPH) (0, 10 micrograms) or DA (0, 25 micrograms) was administered through cannula which had been implanted into the right (intact) striatum. Both DA-active agents were given prior to pump implantation and on day 4 of prolactin administration. The AMPH was dissolved in saline (1 microliter; pH, 5.5-6.0), while DA was dissolved in N2 bubbled distilled H2O (1 microliter; pH, 5.5-6.0) and the animals were pretreated with nialamide (50 mg/kg) intraperitoneally 1 hr before DA or DA-vehicle injection. The order of drug administration was counterbalanced within the age groups. Results showed that both groups of animals exhibited higher rotational behavior scores following prolactin treatment. In fact, there was a trend toward greater enhancement of rotational behavior in the senescent animals following prolactin treatment than that seen in mature animals. These results parallel those reported previously wherein it was found that striatal DA receptor concentrations (as assessed with [3H]spiperone binding) were higher in prolactin treated mature and senescent animals than in their respective controls. The findings suggest that there is a relationship between increases in the density of striatal DA receptors and improvement in motor performance tasks in senescent animals.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Corpus Striatum
- Dopamine
- Drug Interactions
- Hydroxydopamines
- Male
- Oxidopamine
- Prolactin
- Psychomotor Performance
- Rats
- Rats, Inbred Strains
- Receptors, Dopamine
- Rotation
In the present experiments we examined the effects of two different modes of infusion (two separate 10 min versus continuous infusions) of a depolarizing concentration of potassium (K , 30 mM), amphetamine (AMPH, 10 microM), or L-DOPA (5 microM) upon dopamine (DA) release in vitro from superfused corpus striatal (CS) tissue fragments of young (2-4 months) and aged (18-24 months) male rats. The relative changes in DA release to two infusions of K and AMPH (R2/R1) were virtually identical for CS from both young and aged rats. In the case of L-DOPA, DA release from CS of young rats was markedly increased in response to the second compared to the first L-DOPA infusion (R2/R1 = 2.48 /- 0.33, N = 7) and significantly greater than that of aged rats (R2/R1 = 1.24 /- 0.17, N = 6). A continuous infusion of K and AMPH resulted in an overall greater amount of DA release from the CS of young versus aged rats. In contrast, DA release from CS of aged rats showed an overall more rapid and greater amount of DA release to continuous L-DOPA infusion than that from the CS of young rats. These results demonstrate age-dependent differences in DA release from the CS as a function of the infusion mode of specific secretagogues. Particularly interesting were the responses to L-DOPA where a pulsatile administration resulted in an overall greater amount of DA release from the CS of young rats while a continuous infusion produced a greater amount of DA release from the CS of aged rats.
MeSH Terms
- Aging
- Amphetamine
- Animals
- Chromatography, High Pressure Liquid
- Corpus Striatum
- Dopamine
- Infusions, Parenteral
- Levodopa
- Male
- Potassium
- Rats
- Rats, Inbred Strains
- Reference Values
Clinical evidence suggests different actions of amphetamine (AMPH) in children and adults. Using intracellular recording techniques, the actions of AMPH at 10 and 40 microM were investigated in granule neurons of hippocampal slices from pre- and postpubertal rats. AMPH (10-40 microM) caused depolarization of most postpubertal neurons, often with increased spontaneous activity, whereas most prepubertal neurons were hyperpolarized. In both age groups, AMPH caused increased neuronal excitability by reducing spike threshold, attenuating the postspike train afterhyperpolarization, reducing spike frequency adaptation, and potentiating excitatory postsynaptic potentials. Changes in cell input resistance were variable and Ca2 currents were unaffected. AMPH actions took 10-15 min to appear and became maximal 30-55 min after application. The effects were reversible at 10 microM, but at 40 microM, prolonged washout for up to 2 h did not completely reverse these actions. The beta-adrenergic blocker, propranolol, partially blocked AMPH actions. The dopamine (D2) blocker, haloperidol, did not block AMPH actions. Mature neurons were also tested with 2.5 microM AMPH showing similar but more reversible effects as the higher concentrations. Depleting catecholamines by reserpine partly attenuated the effects of 40 microM AMPH in mature neurons. Perfusion of neurons with 10 and 20 microM cocaine did not produce effects similar to those of AMPH. It is suggested that AMPH produces its effects on granule neurons only in part through the release of norepinephrine. The involvement of other neurotransmitters and/or neuromodulators released by AMPH, or direct postsynaptic actions of AMPH are also possible.
MeSH Terms
- Aging
- Animals
- Atenolol
- Calcium Channels
- Cocaine
- Dextroamphetamine
- Evoked Potentials
- Haloperidol
- Hippocampus
- In Vitro Techniques
- Male
- Membrane Potentials
- Neurons
- Propranolol
- Rats
- Rats, Inbred Strains
- Reserpine
- Sexual Maturation
- Synapses
In young Wistar rats conditioned emotional stress can be characterized by a learned bradycardiac response to an inescapable footshock. In aged rats this bradycardiac response is attenuated and accompanied by suppressed behavioral arousal in response to novelty. In the present study, cardiac responses to emotional stress and behavioral reactivity to a novel experience in an open field were tested in aged and young rats under the influence of a low dose of d-amphetamine (AMPH, 0.5 mg/kg IP). AMPH administration in 27-month-old rats reinstated the bradycardiac response to emotional stress, while it failed to influence the resting heart rate in the home cage. Age-associated differences in open-field ambulation, present in drug-free conditions, were antagonized by low doses of AMPH (0.25-1.0 mg/kg). It is concluded that enhanced arousal by aminergic stimulation with AMPH in the aged rat invoked cardiac and behavioral response patterns resembling those at younger ages.
MeSH Terms
- Aging
- Animals
- Arousal
- Avoidance Learning
- Blood Pressure
- Dextroamphetamine
- Dose-Response Relationship, Drug
- Electrocardiography
- Electroshock
- Heart
- Heart Rate
- Motor Activity
- Punishment
- Rats
- Rats, Inbred Strains
- Stress, Psychological