Chronic D-amphetamine induces sexually dimorphic effects on locomotion,recognition memory,and brain monoamines

While acute and chronic D-amphetamine (AMPH) treatments produce greater scores for locomotor activity in female rats in comparison with male rats, little is known about AMPH-induced gender differences on cognition. The objectives of the present study were to (1) investigate during a withdrawal period following chronic AMPH treatment whether performance of two memory tasks, object recognition (OR) and object placement (OP) are altered, and (2) determine if an AMPH challenge dose after a withdrawal period amplifies previously reported gender differences in locomotor activity and neurochemistry. Sprague-Dawley male and female adult rats were included in a chronic AMPH treatment (10 injections, 1 every other day; males: 3 mg/kg, females 2.6 mg/kg). Locomotor activity was quantified (acute, chronic, and after a 16-day withdrawal period). Neurotransmitter levels in brain areas were evaluated after an AMPH challenge dose on the 16th withdrawal day. During the withdrawal period, OR (2- and 4-h delays) was impaired in AMPH-treated males but they did not show any impairment in OP; AMPH females also showed impairments in OR (only 4-h delay). AMPH females showed more locomotion after acute and chronic treatment but AMPH-induced hyperactivity was comparable for females and males after a challenge dose. Following a challenge dose of AMPH after a withdrawal period, gender differences in dopaminergic and serotonergic neurotransmission in the striatum were found. These gender differences elicited by AMPH in monoaminergic pathways may be related to sex differences on behavioral components involved in locomotion and OR memory.     

Neonatal cholinergic lesions and development of exploration upon administration of the GABAa receptor agonist muscimol in preweaning rats

Neonatal rats were administered 192 IgG-saporin (192 IgG-Sap), a selective cholinergic immunotoxin, on postnatal day (PND) 7. Behavioural responsiveness to muscimol, a GABAa receptor agonist, was then assessed using locomotor activity and object exploration tests on PND 18. In Experiment 1, 192 IgG-Sap-lesioned and control rats were injected with the GABAa agonist, muscimol, on PND 18 and tested in a standard open field test. Muscimol reduced rearing responses in both control and 192 IgG-Sap-lesioned animals whereas reduced wall-rearing responses occurred in control animals only. 192 IgG-Sap also reduced rearing and wall-rearing responses. In Experiment 2, muscimol effects were evaluated on PND 18 in a spatial open field test in which object exploration in addition to locomotion and rearing responses was assessed. Neonatal cholinergic lesion per se increased locomotion during object exploration while decreasing time spent exploring objects. Depressant effects of muscimol on object exploration were also evident. As a whole, these data provide evidence for (i) basal forebrain (BF) cholinergic control on locomotor activity and object exploration and (ii) GABAa-mediated regulation of selective behavioural patterns associated with locomotion and exploration in weaning rats. Neonatal cholinergic lesions, however, do not appear to alter reactivity to GABAergic agonists in juvenile rats.     

Amphetamine withdrawal does not produce a depressive-like state in rats as measured by three behavioral tests

Administration of amphetamine (AMPH) can induce symptoms of psychosis in humans and locomotor sensitization in rats; in contrast, withdrawal from a period of AMPH intake is most often associated with symptoms of human endogenous depression. The aim of this study was to determine whether AMPH withdrawal produces a depressive-like state in rats. The present study examined the effects of withdrawal from an escalating-dose AMPH schedule (ESC; three daily injections over 6 days, 1-5 mg/kg, i.p.) and an intermittent-dose AMPH schedule (INT; one daily injection over 6 days, 1.5 mg/kg, i.p.) on animals' performance in three behavioral paradigms related to depression: the Porsolt swim test, the learned helplessness assay and operant responding for sucrose on a progressive ratio schedule. ESC and INT AMPH withdrawal had no effect on any of these tests or on stress responsiveness as measured by increased plasma levels of corticosterone (CORT) and adrenocorticotropin following the swim test, although basal CORT levels were higher in AMPH-withdrawn animals compared to controls. Finally, we confirmed the presence of locomotor sensitization for both AMPH schedules after 30 days of withdrawal. Our results suggest that the ability of AMPH withdrawal to produce symptoms of depression may not be evident in all behavioral screens for depressive symptoms in the rat.     

A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice

The identification of critical ontogenetic periods of increased vulnerability to the effects of drugs of abuse could have a great psychobiological and clinical-therapeutical importance. Potential age-related differences in the response of the hypothalamic-pituitary-adrenal (HPA) axis to both stress and psychostimulants has been tested here in an animal model of adolescence. Periadolescent (PND 33-43) and Adult (PND>60) mice of both sexes were injected with d-amphetamine (AMPH, 0, 2, or 10 mg/kg i.p.) and immediately faced with a mild psychological stress experience, i.e. placement in a novel environment. A detailed time-course analysis of both hormonal and behavioral profiles was performed, with animals being sacrificed for trunk-blood collection at different time-points during the test (before the injection, NT group; 15, 30, or 120 min after the injection). Basal corticosterone (CORT) levels (NT group) were consistently higher in periadolescents than in adults. As a whole, a marked increment of blood CORT levels was found in mice of both ages exposed to forced novelty. However, important age-related differences were also observed, with Saline-injected periadolescents still exhibiting elevated levels of locomotion at the end of the 120-min test session and failing to show the increasing profile of CORT release over the baseline that was typical of adults. Upon an AMPH 2 administration, periadolescents exhibited a much lower profile of locomotor hyperactivity than adults, and also failed to show an increase across the course of the session in CORT release, that was observed in adults. When treated with the high AMPH 10 dose, a marked locomotor hyperactivity was found in periadolescents, which however showed much lower levels of the stereotyped licking and gnawing behavior, that was typical of adults. The present results suggest a unique profile of integrated behavioral and physiological hyporesponsivity in mice during periadolescence. The latter also represents a very useful model for the study of the issue of psychobiological risk factors involved in vulnerability to drugs of abuse in human adolescents.     

Effects of nicotine and stress on locomotion in Sprague-Dawley and Long-Evans male and female rats

Locomotor activity is widely used to study nicotine effects, including genotypic differences, in rodents. In rats, chronic nicotine's (administered via osmotic minipump) effects on locomotion may differ based on animal strain, with Long-Evans rats more sensitive than Sprague-Dawley rats. Males and females also may differ in sensitivity. No studies, however, have compared males and females of the two strains. In addition, stress relief is a frequently cited reason for smoking, but the behavioral consequences of nicotine-stress interactions have rarely been examined. This experiment evaluated locomotor responses of male and female Sprague-Dawley and Long-Evans rats to 0, 6, or 12 mg/kg/day nicotine administered by minipump. Half of the animals in each drug condition were exposed to 20 min/day of immobilization stress to examine nicotine-stress interactions. Horizontal and vertical activities were measured on Drug Days 4 and 10. Stress effects were minimal and stress did not alter effects of nicotine. Nicotine (6 mg/kg/day) increased horizontal activity among Long-Evans but not among Sprague-Dawleys, with greater effects in Long-Evans females. Nicotine (6 mg/kg/day) increased vertical activity of all groups and 12 mg/kg/day decreased vertical activity of all groups except for Sprague-Dawley males. Results indicate that genotype and sex are relevant to understand nicotine's behavioral actions.     

Gingko biloba extract diminishes stress-induced memory deficits in rats

Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and undesired effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2 h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg/kg) impaired nonspatial memory as measured by an object recognition test. In control rats, EGB 761 improved spatial and nonspatial memory in Morris water maze and object recognition tests. Preventive doses of EGB 761 (100 mg/kg) normalized cognitive deficits, seen in rats chronically stressed or treated with corticosterone in object recognition test, and improved memory processes in these rats measured by Morris water maze test. There was no influence of our treatments on locomotor exploratory activity and anxiety measured in open field and elevated 'plus' maze tests, making a contribution of unspecific motor and emotional effects of the used drugs to their performance in the memory tests improbable.     

Differences between<Emphasis Type="Italic"> d</Emphasis>-methamphetamine and<Emphasis Type="Italic"> d</Emphasis>-amphetamine in rats: working memory,tolerance, and extinction

Rationale Previously, we have shown that d-amphetamine (AMPH) was more potent than d-methamphetamine (METH) at increasing extracellular levels of dopamine (DA) in the prefrontal cortex (PFC) at doses that had similar effects in the nucleus accumbens. Since working memory depends on PFC DA, it was postulated that AMPH would also be more potent than METH at affecting working memory. Objective To determine if AMPH is more potent than METH at affecting working memory. Methods Working memory was measured in adult female Sprague-Dawley rats using a delayed-alternation T-maze task with multiple delays (1, 10, 60 s) and food rewards. The percentage of food rewards consumed was also recorded. Animals were tested with METH and AMPH before and after a chronic protocol, with measurements of locomotor activity used to test for pharmacological tolerance or sensitization. The effects of METH and AMPH on extinction were also examined by omitting the food rewards from the T-maze. Results Both METH and AMPH produced dose-related bimodal effects on working memory at the intermediate delay (10 s); however, AMPH was more potent than METH. Both METH and AMPH initially also decreased the percentage of food rewards consumed in the T-maze. After chronic testing, animals displayed tolerance to both the working memory impairments and the reduction in food reward intake produced by AMPH. Animals did not display significant tolerance to the effects of METH on food reward consumption and performed worse in the T-maze after chronic testing. METH, but not AMPH, interfered with extinction. Conclusions These results indicate that METH and AMPH differ in altering working memory and the expression of tolerance, perhaps due to differences in behavioral inhibition.     

The mGlu2/3 receptor agonist LY379268 blocks the expression of locomotor sensitization by amphetamine

The present experiments assessed the effect of the Group II-specific metabotropic glutamate receptor (mGluR) agonist, LY379268, on the expression of the locomotor sensitization observed following repeated exposure to amphetamine (AMPH). Rats in different groups were administered five injections of AMPH (1 mg/kg ip), one injection every 2-3 days. Two weeks after the last injection, rats were challenged with either AMPH (1 mg/kg ip) or AMPH coinjected with LY379268 (1 mg/kg ip). As expected, AMPH produced levels of locomotion that increased progressively from the first to the fifth injection. This locomotor sensitization was still evident 2 weeks later in rats challenged with AMPH. Rats challenged on this test with AMPH+LY379268, however, showed levels of locomotion similar to those observed following the first AMPH injection. These results indicate that Group II mGluRs can play an important role in the expression of locomotor sensitization by AMPH. The ability of Group II mGluR activation to block the expression of sensitization indicates that it can be targeted as a possible molecular candidate for the development of therapeutic drugs directed at drugs of abuse.     

Acute treatment with low doses of memantine does not impair aversive,non-associative and recognition memory in rats

Memantine is a non-competitive N-methyl-d-aspartate receptor antagonist, which has been employed in the clinic as a neuroprotective agent for the treatment of several dementias, particularly Alzheimer’s disease. In this study, we evaluated pharmacological effects of the acute administration of memantine on memory process. Memory retention scores were evaluated in normal adult Wistar rats injected with saline and memantine (2, 5, 10, and 20 mg/kg, IP) and then subjected to the step-down inhibitory avoidance task, habitation to an open-field apparatus, and object recognition task. The treatment with higher doses of memantine (10 and 20 mg/kg) injected 60 min before or immediately after training-session impaired acquisition and retention of aversive memory in the inhibitory avoidance task. In addition, higher doses of memantine injected 60 min before the first open-field exposure also impaired habituation during the second exposure to the apparatus. No significant differences were observed in the performance of rats treated with memantine, in all doses tested, compared to saline-treated rats in the object recognition task. Notably, we observed that at 5 mg/kg, memantine increased spontaneous locomotion and exploration in the rat open-field test. In conclusion, present findings support the view that memantine at lower doses did not affect memory formation in normal rats, but at high doses memantine, induce hyperlocomotion, which could bias the interpretation of the animal behavior assessed in memory tests.     

Strain and sex alter effects of stress and nicotine on feeding, body weight, and HPA axis hormones

Gender and genotype result in differential sensitivity to stress and to nicotine. Male and female Sprague–Dawley and Long–Evans rats exhibit different behavioral responses to immobilization stress and to chronically-administered nicotine, suggesting that these animals may be useful to model human variability in stress and nicotine sensitivity. It is possible that differences in sensitivity of the hypothalamo–pituitary–adrenocortical (HPA) axis might account for these sex and strain differences. This experiment examined corticosterone (CORT) and adrenocorticotropin hormone (ACTH) responses of male and female Sprague–Dawley (n=117) and Long–Evans (n=120) rats administered 0, 6, or 12 mg/kg/day nicotine for 14 days; half of each treatment group was exposed to immobilization stress (20 min/day). Feeding and body weight also were measured. Nicotine increased CORT and ACTH levels of Sprague–Dawley females only. Stress increased CORT and ACTH levels of all groups except for Long–Evans females. Nicotine and stress decreased feeding and body weight with greatest effects in Long–Evans females. CORT, feeding, and body weight were positively correlated among stressed females. These findings suggest that strain differences in HPA axis, body weight, and feeding responses to nicotine and to stress are robust among females but not among males. CORT reactivity and female sex hormones may explain these differences.     

The relationship between stereotypy and memory improvement produced by amphetamine

This study examined the possibility that amphetamine-induced stereotypy and facilitation of memory consolidation are both mediated by amphetamine's stimulation of dopaminergic activity in the caudate nucleus. In the first experiment, rats were given pairings of a tone and a shock followed by SC amphetamine (2 mg/kg). The amount of stereotypy and increased locomotor activity produced by the injection were measured immediately. Retention of the tone-shock association was evaluated 48 h later by observing the ability of the tone to suppress drinking. The degree of retention was significantly correlated with the amount of stereotypy but not with the amount of locomotion previously measured. In the second experiment, amphetamine was microinjected into the caudate nucleus (10 g/l) and its ability to produce the same three behavioral effects was examined. These injections produced increased stereotypy and improved retention, but no increase in locomotion. The correlation of memory facilitation with stereotypy and the fact that both were produced by intracaudate amphetamine suggest that they may be mediated by the same neuropharmacological substrate, namely amphetamine-induced release of dopamine in the caudate.     

Neuropeptide S produces hyperlocomotion and prevents oxidative stress damage in the mouse brain: A comparative study with amphetamine and diazepam

Neuropeptide S (NPS) is a recently discovered peptide which induces hyperlocomotion, anxiolysis and wakefulness. This study aimed to compare behavioral and biochemical effects of NPS with amphetamine (AMPH), and diazepam (DZP). To this aim, the effects of NPS (0.01, 0.1 and 1 nmol, ICV), AMPH (2 mg/kg, IP) and DZP (1 mg/kg, IP) on locomotion and oxidative stress parameters were assessed in mouse brain structures. The administration of NPS and AMPH, but not DZP, increased locomotion compared to control. Biochemical analyses revealed that AMPH increased carbonylated proteins in striatum, but did not alter lipid peroxidation. DZP increased lipid peroxidation in the cortex and cerebellum, and increased protein carbonyl formation in the striatum. In contrast, NPS reduced carbonylated protein in the cerebellum and striatum, and also lipid peroxidation in the cortex. Additionally, the treatment with AMPH increased superoxide dismutase (SOD) activity in the striatum, while it did not affect catalase (CAT) activity. DZP did not alter SOD and CAT activity. NPS inhibited the increase of SOD activity in the cortex and cerebellum, but little influenced CAT activity. Altogether, this is the first evidence of a putative role of NPS in oxidative stress and brain injury.     

Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats

This experiment was designed to characterize the withdrawal syndrome produced by discontinuation of treatment with escalating, non-neurotoxic doses ofd-amphetamine (AMPH). AMPH withdrawal was associated with both transient and persistent changes in behavior and postmortem brain tissue catecholamine concentrations. During the first week of withdrawal rats showed a significant decrease in spontaneous nocturnal locomotor activity. This behavioral depression was most pronounced on the first 2 days after the discontinuation of AMPH pretreatment, was still evident after 1 week, but had dissipated by 4 weeks. Behavioral depression was not due to a simple motor deficit, because AMPH-pretreated animals showed a normal large increase in locomotion when the lights initially went out, but they did not sustain relatively high levels of locomotor activity throughout the night, or show the early morning rise in activity characteristic of controls. Behavioral depression was associated with a transient decrease in the concentration of norepinephrine (NE) in the hypothalamus, and a transient decrease in the ability of an AMPH challenge to alter dopamine (DA) concentrations in the caudateputamen and nucleus accumbens. AMPH pretreatment also produced persistent changes in brain and behavior. The persistent effects of AMPH were not evident in spontaneous locomotor activity, but were revealed by a subsequent challenge injection of AMPH. AMPH pretreated animals were markedly hyper-responsive to the stereotypy-producing effects of an AMPH challenge. This behavioral sensitization was not fully developed until 2 weeks after the discontinuation of AMPH pretreatment, but then persisted undiminished for at least 1 year. It is suggested that the transient changes in brain and behavior described here may represent an animal analogue of the distress syndrome seen in humans during AMPH withdrawal, which is associated with symptoms of depression and alterations in catecholamine function. On the other hand, persistent behavioral sensitization may be analogous to the enduring hypersensitivity to the psychotogenic effects of AMPH seen in former AMPH addicts.     

The sensitizing effect of acute nicotine on amphetamine-stimulated behavior and dopamine efflux requires activation of β2 subunit-containing nicotinic acetylcholine receptors and glutamate N-methyl-D-aspartate receptors

Nicotine has been demonstrated to enhance the subsequent use of illicit drugs in animals and humans. We previously demonstrated in female, Holtzman rats that one low dose of nicotine will potentiate locomotor activity and dopamine (DA) efflux in response to a subsequent low dose of d-amphetamine (AMPH) given 1-4 h later. In the present study, we show this also occurs in male rats and characterize the receptors required for the rapid sensitizing effect of nicotine on AMPH-stimulated locomotor behavior and AMPH-induced DA efflux. Pretreatment of male, Holtzman rats with a low dose (0.1 mg/kg, i.p.) of nicotine 2-4 h before a challenge with AMPH (0.32 mg/kg, i.p.) enhanced locomotor behavior as compared to saline pretreatment. Dihydro-β-erythroidine (DHβE), a relatively selective antagonist at β2 subunit-containing (β2?) nicotinic acetylcholine receptors (nAChR), but not methyllycaconitine (MLA), a relatively selective antagonist at α7 nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor activity. Pretreatment with varenicline, a partial agonist selective for β2? nAChRs, blocked the sensitizing effect of nicotine on AMPH-stimulated locomotor behavior. Nicotine pretreatment sensitized AMPH-induced DA overflow in slices from ventral (nucleus accumbens, NAc), but not dorsal striatum as compared to saline-pretreated rats. Nicotine sensitization of the DA overflow was blocked by DHβE. Pretreatment with the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (0.1 mg/kg, s.c.) 30 min before nicotine blocked sensitization of both locomotion and DA overflow in response to AMPH challenge. These results demonstrate that activation of the β2? nAChRs and NMDA receptors are required for the rapid sensitizing effect of nicotine on AMPH actions. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Cannabinoids alter recognition memory in rats

Cannabinoids are known to attenuate learning and memory in both humans and animals. In rodents, disruptive effect of cannabinoids on memory, reversed by SR 141716, a specific CB(1) receptor antagonist, was shown in behavioral tests based on conditioning. There are no data concerning the influence of cannabinoids on recognition memory. Recently, the improvement of recognition memory in cannabinoid CB(1) receptor knock-out mice was reported. Therefore, the purpose of the present study was to determine whether a stable analogue of endogenous cannabinoid anandamide, R-(+)-methanandamide (0.25 and 2.5 mg/kg, i.p.) and a potent CB(1) receptor agonist, CP 55,940 (0.025 and 0.25 mg/kg i.p.) affect recognition memory in rats evaluated in an object recognition test, based on discrimination between the familiar and a new object presented at 1h interval. Because cannabinoids at the higher doses can produce motor inhibition, the influence of both compounds on psychomotor activity was evaluated in an open field test. CP 55,940 and R-(+)-methanandamide, at both doses given once, 15 min before the learning trial, significantly attenuated recognition memory, measured by the difference in exploration of a new object and a duplicate of the familiar object. Moreover, CP 55,940 at the higher dose significantly attenuated ambulation, and bar approaches, and at both doses also rearings, evaluated in an open field, performed immediately after an object recognition test, while R-(+)-methanandamide at both doses did not alter locomotor and exploratory activity of rats. This is the first evidence that cannabinoids impair recognition memory in rats.     

Clorgyline-induced increases in presynaptic DA: changes in the behavioral and neurochemical effects of amphetamine using in vivo microdialysis.

Microdialysis was used in behaving rats to further characterize the behavioral and regional dopamine (DA) response to the monoamine oxidase (MAO) inhibitor clorgyline and determine how MAO inhibition affects amphetamine (AMPH)-induced changes in behavioral and extracellular DA dynamics. Although clorgyline (4.0 mg/kg) did not significantly alter behavior, it produced prolonged increases in caudate and accumbens extracellular DA and 3MT and corresponding decreases in homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Clorgyline pretreatment altered the behavioral response to both low (0.25 mg/kg) and moderate (2.5 mg/kg) doses of AMPH, which was characterized by a shift to more intense forms of stereotype and corresponding decreases in locomotion. The caudate and accumbens DA response to AMPH (0.25 mg/kg) was also significantly augmented, consistent with an increase in AMPH-releasable cytoplasmic DA. Thus, the potentiated DA response in clorgyline-pretreated animals may be responsible for the changes in the stereotypy profile. Possible implications of these observations for the augmented behavioral response observed with repeated AMPH administration are discussed.     

Repeated administration of phencyclidine, amphetamine and MK-801 selectively impairs spatial learning in mice: a possible model of psychotomimetic drug-induced cognitive deficits

Cognitive deficits are a key feature of schizophrenia. N-Methyl-D-aspartate (NMDA) receptor antagonists and amphetamine are known to induce psychotic behaviors and cognitive deficits in animals and humans, often affecting visuo-spatial abilities. Phencyclidine (PCP), MK-801 and amphetamine (AMPH) have been used in pharmacological animal models of schizophrenia, but none of these models has focused so far on spatial learning after repeated administration of the drugs. The objective of this study was to test whether repeated administration of PCP, AMPH or MK-801 influenced the performance of mice in a non-associative spatial learning test. CD-1 male mice were given i.p. daily injections of either saline, PCP (5.0, 10.0 mg/kg), AMPH (2.5, 5 mg/kg) or MK-801 (0.3, 0.6 mg/kg), for 5 days. On day 6 all mice were tested in an open field containing five different objects. After three sessions of habituation, each animal's reactivity to object displacement and object substitution was assessed. No significant differences among treatment groups were observed in object exploration or locomotion during the habituation phase. Five days of repeated PCP, AMPH or MK-801 administration selectively and differentially impaired the ability of mice to discriminate a spatial change, while leaving intact the ability to react to a non-spatial change. These data suggest that neurobiological adaptations to drug regimens known to induce psychotic behaviors and alterations in locomotor activity or stereotypies can also alter spatial learning, as assessed in this test, thus indicating that these regimens could also mimic some of the cognitive deficits observed in schizophrenia.     

Dissociation between long-lasting behavioral sensitization to amphetamine and impulsive choice in rats performing a delay-discounting task

RATIONALE: Repeated amphetamine (AMPH) exposure is known to cause long-term changes in AMPH-induced locomotor behavior (i.e., sensitization) that are associated with similarly long-lasting changes in brain function. It is not clear, however, if such exposure produces long-lasting changes in a cognitive behavior that, in humans, is hypothesized to contribute to addiction. OBJECTIVES: To examine whether repeated AMPH exposure induces both locomotor sensitization and alters impulsive choice in a delay-discounting task. MATERIALS AND METHODS: Adult, male Sprague-Dawley rats (n = 29) were pretreated with 3.0 mg/kg AMPH or saline every other day for 20 days and were then trained to lever press for small, immediately delivered food reinforcement or larger reinforcements delivered after delays. We subsequently assessed the effects of acute AMPH (0.1-2.0 mg/kg) on delay-discounting. Lastly, we tested for long-lasting effects of pretreatment by giving an AMPH challenge (3.0 mg/kg) 1 week after the final delay-discounting session. RESULTS: Repeated AMPH produced sensitization to the drug's stereotypy-inducing effects but did not alter acquisition or baseline behavior in the delay-discounting task. Following acute AMPH, impulsive choice and other measures of delay-discounting were altered, but to a similar extent in both saline- and AMPH-pretreated groups. The AMPH challenge, given approximately 3 months after the last pretreatment injection, revealed that sensitization was still evident. CONCLUSIONS: Our results suggest that one behavioral consequence of repeated AMPH exposure-sensitization-does not overlap with another potential outcome-increased impulsivity. Furthermore, the neuroadaptations known to be associated with sensitization may be somewhat distinct from those that lead to changes in impulsive choice.     

Group II, but not group I, metabotropic glutamate receptors in the rat nucleus accumbens contribute to amphetamine-induced locomotion

Recently, it was reported that blocking metabotropic glutamate receptors (mGluRs) in the rat nucleus accumbens (NAcc) prevents the generation of locomotion by amphetamine (AMPH) in this site. In these studies, the non-selective group I/group II mGluR antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine [(R,S)-MCPG] was used. The present study used more selective receptor antagonists to examine the specific contribution of group I and group II mGluRs to this effect. When co-injected bilaterally with AMPH into the NAcc, the group II selective mGluR antagonist (2S)-alpha-ethylglutamic acid [EGLU; 0.5-5.0 nmole/side] dose-dependently blocked the locomotion and rearing produced by AMPH. Equimolar concentrations of the group I selective antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid [AIDA; 0.5-5.0 nmole/side] were without effect. As previously reported for (R,S)-MCPG, neither of these receptor antagonists produced locomotor effects when injected alone in these concentrations into the NAcc. These results suggest that group II, but not group I, mGluRs in the rat NAcc contribute importantly to the ability of AMPH to produce locomotor activation.