Locomotor Stimulant Effects Of Amphetamine Research Articles

Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice.

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

Role of Organic Cation Transporter 3 in the Locomotor Sensitizing Effects and Rewarding Properties of Amphetamine in Male and Female Mice

Strategies targeting the dopamine (DA) transporter have yielded little benefit in treating addiction to amphetamine or amphetamine-like psychostimulants, possibly due to significant action of these stimulants elsewhere to modulate dopaminergic transmission. Our recent studies support organic cation transporter 3 (OCT3) as a previously unsuspected player in the actions of amphetamine. (Mayer et al., 2018, PMID: 29773909). Here, we investigated the role of OCT3 in the rewarding effects of amphetamine, in sensitization to the locomotor stimulant effects of amphetamine, and in the sex-dependency of these effects. We used genetic (constitutive OCT3 knockout (-/-) mice), and pharmacological (decynium-22 (D22, 0.1 mg/kg), a blocker of OCTs and the plasma membrane monoamine transporter (PMAT)) approaches to test the hypothesis that sensitization and conditioned place preference (CPP) for amphetamine (1 mg/kg) would be attenuated in OCT3-/- mice compared with wild-type (OCT3+/+) mice, and that D22 would attenuate the behavioral effects of amphetamine in OCT3+/+ mice, but not in OCT3-/- mice. Supporting our hypothesis, D22 prevented amphetamine CPP in male and female OCT3+/+ mice. In partial support of our hypothesis, OCT3-/- male mice did not develop CPP for amphetamine, however CPP for amphetamine persisted in OCT3-/- female mice, though not as robustly as in OCT3+/+ counterparts. Saline-pretreated female OCT3+/+, but not OCT3-/-, mice given an acute injection of amphetamine showed a robust increase in locomotor activity, whereas male OCT3+/+ and OCT3-/- mice displayed only a modest increase in locomotor activity. Sensitization to the locomotor stimulant effects of amphetamine occurred in females regardless of pretreatment or genotype. Male mice did not develop sensitization, regardless of pretreatment or genotype. D22 pretreatment did not affect the locomotor response to amphetamine in either sex or genotype. The main findings from this study are that 1) OCT3 is a key, and necessary player in the rewarding properties of amphetamine in males, but not females; 2) CPP for amphetamine persisted in female OCT3-/- mice, and was blocked by D22, suggesting that another D22-sensitive transporter, putatively PMAT (which avidly transports DA), is critical for the rewarding properties of amphetamine in females; 3) Consistent with literature, OCT3+/+ females are more sensitive to the locomotor stimulant effects of amphetamine than males; 4) OCT3 is important for the locomotor stimulant effect of amphetamine, and 5) Sensitization to the locomotor stimulant effects of amphetamine does not appear to be dependent on OCT3, and is not affected by D22. These data support OCT3 as a novel mechanism contributing to sex-dependent variation in the rewarding effects of amphetamine-like stimulants, and introduce a role for other D22 sensitive transporters, putatively PMAT, in the actions of amphetamine in females. These results have important implications for OCT3 and PMAT as sex-specific targets for therapeutic intervention in the treatment of amphetamine addiction.

Chronic risperidone administration leads to greater amphetamine-induced conditioned place preference

Risperidone is an atypical antipsychotic drug used increasingly in children to manage symptoms of ADHD and conduct disorder. In rats, developmental risperidone administration is accompanied by increased locomotor activity during adulthood, as well as heightened sensitivity to the locomotor stimulating effects of amphetamine. This study compared sensitivity to the rewarding effects of amphetamine, as measured by conditioned place preference (CPP), between groups of rats administered chronic risperidone (3.0 mg/kg, s.c.) during development (postnatal days 14–42) or adulthood (postnatal days 77–105). Locomotor activity in a novel test cage and amphetamine-induced CPP were measured beginning three and four weeks, respectively, after the final risperidone injection. Female rats administered risperidone early in life were more active than any other group tested. Previous risperidone administration enhanced amphetamine CPP regardless of sex, and this effect appeared more prominent in the developmentally treated group. The density of forebrain dopamine transporters, a primary target of amphetamine, was also quantified in rats administered risperidone early in life and found to be reduced in the medial anterior, posterior, and ventral caudate nucleus. These results suggest that chronic risperidone treatment modifies later locomotor activity and sensitivity to the reinforcing effects of amphetamine, perhaps via a mechanism related to decreased forebrain dopamine transporter density.

5-HT2C receptors in the ventral tegmental area, but not in the arcuate nucleus, mediate the hypophagic and hypolocomotor effects of the selective 5-HT2C receptor agonist AR231630 in rats

Central serotonin systems have long been associated with the control of feeding behavior and the modulation of behavioral effects of psychostimulants. 5-HT2C receptors are present in hypothalamic centers such as the arcuate nucleus (ARC), controlling homeostatic regulation of food intake, as well as in the ventral tegmental area (VTA), a region involved in motivation aspects in multiple behaviors, including feeding. In the present study, we investigated whether the 5-HT2C receptors control amphetamine-evoked locomotor activity and regulate food consumption. Localized microinjections into the VTA or the ARC were used to assess the effects of a highly selective 5-HT2C receptor agonist, AR231630, on the locomotor stimulant effect of amphetamine as well as on food intake. AR231630 injected into the VTA, but not into the ARC, dose-dependently reduced locomotor activity elicited by amphetamine. Unexpectedly, intra-ARC injection of AR231630 did not reduce food intake even at the dose of 10 μg, whereas intra-VTA injection of the same dose of AR231630 did. In addition, we showed that pretreatment with the selective 5-HT2C receptor antagonist SB242084 infused into the VTA partially prevented hypophagia induced by peripheral administration of AR231630. We can conclude that 5-HT2C receptor in the VTA, but not in the ARC, participates in both homeostatic and hedonic food intake and brain reward function.

GPR88 in A2A receptor-expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating.

The orphan receptor, GPR88, is emerging as a key player in the pathophysiology of several neuropsychiatric diseases, including psychotic disorders. Knockout (KO) mice lacking GPR88 throughout the brain exhibit many abnormalities relevant to schizophrenia including locomotor hyperactivity, behavioural hypersensitivity to dopaminergic psychostimulants and deficient sensorimotor gating. Here, we used conditional knockout (cKO) mice lacking GPR88 selectively in striatal medium spiny neurons expressing A2A receptor to determine neuronal circuits underlying these phenotypes. We first studied locomotor responses of A2A R-Gpr88 KO mice and their control littermates to psychotomimetic, amphetamine, and to selective D1 and D2 receptor agonists, SKF-81297 and quinpirole, respectively. To assess sensorimotor gating performance, mice were submitted to acoustic and visual prepulse inhibition (PPI) paradigms. Total knockout GPR88 mice were also studied for comparison. Like total GPR88 KO mice, A2A R-Gpr88 KO mice displayed a heightened sensitivity to locomotor stimulant effects of amphetamine and SKF-81297. They also exhibited enhanced locomotor activity to quinpirole, which tended to suppress locomotion in control mice. By contrast, they had normal acoustic and visual PPI, unlike total GPR88 KO mice that show impairments across different sensory modalities. Finally, none of the genetic manipulations altered central auditory temporal processing assessed by gap-PPI. Together, these findings support the role of GPR88 in the pathophysiology of schizophrenia and show that GPR88 in A2A receptor-expressing neurons modulates psychomotor behaviour but not sensorimotor gating.

Inhibition of Wnt signalling dose-dependently impairs the acquisition and expression of amphetamine-induced conditioned place preference

The mechanisms by which dopaminergic neurotransmission in the nucleus accumbens (NAc) is involved in incentive learning produced by rewarding stimuli remain unclear. Recently, Wnt signalling has been implicated in synaptic plasticity and learning and memory. Functional interactions between Wnt and dopamine (DA) signalling has been demonstrated using in vitro and tissue physiology approaches, however there remains a lack of in vivo research into the involvement of Wnt in DA-mediated learning in behaving animals. The present study assessed the role of Wnt signalling in DA-mediated incentive learning using the conditioned place preference (CPP) paradigm. We hypothesized that inhibition of Wnt with intra-NAc microinjections of Wnt palmitoylation inhibitor IWP-2 will dose-dependently block the acquisition and expression of amphetamine (AMPH)-induced CPP in rats. Intra-NAc IWP-2 (0.001, 0.05, 1.0 but not 0.0001μg/0.5μl/side) prior to conditioning with AMPH (20.0μg/0.5μl/side) blocked acquisition of CPP. Intra-NAc IWP-2 (0.05, 0.5, 1.0 but not 0.001μg/0.5μl/side) during test following conditioning with AMPH blocked expression but at a higher dose than was need to block acquisition. Sensitization of locomotor activity to AMPH was observed during conditioning and this effect was blocked in groups given IWP-2 prior to AMPH. However, intra-NAc IWP-2 during conditioning did not block the locomotor stimulant effects of AMPH. These results implicate Wnt in DA-mediated incentive learning and suggest that Wnt signalling may be more important for the acquisition of CPP then for its expression. However, mechanisms by which Wnt and DA signalling pathways interact to influence DA-mediated reward-related learning remain to be elucidated.

Role of context in neurotensin-induced sensitization to the locomotor stimulant effect of amphetamine

Previous studies have shown that repeated central injections of neurotensin, or its active analog, d-Tyr[11]neurotensin, sensitize to the locomotor stimulant effect of amphetamine. The development of sensitization to amphetamine can be modulated by contextual stimuli associated with the drug and as a consequence the expression of sensitization becomes context-dependent. The present study was thus aimed at determining whether the induction of amphetamine sensitization by neurotensin is modulated by the context in which neurotensin is administered. Different groups of adult male Long Evans rats were injected on four occasions with d-Tyr[11]neurotensin (18nmol/10μl; i.c.v.) in the locomotor activity cages (paired group) or in their home cage (unpaired group); control group received vehicle injection in both environments. One week after the last central injection, the locomotor response to a single dose of amphetamine (0.75mg/kg; i.p.) was measured in all the rats. Results show that amphetamine induced higher ambulatory, non-ambulatory and vertical activity in the paired group than in the control group confirming the sensitization effect. The paired group also displayed significant higher ambulatory activity than those in the unpaired group, confirming that the expression of sensitization was context-dependent. This context-dependency was not found however for amphetamine-induced non-ambulatory and vertical activity suggesting that neurotensin can induce both a context-dependent and context-independent sensitization.

Constitutive Genetic Deletion of the Growth Regulator Nogo-A Induces Schizophrenia-Related Endophenotypes

The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders.

The role of the CB 1 cannabinoid receptor and its endogenous ligands, anandamide and 2-arachidonoylglycerol, in amphetamine-induced behavioural sensitization

Cannabinoid receptors and their endogenous ligands (endocannabinoids) have been implicated in cocaine and amphetamine reward. Their role in psychostimulant-induced behavioural sensitization still has to be determined. The purpose of the present study was, for one, to compare the effects of a pharmacological and genetic manipulation of CB 1 cannabinoid receptors on amphetamine-induced locomotor sensitization in mice, and, secondly, to quantify the concentration of anandamide and 2-arachidonoylglycerol in different forebrain areas of behaviourally sensitized animals. The results can be summarized as follows: CB 1 knockout mice failed to sensitize to the locomotor stimulant effects of amphetamine. On the contrary, administration of the CB 1 receptor antagonist SR141716A (rimonabant; 3 mg/kg; i.p.) increased amphetamine sensitization in wild-type animals, indicating that the difference between CB 1 knockouts and SR141716A treated animals could be due to the ‘chronic’ versus ‘acute’ loss of CB 1 receptor function, or, alternatively, that SR141716A could exert pharmacological effects beyond its proposed CB 1 antagonistic action. Furthermore, sensitized wild-type mice and animals, which had received a single amphetamine injection on the challenge day, both had increased anandamide concentrations in the dorsal striatum and decreased anandamide levels in the ventral striatum, comprising nucleus accumbens. 2-Arachidonoylglycerol levels were decreased in the ventral striatum of sensitized animals only. Together, these findings suggest that prolonged activation of dopamine receptors could alter endocannabinoid levels and support the proposed involvement of the CB 1 receptor in amphetamine sensitization.

Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: Evidence for altered striatal function

PDE10A is a newly identified phosphodiesterase that is highly expressed by the medium spiny projection neurons of the striatum. In order to investigate the physiological role of PDE10A in the central nervous system, PDE10A knockout mice (PDE10A −/−) were characterized both behaviorally and neurochemically. PDE10A −/− mice showed decreased exploratory activity and a significant delay in the acquisition of conditioned avoidance behavior when compared to wild-type (PDE10A +/+) mice. However, in a variety of other well-characterized behavioral tasks, including the elevated plus maze (anxiety), forced swim test (depression), hot plate (nociception) and two memory models (passive avoidance and Morris water maze), PDE10A −/− mice performed similarly to wild-type mice. When challenged with PCP or MK-801, PDE10A −/− mice showed a blunted locomotor response in comparison to PDE10A +/+ mice. In contrast, PDE10A −/− and PDE10A +/+ mice responded similarly to the locomotor stimulating effects of amphetamine and methamphetamine. Our findings suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation. These results are discussed in relationship to the hypothesis that PDE10A inhibition presents a novel treatment for psychosis.

Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine

The GABAB agonist baclofen (BCF) has recently been reported to block the expression of sensitization to the locomotor effect of amphetamine (AMPH), and to reverse it after repeated administration. The present study was undertaken to investigate whether baclofen could also prevent the development of sensitization to the psychostimulant. Chronic AMPH treatment (1.5 mg/kg i.p. for 10 days) led to an increased locomotor response to AMPH (1.5 mg/kg) when the animals were challenged 3 and 30 days after the end of repeated treatment. Chronic co-administration of BCF (2 mg/kg, i.p.) and AMPH blocked the development of sensitization to the stimulant effect of AMPH. An ancillary experiment excluded that a 'state-dependency' hypothesis could account for the effect of baclofen. Furthermore, a previous repeated treatment with baclofen alone had no influence either on the acute AMPH effect or on the subsequent development of sensitization to AMPH. In conclusion, the results confirm that GABAB receptors play an important role in the acquisition of AMPH behavioural sensitization and further support a potential use of GABAB agonists in the treatment of psychostimulant addiction.

Deficits in dopamine clearance and locomotion in hypoinsulinemic rats unmask novel modulation of dopamine transporters by amphetamine

Insulin affects brain reward pathways and there is converging evidence that this occurs through insulin regulation of the dopamine (DA) transporter (DAT). In rats made hypoinsulinemic by fasting, synaptosomal DA uptake is reduced. Interestingly, [3H]DA uptake is increased in hypoinsulinemic rats with a history of amphetamine self-administration. The possibility that amphetamine and insulin act in concert to regulate DAT activity prompted this study. Here we show that [3H]DA uptake, measured in vitro and clearance of exogenously applied DA in vivo, is significantly reduced in rats made hypoinsulinemic by a single injection of streptozotocin. Strikingly, amphetamine (1.78 mg/kg, given every other day for 8 days) restored DA clearance in streptozotocin-treated rats but was without effect on DA clearance in saline-treated rats. Basal locomotor activity of streptozotocin-treated rats was lower compared to control rats; however, in streptozotocin-treated rats, hyperlocomotion induced by amphetamine increased over successive amphetamine injections. In saline-treated rats the locomotor stimulant effect of amphetamine remained stable across the four amphetamine injections. These results provide exciting new evidence that actions of amphetamine on DA neurotransmission are insulin-dependent and further suggest that exposure to amphetamine may cause long-lasting changes in DAT function.

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine.

The purpose of the present study was to test the possible influence of baclofen, a GABAB agonist, on the long-term sensitisation to amphetamine in rats. As expected, chronic amphetamine treatment (1.5 mg/kg i.p. daily for 10 days) led to an increased locomotor response to amphetamine (0.75 mg/kg i.p.), when the animals were challenged 20 days after the end of repeated treatment. Baclofen (2 mg/kg i.p.), administered before the test session, did not significantly modify the spontaneous locomotor activity of rats, but decreased the normal and, to a greater extent, the sensitised locomotor response to amphetamine; thus baclofen prevented the expression of sensitisation to amphetamine. Moreover a previous chronic treatment with baclofen (2 mg/kg i.p. daily for 10 days) attenuated the amphetamine-induced locomotor activity in sensitised, but not in control animals. This effect was observed 20 days after the last baclofen administration. In conclusion, the present results demonstrate that GABAB receptors play an important role in the expression of the sensitised behavioural response to amphetamine and further support a potential role of GABAB agonists in the treatment of psychostimulant addiction.

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in an NMDA, AMPA/kainate, and metabotropic glutamate receptor-dependent manner.

Previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) enhances cocaine self-administration in a D(1) dopamine receptor-dependent manner. The present study examined the contribution of VTA NMDA, AMPA/kainate, and metabotropic glutamate (mGlu) receptors to this effect. Rats in different groups received three intra-VTA injections, one every third day, of either saline (0.5 microl/side), AMPH (2.5 microg/0.5 microl/side), AMPH+CPP (NMDA receptor antagonist; 10 microM or 100 microM/0.5 microl/side), AMPH+CNQX (AMPA/kainate receptor antagonist; 0.3 mM or 1 mM/0.5 microl/side), AMPH+MCPG (mGlu receptor antagonist; 0.5 mM or 50 mM/0.5 microl/side), or the glutamate receptor antagonists alone. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) and then tested under a progressive ratio (PR) schedule of reinforcement for 6 consecutive days. As reported previously, VTA AMPH pre-exposed rats worked more and obtained more infusions of cocaine than saline pre-exposed animals. Coadministration of CPP, CNQX, or MCPG with AMPH during pre-exposure dose-dependently blocked this enhancement of cocaine self-administration. Rats pre-exposed to the glutamate receptor antagonists alone did not differ on the test days from the saline pre-exposed controls. These results indicate that, in a manner paralleling the induction of sensitization of the locomotor stimulating effects of AMPH, activation of NMDA, AMPA/kainate, and mGlu receptors during pre-exposure to AMPH in the VTA is necessary for the enhancement of cocaine self-administration to develop.

Blockade of the locomotor stimulant effects of amphetamine by group I, group II, and group III metabotropic glutamate receptor ligands in the rat nucleus accumbens: possible interactions with dopamine receptors

Previous investigations have shown that mGlu receptors would be involved in the amphetamine-induced motor response. However, data are somewhat controversial across studies where methodological protocols vary. The aim of the present study was to determine the involvement of mGlu receptors in the NAcc in the locomotor-activating properties of amphetamine in rats well habituated to their experimental environment, a condition known to modulate the motor response to amphetamine. Focal infusion of the group I mGlu receptor antagonist S-4-CPG, which has no effect on basal motor activity, virtually suppressed the locomotor response to amphetamine, while infusion of the group II mGlu receptor antagonist LY 341495 or the group III mGlu receptor agonist AP4, at the minimal dose that produces locomotor activation, reduced it by approximately a half. These effects were blocked by the group I mGlu receptor agonist DHPG, the group II mGlu receptor agonist APDC, and the group III mGlu receptor antagonist MPPG, respectively. These data confirm that mGlu receptors in the NAcc contribute to the psychostimulant motor effect of amphetamine. Results are discussed from the view of recent neuropharmacological studies that have defined the effects of these mGlu receptor ligands on basal motor activity and DA receptor agonists-induced locomotor responses in rats exposed to similar experimental procedures (Eur J Neuroscience 13 (2001) 2157; Neuropharmacology 41 (2001) 454; Eur J Neuroscience 13 (2001) 869). It is suggested that the contribution of mGlu receptors to the amphetamine-induced motor response may result mainly from their functional, either direct or indirect, interactions with D1-like receptors in the NAcc.

Startle and Sensorimotor Gating in Rats Lacking CCK-A Receptors

Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics.

SR 141716A, a CB1 cannabinoid receptor antagonist, potentiates the locomotor stimulant effects of amphetamine and apomorphine

The intraperitoneal (i.p.) injection of apomorphine or d-amphetamine significantly increased locomotor activity in Sprague-Dawley rats. Prior administration of the cannabinoid receptor antagonist, SR 141716A, significantly enhanced the stimulant effect of both d-amphetamine and apomorphine in a dose-dependent manner. Administration of SR 141716A alone had no effect on locomotor activity. These data indicate that endogenous cannabinoids exert an inhibitory action on the increase in locomotor activity produced by amphetamine and apomorphine.

Environmental enrichment enhances the stimulant effect of intravenous amphetamine: Search for a cellular mechanism in the nucleus accumbens

The nucleus accumbens and its related neural circuitry are known to be involved in mediating drug reward. The present brief review provides evidence that manipulation of the stimulus environment may alter the behavioral effects of drugs of abuse by altering accumbal circuitry. In experiments conducted in our laboratory, rats were raised in either an enriched condition (EC) or an impoverished condition (IC) and then were challenged with acute intravenous amphetamine. EC rats were more sensitive than IC rats to the locomotor stimulant effect of amphetamine, as well as to the accumbal dopamine release measured by in vivo microdialysis. No environment-induced difference in [3H]-amphetamine pharmacokinetics was observed. In vitro neurochemical experiments also indicated that accumbal tissue slices isolated from EC and IC rats did not differ in dopamine levels, electrically evoked dopamine release, or dopamine autoreceptor sensitivity. Although the kinetic parameters for [3H]-dopamine uptake into striatal synaptosomes were not different between EC and IC rats, the transport inhibitor GBR 12935 was more potent in inhibiting uptake in EC rats than in IC rats. The latter results suggest that dopamine transporter proteins in the nucleus accumbens may be an important target for future studies aimed at identifying the cellular mechanism responsible for the environmentinduced difference in the behavioral response to amphetamine.

Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen.

The development of behavioural sensitization is thought to depend on the dose and temporal pattern of drug treatment. Previous studies have shown that two distinct morphine pretreatment regimens cause different long-term neuroadaptations in rat striatum. Therefore, in the present study the ability of these pretreatment regimens to induce long-term behavioural sensitization was investigated. One pretreatment regimen, termed "chronic", consisted of three daily injections, for 5 days, with escalating doses (10-50 mg/kg) of morphine, and the other, termed "intermittent", of 14 daily injections with morphine (10 mg/kg). Both intermittent and chronic morphine pretreatment caused sensitization to the locomotor effects of morphine, 3 weeks post-treatment, although the former induced a far greater level of sensitization. Moreover, 3 weeks post-treatment, intermittent, but not chronic, morphine pretreatment induced cross-sensitization to the locomotor stimulant effects of amphetamine. Behavioural sensitization following intermittent morphine pretreatment was clear-cut both 1 day and 3 weeks post-treatment, while after 9 weeks, the locomotor effects of morphine were still slightly augmented. It is concluded that intermittent morphine pretreatment is far more effective in inducing long-term behavioural sensitization than chronic morphine pretreatment.

Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT 2 A antagonist

MDL 100,907 is a potent and selective antagonist of the 5-HT 2 A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT 2 C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT 2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT 2 receptor antagonists as a novel therapeutic strategy for schizophrenia.