Psychomotor Stimulant Effects Research Articles

Isothiocyanate derivatives of 9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole (rimcazole): irreversible ligands for the dopamine transporter.

Cocaine has been reported to bind to the dopamine transporter in a biphasic fashion, and it has been hypothesized that the low-affinity component may play a modulatory role in cocaine's psychomotor stimulant effects. In an effort to gain further insight into the roles of the two sites, we have prepared a series of irreversible ligands based on rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole, 2), a compound that has been postulated to bind only to the low-affinity site. The alkylating moiety (isothiocyanate) is attached to the distal nitrogen of the piperazine ring via alkyl chains of varying lengths or directly attached to one of the aromatic groups. It was found that substitution on the piperazine nitrogen caused an initial decrease in affinity that was recovered as the alkyl chain length increased. Importantly, the analogue 16, with the highest affinity for the dopamine transporter (DAT), binds in a monophasic and irreversible manner, as evidenced by the greatly diminished binding of [3H]WIN 35,428 in tissue that had been preincubated with the ligand and then thoroughly washed using centrifugation. The dose-dependent reduction in Bmax was accompanied by a concentration-related decrease in KD values. This shift in KD to a lower value suggests that the preincubation with 16 produced a preferential irreversible binding to the low-affinity [3H]WIN 35,428 site on the dopamine transporter. These ligands may prove to be important tools with which to study the significance of the low-affinity site on the DAT. Since rimcazole does not share the behavioral profile of cocaine, and in fact appears to play a modulatory role, these compounds may provide leads for a novel cocaine-abuse treatment.

Concurrent elevation of the levels of expression of striatal preproenkephalin and preprodynorphin mRNA in the rat brain by chronic treatment with caffeine

Caffeine is a widely consumed substance that elicits psychomotor stimulant effects and also displays addictive properties. In order to assess the effect of caffeine on striatal neuropeptide mRNA expression, male rats were injected (i.p.) with caffeine at 20, 40 or 80 mg/kg of body weight twice daily for 9 consecutive days. Preproenkephalin (PPE), preprotachykinin A (PPT-A) and preprodynorphin (PPD) mRNA levels were determined in coronal sections of brain tissue by in situ hybridization histochemistry. PPE mRNA levels were increased by chronic caffeine in all subdivisions of the striatum at 80 mg/kg (dorsolateral caudate-putamen (dlCPu), +139%; dorsomedial CPu (dmCPu), +42%; ventrolateral CPu (vlCPu), +102%; ventromedial CPu (vmCPu), +20%; and anterior CPu (aCPu), +75% relative to vehicle-injected controls that were normalized to 0% change). Similarly, PPD mRNA expression was increased in all aspects of the striatum at 80 mg/kg (dlCPu, dmCPu, vlCPu, vmCPu and aCPu, +98%, +25%, +104%, +9% and +85%, respectively). In contrast to PPE mRNA, PPD mRNA was increased +117% above control in the nucleus accumbens (NAc) at 20 mg/kg of caffeine. PPT-A mRNA expression was not significantly affected by caffeine treatment in the CPu or NAc. The data demonstrate that repeated exposure to caffeine selectively increases opioid neuropeptide mRNA expression in the striatum and the NAc of the rat brain by a dopamine-independent mechanism.

Relations Between Heterogeneity of Dopamine Transporter Binding and Function and the Behavioral Pharmacology of Cocaine

Both in vitro binding studies and studies of dopamine uptake have indicated that there is a heterogeneity of action of cocaine and cocaine analogs. Both high- and low-affinity binding sites have been identified. Some drugs that bind to the dopamine transporter show both high- and low-affinity components whereas others do not. Behavioral studies have indicated that the high-affinity component appears to be the one most directly involved in the actions of cocaine related to abuse. These conclusions are based on correlations of affinities and psychomotor stimulant effects. In addition, tolerance to the psychomotor stimulant effects of cocaine occurs with a concomitant change in only the high-affinity component for dopamine uptake. Certain dopamine uptake inhibitors may have only actions mediated by the low-affinity component. These drugs bind to the dopamine transporter and inhibit dopamine uptake; however, they do not have behavioral effects like those of cocaine. This finding is a critical point of inquiry for the dopamine hypothesis because, based on the neurochemical data, these drugs should have behavioral actions like those of cocaine. In contrast, some of these drugs antagonize the behavioral effects of cocaine, suggesting that the low-affinity site somehow modulates the actions mediated by the high-affinity site. Recently, some benztropine analogs have been discovered that bind to the dopamine transporter and inhibit dopamine uptake monophasically but have behavioral effects that are dissimilar to those of cocaine. These compounds may prove useful in determining the behavioral significance of heterogeneity of actions at the dopamine transporter. Further, these studies may provide leads to novel therapeutics for the treatment of cocaine abuse.

Pharmacological interactions between serotonin and dopamine on behavior in the squirrel monkey.

The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions.

Antiparkinsonian and other motor effects of flupirtine alone and in combination with dopaminergic drugs

In this study we attempted to specify the behavioural profile of the analgesic flupirtine (1, 10 and 20 mg/kg p.o.) in the rat with respect to (i) its antiparkinsonian potential alone and as an adjunct to l-dihydroxyphenylalanine ( l-DOPA) in the haloperidol-induced catalepsy (0.5 mg/kg haloperidol i.p.), (ii) locomotion and exploratory behaviour in the open field with holeboard, and (iii) possible psychomotor stimulating effects in the experimental chamber. In the two latter tests, behaviour was additionally challenged by d-amphetamine (2 mg/kg i.p.). In the catalepsy tests (horizontal bar, podium, grid) flupirtine alone was anticataleptic at doses of 10 and 20 mg/kg p.o., and the antiparkinsonian potential of a subthreshold dose of l-DOPA (50 mg/kg p.o.) was potentiated by 1 and 10 mg/kg p.o. flupirtine. On spontaneous forward locomotion in the open field with holeboard, flupirtine (1 and 10 mg/kg p.o.) had no marked effect but increased the frequency and duration of head dips, indicative for augmenting exploratory behaviour. Spontaneous rearing was reduced and d-amphetamine-induced rearing was enhanced by 1 mg/kg p.o. flupirtine. Grooming was reduced by 1 and 10 mg/kg p.o. flupirtine. In contrast, turning and grooming behaviour (spontaneous as well as d-amphetamine-induced) was not markedly influenced by flupirtine in the experimental chamber. Sniffing was increased in this test by 1 mg/kg p.o. flupirtine but not by the higher dose. Flupirtine is highly effective in antagonising neuroleptic-induced catalepsy as well as in potentiating l-DOPA treatment in the rat, suggesting it is a prospective new candidate for the therapy of Parkinson's disease.

Acute blockade of corticosterone secretion decreases the psychomotor stimulant effects of cocaine

Previous reports have shown that long-term blockade of corticosterone secretion, by either adrenalectomy or repeated treatment with an inhibitor of corticosterone synthesis, metyrapone, profoundly reduces sensitivity to drugs of abuse. In this report we investigated whether acute blockade of corticosterone secretion has similar effects. Animals received a single injection of metyrapone (50 mg/kg SC) and were tested for their locomotor response to cocaine (15 mg/kg IP) 3 hours later. Acute metyrapone treatment reduced the locomotor response to cocaine by about 50%, and this effect was reversed by corticosterone (20 mg/kg SC). The behavioral effects of these treatments paralleled changes in plasma corticosterone levels 20 minutes after an injection of cocaine. Despite the differences in behavior and corticosterone levels, the brain levels of cocaine in these groups did not differ. These results indicate that the behavioral effects of cocaine can be modified by an acute pharmacological manipulation of corticosterone secretion.

Cross-Sensitization Between Phencyclidine and (−) But Not (+)Pentazocine

Repeated administration of psychomotor stimulants such as amphetamine and cocaine, and psychotomimetics such as phencyclidine, produce progressively enhanced behavioral effects, a phenomenon known as behavioral sensitization. Little is known about the effects of repeated treatment with sigma ligands on locomotor activity. The present research determined the psychomotor stimulant effects of the sigma ligand (+)pentazocine and its enantiomer; and investigated whether reciprocal cross-sensitization occurs between them and PCP-induced locomotor activity and ambulation. Adult female Sprague–Dawley rats were used. Total locomotor activity and ambulation were assessed with an automated photoelectric system. Acute (+) or (−)pentazocine given IP produced slight but insignificant locomotor stimulant effects. Repeated administration of (+)pentazocine failed to produce behavioral sensitization. However, four repeated injections of (−)pentazocine or PCP produced behavioral sensitization. (−)Pentazocine sensitized rats showed cross-sensitization to PCP-induced locomotion and ambulation. Furthermore, PCP sensitized rats showed cross-sensitization to (−)pentazocine-induced locomotion and ambulation. These findings suggest that (+) and (−)pentazocine act at different receptor sites. (−)Pentazocine is more similar to PCP in producing locomotor stimulant effects.

Sensitization to the psychomotor stimulant effects of amphetamine: Modulation by associative learning.

Sensitization to the psychomotor stimulant effects of amphetamine: Modulation by associative learning.

Acamprosate and alcohol: II. Effects on alcohol withdrawal in the rat

The suppressing effect of acamprosate (calcium-acetyl homotaurinate) on alcohol drinking is well established; however, little is known about its effects upon the alcohol-induced withdrawal syndrome. Male Wistar rats received as a sole drinking fluid a 20% (v/v) alcohol solution for one week. Animals consumed on average 5.3 ± 0.3 g/kg per day alcohol, which resulted in blood alcohol levels of 38 ± 14 mg/dl. For the quantification of alcohol withdrawal we used a new radio-telemetric system which enabled us to monitor body temperature, locomotor activity, food and water intake patterns constantly during alcohol withdrawal. Although alcohol intake and the resulting blood alcohol levels were low, clear signs of withdrawal could be observed. Thus, hyperthermia and hyperlocomotion occurred 18 h after the termination of forced alcohol drinking. Food intake was initially enhanced but dropped significantly below basal food intake in control animals one day after the termination of forced alcohol drinking. Acamprosate given twice a day (200 mg/kg, i.p., 8 a.m. and 8 p.m.) reduced hyperlocomotion and food intake significantly in the alcohol withdrawal animals, however, it did not change withdrawal-induced hyperthermia. When acamprosate was given to alcohol-naive animals, it increased locomotor activity and body temperature transiently, in particular during the rats' active night phase. In summary, (i) the radio-telemetric system used in the present study proved to be a very sensitive method for quantifying alcohol-induced withdrawal symptoms; (ii) acamprosate reduced alcohol-induced physical signs of withdrawal, however, this effect could not be observed for all parameters measured, which might be explained by the fact that (iii) acamprosate exerts a slight, transient psychomotor stimulant effects by itself.

Fimbria-fornix lesions do not block sensitization to the psychomotor activating effects of amphetamine

The repeated, intermittent administration of amphetamine produces a long-lasting sensitization to its behavioral activating effects. Excitatory amino acid receptors in the striatum have been implicated in the development of amphetamine sensitization, and one source of excitatory amino acid input to the striatum is the hippocampus. The purpose of this experiment, therefore, was to determine if an intact hippocampal system is necessary for either the development or expression of sensitization to the psychomotor activating effects of amphetamine. Rats received either fimbria-fornix lesions or sham lesions and approximately 2 weeks later received 10 injections of 3.0 mg/kg d-amphetamine or saline (IP) every other day. Rotational behavior was quantified as an index of amphetamine's psychomotor stimulant effects. Animals with a fimbria-fornix lesion were hyperresponsive to an acute injection of amphetamine, but animals with a fimbria-fornix lesion and control animals did not differ in the development of sensitization (i.e., the rate of sensitization). Furthermore, both groups expressed comparable sensitization (relative to their respective saline-pretreated control groups) when given a challenge injection of amphetamine. These results suggest an intact hippocampal system is not necessary for the development or expression of amphetamine sensitization.

Cocaine cross-sensitization to dopamine uptake inhibitors: Unique effects of GBR12909

Repeated administration of cocaine will cross-sensitize the locomotor response to a variety of psychomotor stimulants. The ability of cocaine to cross-sensitize the locomotor effects of other psychomotor stimulants provides information relevant to the pharmacological mechanisms underlying the sensitization process. The purpose of the current experiment was to investigate the ability of cocaine to cross-sensitize the locomotor effects of several dopamine uptake blockers with unique pharmacological profiles. Cocaine (40 mg/kg, IP) or saline was administered prior to a locomotor session on day one. On day 2, a full dose-effect curve was established for the locomotor effects of cocaine, RTI-55, mazindol, and GBR12909. Previous exposure to cocaine significantly affected locomotor activity and stereotopy-like behavior produced by cocaine, mazindol, RTI-55, and GBR12909. However, GBR12909 was unique in that the maximal stimulant effect and slope of the dose-effect curve was significantly depressed and the stereotopy-like behavior was unchanged. Thus, despite the similarity of these compounds in their ability to inhibit dopamine uptake, cocaine-induced sensitization did not generalize to GBR12909. This study further demonstrates the unique pharmacology of GBR12909 and supports the further study of this compound as a potential treatment medication for cocaine abuse.

Acute sensitivity vs. context-specific sensitization to cocaine as a function of genotype

Individual variability in the acute and chronic effects of psychomotor stimulants is due, in part, to genetic factors. The purpose of this series of studies was to utilize a behavioral model of sensitization, namely increased locomotor activity, to assess individual variability in sensitization to the chronic effects of cocaine and its relationship to the acute stimulant effects of cocaine. Because the degree of sensitization is proportional to the training dose, genetic differences in acute sensitivity to cocaine were assessed and incorporated into the sensitization paradigm. Acute sensitivity and context-dependent sensitization were determined in six inbred mouse strains. Large quantitative and qualitative differences were found in the acute potency and efficacy of cocaine to stimulate locomotor activity. The ED 50, was higher in the strains in which cocaine was most efficacious. Context-specific sensitization was determined via chronic administration of equiactive doses of cocaine (ED 50) specifically paired with the test apparatus or with the home colony. Sensitization was time, environment, and genotype dependent. The differences in the number of trials required to show sensitization were unrelated to the acute locomotor stimulant effects of cocaine. These findings suggest that acute cocaine-induced locomotor activity and context-specific sensitization reflect different pharmacological properties of cocaine.

Pavlovian conditioning of psychomotor stimulant-induced behaviours

In order to classically condition the behavioural effects of psychomotor stimulants within a test context, rats were treated for 10 days with (+)-amphetamine (1.5mg/kg), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 30µg/kg) or vehicle prior to a 1h placement into a test box. Conditioned behavioural effects were then measured in the previously drug-paired context after a vehicle injection (drug-free test day). Each rat was videotaped for the 1h test box exposure on days 1, 4, 7 and 10 of the drug conditioning trials, and on the drug-free test day. Eleven of 28 behaviours that were scored for frequency, duration and mean bout duration (bout length) were significantly influenced by at least one of the two drugs. Amphetamine predominantly increased bout lengths while PHNO predominantly increased bout frequency. Only two measures that were influenced by the drugs exhibited clear increases over controls in a manner consistent with a classical conditioning interpretation. Behavioural sensitization clearly occurred to some of the effects of amphetamine and PHNO, but these were not the same effects as those increased on the non-drug day testing for classical conditioning. Most behavioural effects of amphetamine and PHNO are not classically conditioned, and behavioural sensitization to these drugs, while perhaps context-specific, is not due to classical conditioning. Automated measures of behaviours have provided misleading evidence concerning the similarity among behavioural effects of stimulants, sensitization and effects of exposure to an environment previously paired with stimulants. Analysis of transitions between behaviours does not support the view that stimulants increase switching or response competition, or that behavioural reorganization is responsible for sensitization. Rather, it is suggested that stimulants selectively facilitate current stimulus-guided behaviours.

Chromosomal mapping of the psychomotor stimulant effects of cocaine in BXD recombinant inbred mice.

To elucidate genes associated with cocaine's locomotor stimulant effects, we used recombinant inbred-quantitative trait loci (RI-QTL) analyses to identify chromosomal loci associated with locomotor activity before (baseline) and after cocaine treatment. RI-QTL analyses seek to identify associations between a quantitative measure of a phenotype and one or more previously mapped marker loci across a panel of RI strains. In the present study, 11 BXD RI strains were used to identify several putative QTLs for each phenotype. Both baseline locomotor activity and cocaine's locomotor stimulant effects are polygenic, with both unique and overlapping genetic influences. The largest associations for baseline activity were observed on chromosomes 5 and 9 and the largest associations for cocaine's psychomotor stimulant effects on chromosomes 3 and 17.

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice

1. 1. The present study examined a comparison of the effect of DEX on psychomotor stimulant effects of cocaine and amphetamine in mice by using the locomotor activity test. 2. 2. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0–10 mg/kg/i.p.) did not modify the activity of control mice. 3. 3. DEX pretreatment decreased the stimulating effects induced both by cocaine and amphetamine but no consistent dose-related effects were observed. 4. 4. The results suggest that DEX may play an important role on the stimulating effects of cocaine and amphetamine and that it may be of some utility in the clinical management of psychostimulants abuse.

(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses.

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.

Isradipine suppresses amphetamine-induced conditioned place preference and locomotor stimulation in the rat

The locomotor activating and the reinforcing effects of psychomotor stimulants are considered to be correlated with and responsible for the development and maintenance of stimulant addiction. Experiments were conducted to examine the effects of isradipine, the L-type calcium channel inhibitor, on the d-amphetamine-induced (1 mg/kg IP) reinforcement (conditioned place preference) and locomotor stimulation. Isradipine dose-dependently (0.6, 1.2, 2.5 mg/kg IP) attenuated the reinforcing effect of amphetamine. Two higher doses completely blocked the induction of place preference. At these doses isradipine also prevented the increase in the number of intercompartment crosses that was observed in both amphetamine- and vehicle-treated controls. In an acute experiment, isradipine failed to affect locomotor activity on its own either in the place preference boxes or in the open field. Amphetamine increased the open field activity but did not change the number of crosses in the place preference boxes. Only the highest (2.5 mg/kg) dose of isradipine significantly suppressed amphetamine-induced hyperactivity in the open field. The present results suggest that isradipine interferes with amphetamine-derived reinforcement at doses lower than those needed to block the acute locomotor effects of amphetamine. Given the qualitatively similar, previously reported results with verapamil, we conclude that the antireinforcing effects of the L-type calcium channel blockers cannot be exclusively explained by the suppression of psychomotor stimulation. The present results further support the notion that the L-type calcium channel blockers may be effective against stimulant addiction.

The role of 5-HT 3 receptors in drug dependence

Since the discovery of serotonin receptor subtypes in 1957, the classification of serotonin receptors now includes 5-HT 1 through 5-HT 7 receptors, with further subtypes of receptors in each family. Unique among this expanding group of 5-HT 1 receptor subtypes is the 5-HT 3 receptor, which is the only known 5-HT receptor that directly gates an ion channel. The channel conducts primarily Na + and K +, resulting in rapid depolarization followed by a rapid desensitization. The immediate consequence of neuronal depolarization resulting from 5-HT 3 receptor activation is the release of stored neurotransmitter. The subsequent release of stored neurotransmitter, particularly dopamine in the mesolimbic pathways, suggest a potentially important role for this receptor system in neuronal circuitry involved in drug abuse. The following review broadly covers the structure, function and distribution of the 5-HT 3 receptor system in the CNS and data addressing the potential role of this receptor system in modulating the effects of a wide variety of abused drugs. Most of the evidence indicates an association between the ability of 5-HT 3 antagonists to decrease mesolimbic dopamine levels and to attenuate the psychomotor stimulant effects of drugs. However 5-HT 3 receptor antagonists are less robust at attenuating other drug effects that are believed to be related to their abuse liability, such as discriminative stimulus and reinforcing effects. The one exception may be ethanol, which directly potentiates the effects of 5-HT at the 5-HT 3 receptor channel complex. In addition to the implications of an interaction with the mesolimbic dopaminergic system, the ability of 5-HT 3 receptor antagonists to function as anxiolytics suggest they could be useful pharmacotherapies during drug withdrawal. However, further studies are needed since currently available 5-HT 3 receptor antagonists do not have uniform behavioral effects, may interact with other receptor systems, and have atypical dose-response effects.

Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats

A lever-release version of the conditioned avoidance response (CAR) task was used to assess the behavioral effects of several psychomotor stimulants in rats. The indirect dopamine agonists, d-amphetamine (0.1 and 0.25 mg/kg) and cocaine (7.5 and 15 mg/kg), enhanced performance on this task. Both drugs increased percent avoidance responses and decreased avoidance latency. A higher dose of amphetamine (0.5 mg/kg) also decreased avoidance latency but failed to improve percent avoidance. Similar effects were seen at low (0.01 and 0.025 mg/kg) and high (0.05 mg/kg) doses of dizocilpine (MK-801), a stimulant that acts as a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. When combined with haloperidol (0.1 mg/kg), a dopamine antagonist, amphetamine (0.25 mg/kg) and dizocilpine (0.025 mg/kg) had differential effects on the lever-release CAR task. Thus, amphetamine-haloperidol was significantly better than haloperidol alone on percent avoidance but not on avoidance latency, whereas dizocilpine-haloperidol had the opposite effect: significantly better than haloperidol alone on avoidance latency but not on percent avoidance. Taken together, these results provide further support for dopaminergic mechanisms in CAR performance but suggest an opposing glutamatergic influence.

Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a ‘novel’ test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to these NOVEL test cages, for each test session. In Expt. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to be independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.