Effects of early drug treatment on adult dominance behavior in rats

Summary Following weaning, one group of rats (N = 11) was administered 2.0mg/kg of amphetamine daily for 25 consecutive days. Another group of the same size received 6.0 mg/kg of chlorpromazine for the same period. Twenty-two other rats received daily injections of saline solution. When rats were 160 days old, animals in the drug groups were paired, for testing purposes, with animals in the saline group. Animals were placed on a food deprivation schedule and were tested in pairs in a food dominance situation for five minutes daily for 15 consecutive days. The measure of dominance was the amount of time a rat in the pair controlled a food container during the trial. Rats were paired only during the five minute dominance trials and then returned to their individual home cages. It was found that 10 out of 11 of the rats that had received amphetamine treatment after weaning were dominant when tested as adults. Six of the 11 animals in the chlorpromazine group were dominant.This research was supported by Public Health Service Research Grant MH 08171-01, from the National Institutes of Health.The second author is presently a Public Health Service Predoctoral Fellow in the Department of Psychology, University of South Dakota.     

Morphine and amphetamine sensitization in rats demonstrated under moderate- and high-dose NMDA receptor blockade with MK-801 (dizocilpine)

Rationale: It has been inferred from indirect tests that MK-801, an NMDA receptor antagonist, blocks sensitization to amphetamine and to morphine. These inferences were made from studies where behavioral scores were not recorded after each drug treatment in the sensitization protocol. Objectives: We reinvestigated the role of NMDA receptors in sensitization to amphetamine or morphine more directly by taking locomotor and stereotypy scores after each of several treatments with MK-801 and amphetamine or morphine. Methods: Each male Long Evans rat was administered intraperitoneal injections of MK-801 (0.1 or 0.25 mg/kg) or saline followed 30 minutes later by amphetamine (0.75 mg/kg), morphine (1.25 mg/kg) or saline and placed immediately in a photocell chamber. Locomotion and stereotypy were measured simultaneously by photobeam breaks and direct observation, respectively. This procedure was repeated on days 1, 2, 3, 4, 5, 8, 11 and 27 for rats receiving amphetamine or saline as the second injection and on days 1–10, 13, 16 and 32 for rats receiving morphine or saline as their second injection (with no testing or treatment on intervening days). Results: The animals treated in the amphetamine condition and animals treated in the morphine condition all showed progressively greater locomotion and stereotypy over the first 5 (amphetamine) or 10 (morphine) test days; the sensitized response was seen regardless of whether the animals were pretreated with saline or with MK-801. Thus MK-801 failed to block the development of psychomotor sensitization seen with these treatment regimens. When, following initial sensitization, amphetamine or morphine was given in the absence of MK-801 (days 8 and 13 for amphetamine and morphine rats, respectively), there was no expression of the sensitized response; the sensitized response of animals previously treated in the MK-801 drug state was expressed only when the animal was tested in the MK-801 drug state. The sensitized response was still expressed, in animals tested in the appropriate drug condition, after a 2-week period in which no drugs were given, confirming that the changes underlying this form of sensitization were long-lasting and thus probably a consequence of some form of synaptic plasticity. Conclusions: Our data provide evidence that behavioral sensitization to amphetamine and to morphine can occur despite the presence of NMDA receptor blockade. These and previous findings suggest that the failure of expression of sensitization seen when MK-801 is withdrawn from a given psychomotor stimulant treatment regimen reflects, at least in part, the dependency of sensitization on the various conditions of training rather than dependency on some essential function of NMDA receptor activation. Received: 14 October 1999 / Accepted: 7 March 2000     

Social influence on the response to drugs. II

Summary Rats were treated with saline, chlorpromazine, or iproniazid and observed in either a solitary condition or in a condition where stimulus rats were present behind a wire mesh barrier. Five categories of behavior were observed and recorded. These included locomotion, barrier-directed behavior, sniffing, grooming, and inactivity. The number of times an animal shifted from one category of behavior to another (behavior shifts) was also obtained. Results showed that the behavior of iproniazid treated rats was most modified by the presence of stimulus rats. Animals in this group spent significantly more time engaged in barrier-directed behavior than rats in the other groups.This investigation was carried out during the tenure of a Postdoctoral Fellowship (MF-8654-C2) from the National Institute of Mental Health, U.S. Public Health Service and supported by research grant MY-5981 (A) from the game organization. The author wishes to express his appreciation to David Rumelhart for his assistance during the study.Chlorpromazine used in this study was furnished by Smith, Kline, and French Laboratories, Philadelphia. Iproniazid was furnished by Hoffmann-LaRoche Inc., Nutley, New Jersey.     

Increases in food intake or food-seeking behavior induced by GABAergic,opioid, or dopaminergic stimulation of the nucleus accumbens: is it hunger?

Rationale Previous work has shown that stimulation of GABAergic, opioid, or dopaminergic systems within the nucleus accumbens modulates food intake and food-seeking behavior. However, it is not known whether such stimulation mimics a motivational state of food deprivation that commonly enables animals to learn a new operant response to obtain food.Objectives In order to address this question, acquisition of lever pressing for food in hungry animals was compared with acquisition in non-food-deprived rats subjected to various nucleus accumbens drug treatments.Methods All animals were given the opportunity to learn an instrumental response (a lever press) to obtain a food pellet. Prior to training, ad lib-fed rats were infused with the -aminobutyric acid (GABA)_A agonist muscimol (100 ng/0.5 µl per side) or the mu-opioid receptor agonist d-Ala², N-me-Phe⁴, Gly-ol⁵-enkephalin (DAMGO, 0.25 µg/0.5 µl per side), or saline into the nucleus accumbens shell (AcbSh). The indirect dopamine agonist amphetamine (10 µg/0.5 µl per side) was infused into the AcbSh or nucleus accumbens core (AcbC) of ad lib-fed rats. An additional group was food deprived and infused with saline in the AcbSh. Chow and sugar pellet intake responses after drug treatments were also evaluated in free-feeding tests.Results Muscimol, DAMGO, or amphetamine did not facilitate acquisition of lever pressing for food, despite clearly increasing food intake in free-feeding tests. In contrast, food-deprived animals rapidly learned the task.Conclusions These findings suggest that pharmacological stimulation of any of these neurochemical systems in isolation is insufficient to enable acquisition of a food-reinforced operant task. Thus, these selective processes, while likely involved in control of food intake and food-seeking behavior, appear unable to recapitulate the conditions necessary to mimic the state of negative energy balance.     

Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area

Rationale: The activation of NMDA receptors in the rat ventral tegmental area has been proposed to be necessary for the induction of locomotor sensitization by amphetamine, yet there has been no direct assessment of this view. Objective: The present study examined the ability of the competitive NMDA receptor antagonist d(–)-2-amino-5-phosphonopentanoic acid (AP-5) to block this effect when infused either into the ventral tegmental area or, for comparison, into the nucleus accumbens. These sites are known to be important for the induction and expression, respectively, of locomotor sensitization by amphetamine. Methods: Rats in different groups received four pairs of injections (one IC and one IP), one pair given every third day. The IC injection (0, 1 or 5 nmol/side AP-5) was administered immediately before the IP injection (saline or amphetamine, 1 mg/kg). Locomotor activity was measured following each pair of injections and again 2 weeks later when all rats were tested for sensitization following a challenge injection of amphetamine (1 mg/kg, IP). AP-5 was not administered on this test. Results: As expected, rats previously exposed to amphetamine alone showed higher levels of horizontal locomotion and rearing on the test for sensitization when compared to saline pre-exposed rats. Preceding the amphetamine pre-exposure injections with infusions of AP-5 into the ventral tegmental area, but not the nucleus accumbens, dose-dependently blocked the induction of this effect. Rats previously exposed to AP-5 alone in either site did not differ significantly from saline pre- exposed rats on the test for sensitization. Conclusion: The results indicate that NMDA receptor activation in the ventral tegmental area, but not the nucleus accumbens, is necessary for the induction of locomotor sensitization by amphetamine. Received: 7 December 1999 / Accepted: 30 March 2000     

Ascorbate antagonizes the behavioral effects of amphetamine by a central mechanism

The behavioral response to amphetamine was monitored in rats that received simultaneous intraventricular infusions of saline or ascorbate. Both groups of animals displayed comparable responses, although ascorbate significantly delayed the onset of amphetamine-induced locomotion and rearing. In rats pretreated with a threshold dose of haloperidol (0.025 mg/kg), virtually all aspects of the amphetamine response were attenuated, and this effect was enhanced by ascorbate. In haloperidol-pretreated rats, ascorbate significantly lowered sniffing and forepaw shuffling throughout the amphetamine response. These results suggest that ascorbate antagonizes dopaminergic transmission by a central mechanism. Offprint requests to: G.V. Rebec     

Drug-induced rotation in rats without lesions: Behavioral and neurochemical indices of a normal asymmetry in nigro-striatal function

Normal unoperated rats were tested for rotation (i.e., circling behavior) in a spherical rotometer and dose-response relationships were generated using d-amphetamine, apomorphine, L-Dopa, haloperidol, and scopolamine. The rotation induced by amphetamine was significantly antagonized by alphamethyl-p-tyrosine and haloperidol, but not by diethyl-dithiocarbamate. The rotation elicited by apomorphine was unaffected by alpha-methyl-p-tyrosine. Rotation was not necessarily in the same direction with high and low doses of amphetamine, or amphetamine and apomorphine administered a week apart from each other. Dopaminergic-cholinergic interactions were evident, since pilocarpine antagonized amphetamine-induced rotation whereas scopolamine did not; scopolamine elicited rotation in the same direction as that induced by amphetamine. Left and right striatal dopamine and tel-diencephalic norepinephrine levels were determined in rats injected with various doses of amphetamine and tested for rotation. There were significant bilateral differences in striatal dopamine which were related to the direction of rotation. Since amphetamine was found to be equally distributed to the two sides of the brain, the difference in striatal dopamine appeared to be the neurochemical substrate for rotation in normal rats. These results suggest that normal rats have asymmetrical levels of striatal dopamine as well as an asymmetrical complement of striatal dopamine receptors.     

Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats

Rationale Psychomotor stimulant drugs such as methylphenidate and amphetamine decrease impulsive behaviour in attention deficit hyperactivity disorder patients by unknown mechanisms. Although most behavioural effects of amphetamine are attributed to the dopaminergic system, some recent evidence suggests a role for serotonin in this paradoxical "calming" effect.Objectives To investigate whether forebrain serotonin depletion affects the action of amphetamine in the rat on a delayed reward task where impulsive choice is measured as the selection of a smaller immediate over a larger delayed reward.Methods Following behavioural training, rats received i.c.v. infusions of either vehicle (n=10) or the serotonergic neurotoxin 5,7-DHT (n=10). Post-operatively, animals received i.p. d-amphetamine (0.3,1.0,1.5, and 2.3 mg/kg/ml), and d-amphetamine co-administered with the dopamine antagonist cis-z-flupenthixol.Results 5,7-DHT (i.c.v.) itself did not affect choice behaviour, despite depleting forebrain serotonin levels by over 85%. Amphetamine increased choice for the large reward, i.e. decreased impulsivity. This effect was attenuated by 5-HT depletion, particularly in animals showing a high level of impulsive choice. Co-administration of cis-z-flupenthixol (0.125 mg/kg) with d-amphetamine abolished the effect of amphetamine in the lesioned group, whereas this was only partially attenuated in the vehicle control group.Conclusions These data suggest that the ability of amphetamine to decrease impulsivity is not solely due to its effects on dopaminergic systems, but may also depend on serotonergic neurotransmission.     

Increased in vivo [C]raclopride binding to brain dopamine receptors in amphetamine-treated rats

The hypothesis that repeated daily doses of amphetamine increases the number of available dopamine D₂ receptors in vivo in rat striatum, and may enhance the response to subsequent amphetamine challenge doses, was examined. The in vivo binding potentials of [¹¹C]raclopride, a D₂ receptor antagonist, were determined in male CD-1 rats under five conditions: (1) drug-naïve with saline challenge, (2) drug naïve with 5 mg/kg amphetamine challenge, (3) amphetamine-dosed (five daily repeated s.c. doses of 5 mg/kg amphetamine) and saline challenge, (4) amphetamine-dosed and amphetamine challenge, and (5) saline treated (five daily repeated s.c. doses) and saline challenged. Radiotracer studies in amphetamine-dosed animals were done after a 10-day drug free interval. In the amphetamine-dosed group the baseline [¹¹C]raclopride binding was increased by 63% compared to saline-treated controls. The response to an amphetamine challenge, evidenced by a reduction of [¹¹C]raclopride binding, was doubled in amphetamine-dosed animals (40%) compared to drug-naïve controls (20%). These results support increased baseline in vivo dopamine D₂ receptor antagonist radioligand binding after repeated amphetamine administration in rats.     

Modulation of morphine sensitization in the rat by contextual stimuli

Rationale: The repeated administration of addictive drugs, such as amphetamine, cocaine, and morphine, produces a progressive enhancement (sensitization) of their psychomotor activating effects. We have previously shown that administration of amphetamine or cocaine in a distinct test environment promotes more robust psychomotor sensitization than if they are given at home. No information is available, however, on whether this environmental manipulation has a similar effect on sensitization to morphine, a drug that enhances dopamine (DA) release in the striatum indirectly by disinhibiting midbrain DA neurons. Objectives: The main goal of present study was to determine whether exposure to a distinct environmental context facilitates morphine sensitization. Methods: As an index of psychomotor activation, we used rotational behavior in rats with a uni- lateral 6-hydroxydopamine lesion of the mesostriatal DA system. There are inconsistencies in the literature regarding the ability of morphine to elicit rotational behavior. Therefore, in experiment 1 we determined the effect of 2.0, 3.0, 4.0, 6.0, and 8.0 mg/kg, IP, of morphine on rotational behavior. In experiment 2, we studied the effect of five consecutive IV infusions of saline or morphine (2.0 mg/kg) in rats treated either in their home cage or in a distinct and relatively novel test environment. After 5 days of withdrawal, all rats received an IV infusion of 2.0 mg/kg morphine (Morphine challenge). The following day all rats received an IV infusion of saline (Saline challenge). Results: Morphine produced a dose-dependent increase in rotational behavior. Environmental novelty enhanced both the acute psychomotor response to morphine and its ability to induce psychomotor sensitization. Furthermore, a conditioned rotational response was seen only in animals treated in the novel environment. Conclusions: Environmental novelty can facilitate the development of sensitization to the psychomotor activating effects of major addictive drugs, such as amphetamine, cocaine, and morphine. Received: 29 November 1999 / Accepted: 14 March 2000     

Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats

Repeated administration of amphetamine to adult rats results in enhanced behavioral responses to subsequent amphetamine exposure. These experiments were designed to determine the earliest age at which behavioral sensitization to amphetamine could be detected. Rats from both sexes (n=6–8/group) at ages of 1, 7, 21 or 49 postnatal days (PNDs) were injected with eitherd-amphetamine sulfate (5 mg/kg) or saline, SC, twice daily for 5 consecutive days. Stereotyped behavior and locomotor activity responses to a challenge dose ofd-amphetamine (2.5 mg/kg), or saline, IP, were assessed for a total of 90 min, 15 days after the last dose of pretreatment. Amphetamine-induced stereotyped behavior was significantly enhanced only when amphetamine pretreatment was initiated at PND 49, but not at the earlier ages of PND 1, 7 or 21. There was no apparent sex difference in this effect. Correspondingly, amphetamine-induced locomotor activity was reduced in both sexes of the same age group (PND 49), but not in gropus pretreated earlier, when compared to the saline-pretreated rats. These results sugges that amphetamine sensitization may be a late-developing effect, one which occurs sometime after the 3rd week of postnatal life.     

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225–250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine.(+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.     

Effects of chlorpromazine on acquisition and extinction of a conditioned response in mice

Summary Mice acquired a tone-shock association under conditions of saline injections, or an injection of 1.5 mgm./kgm. or 4.5 mgm./kgm. of chlorpromazine. Five days later the Ss were tested for retention of the response by being given extinction trials. Each of the three groups were divided and received either a saline injection or an injection of 1.5 mgm./ kgm. chlorpromazine just prior to extinction testing.A significant linear dose response function was obtained between amount of chlorpromazine injected during acquisition and performance under extinction, with the saline group requiring the greatest number of trials to extinguish. The presence or absence of chlorpromazine during extinction did not affect performance, nor was there any interaction between drug levels during acquisition and drug levels during extinction.This study was supported in part by a research grant, M-1604, from the National Institute of Mental Health to the University of Maryland.Summer College student     

Evidence for dissociable mechanisms of amphetamine-and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg IP) or haloperidol (0.10 or 0.25 mg/kg IP). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeatedd-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg IP) 15 min before each of ten amphetamine injections (1.0 mg/kg IP, administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline andd-amphetamine (1.5 mg/kg IP). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine-and stress-induced behavioral sensitization may arise through different mechanisms.     

Modification of the effects of amphetamine sulphate by past experience in the hooded rat

Summary Two experiments are reported in which hooded rats were given subcutaneous injections of 2 mg/kg amphetamine sulphate. It was shown that the effects of the drug on lever pressing for the onset of dim light were modified by the past experience of the animals. In the first experiment, drugged animals produced more responses on the onset lever than saline-treated animals following experience of a Skinner box without light onset. Groups without this experience did not differ. In the second experiment the same relationships were revealed, following experience of light onset before drug or saline administration, or no experience of light onset. It is suggested that amphetamine sulphate augments reactivity in the response-produced light onset situation.A modified version of a paper read to the London Conference of the British Psychological Society, December 1964.     

Activity of centrally acting drugs on amphetamine metabolism

Amitriptyline, nortriptyline and dibenzepine prolong the increase in temperature produced by amphetamine in rats and also increase the level of brain amphetamine above that effected by amphetamine alone. After chlorpromazine and propericiazine, brain amphetamine levels are also higher but the rise of body temperature elicited by amphetamine is inhibited. Phenelzine prolongs and α-methyl-p-tyrosine inhibits the rise in body temperature without modifying the accumulation of brain amphetamine. In reserpinized rats amphetamine causes a temperature increase several degrees greater than in control animals although its level in the brain is lower.     

Amphetamine toxicity in isolated and aggregated mice

Summary The phenomenon of increased amphetamine toxicity in aggregated mice was studied by placing one mouse treated with amphetamine among either 9 untreated (1 A+9 U) or 9 sedated (1 A+9 S) mice. Mortalities were recorded at the fifth and twentieth hour following intraperitoneal injection of dl-amphetamine in doses ranging from 15 to 125 mg/kg. The mortality in these two groups were compared with the mortality in two other groups where one amphetaminetreated mouse was isolated (1 A) and where 10 amphetamine-treated mice were grouped together (10 A). The highest mortality occurred when all the mice in the aggregate received amphetamine (10 A), whereas, the lowest mortality occurred in mice (1 A) isolated after amphetamine injection. The mortality curves for mice placed among untreated (A + 9 U) or sedated (1 A + 9 S) mice were similar and lay in between those for the isolated (1 A) and aggregated (10 A) mice. A biphasic pattern was noted in the dose-mortality curves for the three different aggregated groups.Supported in part by the U.S. Public Health Service Research Grant RH 00507-01 National Center for Radiologic Health and the American Cancer Society (Milwaukee).     

The effects of psychotropic drugs on the double alley frustration effect

Summary Central nervous system stimulants (amphetamine, methylphenidate), depressants (sodium amobarbital, reserpine, tetrabenezine, chlorpromazine) and anti-depressants (iproniazid, pargyline) were administered intraperitoneally to rats prior to their daily trials in an Amsel double runway in an attempt to modify the frustration effect using within-subject comparisons. Absolute running speeds following reinforcement and nonreinforcement were markedly affected by the drugs. However, in contradistinction to conditioned frustration which has proven amenable to pharmacological intervention, the primary frustration in the present paradigm, involving a response that immediately follows nonreward, proved highly resistant to modification.This research was supported, in part, by a grant from the Graduate Research Board of the University of Illinois. The authors acknowledge the assistance of A. Strojney, E. Gentry, V. Williams, L. Rosenberg, K. Yamamoto, and R. Wyer, Jr., in the collection and analysis of the data.     

Effects of chlordiazepoxide on the acquisition of avoidance learning and its transfer to the normal state and other drug conditions

Summary Rats trained after injection of chlordiazepoxide (CDP), 15 mg/kg, acquired the conditioned avoidance response significantly faster than saline controls. When tested in the undrugged state, CDP trained animals showed virtually no retention of the learned response. Conversely, normally trained rats showed a significant decrement in performance with CDP, whether or not they had received a series of CDP injections following the period of training. CDP trained animals performed much worse than controls on tests with chlorpromazine and amphetamine, despite continued perfect performance on intercurrent CDP tests. Both the rapid learning and the dissociation of learning are discussed with reference to the diminution by drug of the spectrum of behavioral responses to novel stimuli, as well as the elimination of the electrical response of hippocampus which normally accompanies these responses to novelty.Librium.This research was supported in part by funds made available by the National Institute of Mental Health under grants MY-2811 and MH-08519. awarded to Dr. E. R. John.     

The development of sensitization to the psychomotor stimulant effects of amphetamine is enhanced in a novel environment

Two experiments were designed to assess the effect of a novel environment on the development of sensitization to the psychomotor activating effects ofd-amphetamine. In the first experiment, rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopamine system received ten daily injections of amphetamine (2 mg/kg), either in their home cages or in novel test cages. The home and novel cages were physically identical (cylindrical transparent buckets), but one group lived and were tested in these cages, whereas the other group was transported from the stainless steel hanging cages where they lived to these novel test cages, for each test session. The first injection of amphetamine produced significantly more rotational behavior in animals tested in a novel environment than in animals tested at home. In addition, animals tested in a novel environment showed greater sensitization than animals tested at home, so the difference between the two groups was even more pronounced following the last injection. In a second experiment, locomotor activity was quantified in rats that received ten injections of either saline or 1.5 mg/kg amphetamine, in their home cages or in a physically identical novel environment. Again, there was a significantly greater locomotor response to the first injection of amphetamine, and greater sensitization, in animals tested in a novel environment than in animals tested at home. These data indicate that environmental factors can exert a large effect on the susceptibility to sensitization, and mechanisms by which this may occur are discussed.