Involvement of dopamine in the aversive stimulus properties of cocaine in rats

Previous studies of cocaine self-administration have demonstrated central dopaminergic involvement in cocaine's positive reinforcing properties. The present study reports the ability of pimozide, a dopamine receptor antagonist, to attenuate a conditioned taste aversion induced by repeated injections of cocaine. Rats placed on a daily water deprivation schedule were subsequently presented with a novel saccharin taste in their drinking fluid immediately followed by administration of four 9 mg/kg injections of cocaine spaced at 20 min intervals. These animals exhibited a reduction in saccharin intake on subsequent presentations. Animals pretreated with pimozide 90 min prior to the saccharin-cocaine pairings failed to show this reduction. In a second experiment using an identical procedure, repeated injections of lithium chloride were shown to induce a CTA both in pimozide-pretreated and control animals. The results of these two experiments are consistent with the notion that a functional relationship may exist between neurochemical mechanisms underlying both the aversive (CTA-inducing) and positive reinforcing properties of self-administered drugs such as cocaine.     

The aversive stimulus properties of repeated infusions of cocaine

When the presentation of a novel food to a rat is followed by the administration of certain compounds, including psychomotor stimulants, the animal consumes less of the food on subsequent presentations relative to an animal administered saline. This phenomenon has been termed gustatory avoidance conditioning. Conflicting results have been obtained when cocaine is used in this procedure. Therefore, the possibility that the weak efficacy of cocaine in this paradigm is due to its relatively short duration of action was investigated. Fluid intake was limited to a single 15 min presentation, seven days a week. Following the determination of baseline water intake, sweetened milk was given during thesession followed by a series of infusions of cocaine through chronic indwelling peritoneal catheters. Four infusions, spaced 15 min apart, of 9.0 mg/kg cocaine induced an avoidance response, while one infusions of 36 mg/kg cocaine followed by three saline infusions did not. This supports the hypothesis that the low efficacy of cocaine in this paradigm is due, at least in part, to its short duration of action.     

Generalization of a restraint-induced discriminative stimulus to cocaine in rats

 The ability of the interoceptive cues produced following exposure to restraint stress to generalize to the discriminative stimulus effects of cocaine was investigated. Rats were trained to discriminate cocaine (10 mg/kg, IP, n=10; or 20 mg/kg, IP, n=6) from saline using a two-choice, food-reinforced, drug discrimination design. Substitution for the 10 mg/kg training dose of cocaine was observed subsequent to exposure to 15 min of restraint when administered immediately following an injection of saline. Restraint-induced generalization in the 20 mg/kg training group was substantial, but not statistically significant. These data suggest that a component of the subjective effects of cocaine may be associated with ”anxiety”. Received: 19 July 1997 / Final version: 1 October 1997     

Adolescent exposure to nicotine alters the aversive effects of cocaine in adult rats

Nicotine is one of the most commonly used drugs in adolescence and has been shown to alter the rewarding effects of cocaine when administered in adulthood. Although the abuse potential of a drug has been suggested to be a balance between its rewarding and aversive effects, the long-term effects of nicotine on the aversive properties of other drugs had not been studied. To that end, in the present study rats exposed to nicotine (0.4 mg/kg) during adolescence (postnatal days 35-44) were tested for the acquisition and extinction of a cocaine-induced conditioned taste aversion (10, 18 or 32 mg/kg) in adulthood. Conditioning consisted of four saccharin-drug pairings followed by six extinction trials. Although cocaine-induced aversions at all doses, no effect of nicotine preexposure was seen during acquisition. During extinction, the nicotine-preexposed groups conditioned with 10 and 18 mg/kg cocaine displayed a decreased rate of extinction compared to their respective controls. These results suggest that while adolescent nicotine exposure does not appear to directly alter the aversive properties of cocaine it may affect other processes related to the response to drugs given in adulthood.     

Influence of a conditioned light stimulus on cocaine self-administration in rats

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.     

Repeated administration of methylphenidate in young,adolescent, and mature rats affects the response to cocaine later in adulthood

Rationale Previous studies have shown that the expression of behavioral sensitization to psychostimulants depends on the age and gender of the animal. Objective This study was conducted to determine the pattern of behavioral sensitization to repeated administration of methylphenidate (MPD) at three different developmental ages and to assess the response to a cocaine challenge in adulthood. Methods We gave five daily i.p. injections of 10 or 20 mg kg⁻¹ of MPD (10 MPD, 20 MPD) or saline to male and female rats beginning on postnatal days (PND) 21, 45, or 60. When all groups reached PND 90, rats were challenged with 10 mg kg⁻¹ cocaine. For both MPD administration and cocaine challenge, locomotion and stereotyped behaviors were assessed for 1 h. Results The 10 MPD dose produced increased locomotion over the other two treatments at all ages. Rats that received 20 MPD showed a decline in locomotion across days with an increase in the time spent in high intensity stereotypy by day 5. Animals treated with 10 MPD showed diverse behavioral responses with adolescents showing somewhat dampened stereotypy than the other two age groups. In response to cocaine, pretreatment with MPD at all ages enhanced the cocaine response and produced qualitatively different patterns of stereotyped behavior for each gender and pretreatment age group. Conclusion MPD produced clear age-specific sensitization of behavior in rats. Furthermore, exposure to MPD cross-sensitized with cocaine regardless of the age at which MPD exposure occurred with each pretreatment age group showing a unique pattern of responses.     

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 incre ased 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 ofN-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.     

Exposure to alcohol during adolescence alters the aversive and locomotor-activating effects of cocaine in adult rats

Objectives

The present study assessed the effect of adolescent alcohol exposure on the later aversive and locomotor-activating effects of cocaine.

Methods

Male rats were exposed to alcohol or vehicle for 10 days [postnatal day (PND) 30-39; 2 g/kg IP]. Taste aversion conditioning began on PND 65. During aversion conditioning, subjects were presented with saccharin followed by cocaine (32 mg/kg; 15, 180 or 300 min post saccharin) or saline. Following each injection, animals were placed in locomotor chambers for 1 h. To determine if any effects seen were specific to the adolescent developmental period, the procedure was replicated in adult animals.

Results

Animals exposed to vehicle during adolescence showed significant aversions at all time delays. Animals exposed to ethanol during adolescence showed a decrease in consumption only at the 15 and 180 min delays. Groups exposed to alcohol during adolescence showed a decrease in gross, and an increase in fine, motor activity in response to cocaine. Animals exposed to alcohol during adulthood also showed attenuated taste aversions.

Conclusions

Exposure to ethanol during adolescence attenuated the aversive effects of cocaine and altered its locomotor-activating effects. Although this effect is not specific to adolescence, this is the time when alcohol use is typically initiated so that such exposure may enhance later abuse liability of cocaine.     

Release of 14C-norepinephrine into the lateral cerebroventricle of rats by exposure to a conditioned aversive stimulus.

Rats chronically implanted with push-pull cannulas were injected with a pulse of 14C-norepinephrine (NE) into the lateral cerebroventricle under a variety of pretreatment and behavioral conditions. Animals pretreated intraventricularly with 6-hydroxydopamine (Group A) or ascorbic acid vehicle (Group B) were subsequently perpised imder fpur conditions: (1) presentation of a novel, visual stimulus in a one-way avoidance chamber; (2) presentation of the light (CS) followed by shock; (3) training to a high level of avoidance behavior, after which the CS was presented in the absence of opportunity for an avoidance response and in the absence of shock; and (4) after forced extinction, followed by CS without opportunity to aboid and with out presentation of shock. Samples of perfusate from rats subjected to the four test conditions were analyzed by thin-layer chromatography for total 14C in a scintillation counter and for proportion of NE and normetanephrine (NM). During Tests 1 and 4 the 14C perfusion wash-out did not differ from control values for either Group A or B. During Test 2, total radioactivity as well as the proportions of NE and NM increased in the perfusate for both Groups A and B. Presenting the CS without shock (3) resulted in 14C and NE and NM for Group B (vehicle), but not for Group A (6-OHDA). To test for non-specific release unrelated to a brain catecholaminergic function, another group of rats was subjected to identical treatments with the exception that 14C-urea replaced 14C-NE as a pulse-label. In these animals Test 2 (shock) induced an increase in 14C in the perfusate, while Tests 1, 3 and 4 yielded wash-out curves essentially identical to controls.     

Corticotropin-releasing factor receptor blockade enhances conditioned aversive properties of cocaine in rats

The behavioral profile of corticotropin-releasing factor (CRF) in mediating anxiogenic-like and aversive responses to stressors may be particularly relevant for dependence and withdrawal in drug-experienced organisms. Moreover, stressful aspects of drug exposure in the drug naive organism may also induce CRF system activation. In the present studies, the dependence of aversive properties of cocaine on activation of endogenous CRF systems has been evaluated in rats using taste conditioning and runway self-administration paradigms. Systemic cocaine administration (20 mg/kg IP) produced a conditioned saccharin aversion which was dose-dependently potentiated by central administration of the CRF receptor antagonist, D-phe CRF (12–41). In addition, IV cocaine administration (0.75 mg/kg per injection IV) produced runway goal-box avoidance and conditioned place avoidance responses which were significantly accelerated by CRF antagonist treatment. In contrast, CRF receptor stimulation using CRF itself abolished cocaine-induced increases in goal latency in the runway paradigm. This generalized involvement of CRF systems in cocaine-related motivational/associative states is consistent with the comprehensive role of CRF in mediating emotional responses to non-drug stressors. Received: 3 June 1997/Final version: 28 August 1997     

Diminished reaction to a novel stimulus during amphetamine withdrawal in rats.

This experiment determined whether reaction to a novel stimulus was diminished in a dose-dependent fashion following 8 consecutive days of d-amphetamine administration. Thirty-two male rats were injected with saline, 0.5, 2.5, or 5.0 mg/kg of d-amphetamine (each N = 8). On the ninth day, all animals received saline injections and were tested (a) in the presence of a novel stimulus, or (b) in the absence of a novel stimulus. Reaction to the novel stimulus varied inversely with the dose of d-amphetamine which had been received during the drug administration period. This reduction in reaction to the novel stimulus did not seem to depend on (a) the level of amphetamine-induced sterotypy at the end of the drug administration period (b) general reduction of activity, or (c) interference by drug-conditioned responses.     

Acute alcohol decreases performance of an instrumental response to avoid aversive consequences in social drinkers

Background  Recent studies demonstrated that alcohol impairs inhibitory control of behavioural responses. Aims  We questioned whether alcohol via its disinhibiting effects would also impair the inhibition of an instrumental avoidance response in the presence of a safety signal. Design  Thirty-six moderate social drinkers were randomly allocated to receiving either alcohol (0.8 g/kg) or placebo before performing an instrumental avoidance procedure. White noise of 102 db was used as aversive outcome presented at a variable interval schedule in S+ trials, while no noise was presented in S− trials. An instrumental response (repeated space bar presses to avoid the noise presented at a variable interval) abolished the noise. The Stop Signal task and the affective Go/No-Go task were administered as inhibitory control tasks. Results  Alcohol did not change the avoidance response rate in the presence of S− (safety signal). However, participants under alcohol performed the avoidance response to a lower extent than placebo subjects in S+ trials. Alcohol impaired performance in the Stop Signal task and increased the number of commission errors in the affective Go/No-Go task. Conditioned attentional and emotional responses to the S+ as well as knowledge of stimulus–response outcome contingencies were not affected by alcohol. Conclusions  Acute alcohol may decrease the motivation to avoid negative consequences and thus might contribute to risky behaviour and binge drinking.     

Enhanced behavioral response to repeated-dose cocaine in adolescent rats

Rationale Most lifelong drug addiction in humans originates during adolescence. Important structural and functional changes in the brain occur during adolescence, but there has been little direct study of how this impacts on drug abuse vulnerability. An emerging literature suggests that adolescents exhibit different behavioral responses to single doses of several addictive drugs, including ethanol, amphetamine, and cocaine. However, few studies have explored behavioral responses to the repeated dosing that is characteristic of human abuse of these substances.Objectives We have investigated age-related behavioral responses to acute “binge” cocaine treatment between adults and adolescents.Results Adolescent rats displayed an exaggerated behavioral response to cocaine administered in two different binge patterns. Total locomotion after cocaine administration was the same in adolescents and adults. However, adolescent rats engaged in more intense stereotypic behaviors, including paw treading, head weaving, and focused sniffing than adult rats. These differences were observable following a modest dose of cocaine and became more robust following subsequent doses within a binge. Cocaine blood and brain levels were not significantly different between age groups during any of the exposure sessions.Conclusions These findings suggest that equivalent tissue concentrations of cocaine produce a greater behavioral response in young rats, and that adolescent animals display an apparent form of intrabinge sensitization.An erratum to this article can be found at     

Repeated injections of sulpiride into the medial prefrontal cortex induces sensitization to cocaine in rats

Rationale Recent studies have suggested that the medial prefrontal cortex (mPFC) plays an important role in the development of sensitization to cocaine. In particular, a recent report proposed that sensitization is associated with a decreased dopamine D₂ receptor function in the mPFC. The present study was designed to further examine the involvement of mPFC dopamine D₂ receptors in cocaine sensitization.Objectives The experiments described below sought to determine the effects of acute or repeated intra-mPFC injections of the dopamine D₂ antagonist sulpiride on subsequent motor-stimulant and nucleus accumbens dopamine responses to cocaine.Methods Rats received bilateral cannulae implants above the ventral mPFC for microinjections and above the nucleus accumbens for in vivo microdialysis. Initial studies examined the effects of intra-mPFC sulpiride pretreatment on the acute motor-stimulant and nucleus accumbens dopamine responses to cocaine. Follow-up studies determined the effects of repeated intra-mPFC sulpiride injections on subsequent behavioral and nucleus accumbens dopamine responses to a cocaine challenge.Results Intra-mPFC sulpiride enhanced the cocaine-induced increases in motor activity and dopamine overflow in the nucleus accumbens. Repeated intra-mPFC sulpiride induced behavioral and neurochemical cross-sensitization to cocaine.Conclusions The data support previous findings that sensitization is associated with a decrease in dopamine D₂ receptor function in the mPFC.     

Discriminative stimulus effects of cocaine in female versus male rats

Eight female and 8 male rats were trained to discriminate 5.6 mg/kg i.p. cocaine from saline on a 2-lever, food-reinforced drug discrimination procedure. Female rats acquired the cocaine discrimination in approximately the same number of sessions that males did (43 ± 7 vs. 51 ± 9 sessions, respectively), and the ED₅₀ for cocaine discrimination was nearly equivalent in female and male rats (2.46 ± 0.41 vs. 2.32 ± 0.49 mg/kg, respectively). The time course for cocaine discrimination was similar in female and male rats, except the offset of cocaine's effects occurred significantly earlier in females than in males. d-Amphetamine dose-dependently substituted for cocaine in all 7 males and 6 of 7 females tested, with no significant sex difference in the ED₅₀ values for d-amphetamine substitution. None of the three opioid agonists tested, morphine (μ), U69,593 (κ) or BW373U86 (δ), fully substituted for cocaine in rats of either sex. The dopamine antagonist fluphenazine blocked the discriminative stimulus effects of cocaine to approximately the same extent in both sexes. Further drug discrimination training with a higher dose of cocaine, 10 mg/kg, did not significantly alter the ED₅₀ for cocaine discrimination, and there was still no significant sex difference in ED₅₀ values (3.50 ± 0.39 vs. 2.36 ± 0.41 mg/kg in females vs. males, respectively). In these same rats, however, cocaine (1–10 mg/kg) produced significantly greater locomotor activation in females than in males on a test of spontaneous locomotor activity. Thus, these results suggest that there are few sex differences in discriminative stimulus effects of cocaine, even at doses that produce significantly different locomotor responses in female versus male rats.     

Characteristics of coping behavior of rats exposed to a long-term hardly escapable aversive stimulus: a possible depression model

The purpose of the present study was to induce a state of depression including both the elements of behavioral despair and chronic stress. Therefore, this study was performed under the hypothesis that a long-term exposure of rats to the experimental situation of difficult to escape from foot-shock in a Skinner box might produce animals with a state of depression containing both the elements. Male Wistar strain rats were trained to press a lever to escape from foot-shock under a fixed ratio (FR) schedule. After the training, rats were exposed daily to a schedule consisting of 20 trials (the early 10 trials, FR 5; the later 10 trials, FR 20) once a day. The exposure resulted in reduction of the number of lever presses and successful escape in FR 20. Only the animals whose number of escapes, reduced to under 20% in FR 20 were treated with psychotropic drugs once a day for 4 days. The results showed that the reduced number of escapes was most improved by antidepressants (imipramine or mianserin), but not by haloperidol and methamphetamine. Although subchronic treatment with chlordiazepoxide partially recovered the reduced escape, the efficiency of lever pressing to escape from foot-shock was lower than that with the antidepressants. The results of the present study suggest that the behavioral suppression observed in this study might include characteristics similar to a state of depression.     

Repeated self-administered cocaine "binges" in rats: effects on cocaine intake and withdrawal

RATIONALE: Repeated access to cocaine may engender behavioral sensitization, which emerges as an enhanced response to the effects of cocaine. Repeated exposure to prolonged self-administration sessions has been shown to produce an escalation in cocaine intake. OBJECTIVE: The objective of the present study was to identify the consequence of repeated exposure to prolonged access to self-administered cocaine. METHODS: Pairs of rats that were matched for training, housing, and surgery were treated as a single experimental unit, and these pairs were separated into groups for two separate experiments. In the first experiment, one animal of the pair acquired and maintained a stable rate for i.v. cocaine self-administration (0.5 mg/infusion), while the second rat was yoked such that it passively received saline infusions in the same pattern. After acquisition, the active self-administration rats were given free access to cocaine for 16 h (binge), while the yoked animal continued to receive infusions of saline. Twenty-four hours after the binge, both animals were exposed to tactile startle stimuli, and ultrasonic vocalizations (USVs) and startle reflexes were measured. The animals were exposed to three cocaine binges and 24 h post-binge startle tests with an interval of 10 days between binges, and then a fourth binge, with an interval of 24 h separating binges three and four. In the second experiment, pairs of rats were separated into three groups (A, B, and C). The active cocaine rats acquired self-administration and were allowed access to a 16-h cocaine binge while their yoked controls received saline. Twenty-four hours after the binge, all animals were tested for emission of USVs and startle reflexes with an identical protocol as that in experiment 1. Immediately after exposure to the startle stimuli, the self-administering animals were again allowed to self-administer cocaine for either 16 (group A), 12 (group B), or 8 h (group C). RESULTS: In experiment 1, the total amount of cocaine self-administered was significantly decreased when the cocaine binges were separated by 10 days, but total cocaine intake during the binge significantly increased when the drug-free interval was 24 h. The pattern of self-administration and the withdrawal response remained unchanged over consecutive binges. In experiment 2, rats that self-administered cocaine for either 16 or 12 h emitted significantly less USVs immediately after renewed access than they emitted 24 h after the first access period. CONCLUSION: It appeared that consecutive prolonged self-administration was insufficient to produce sensitization, as measured by cocaine intake and renewed access to self-administered cocaine was sufficient to reduce the large number of USVs that characterize withdrawal from a cocaine binge.     

Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats

The orexin/hypocretin system has been implicated in multiple phases of drug addiction. Acute orexin receptor blockade with the orexin-1 receptor (OX1R) antagonist, SB-334867, has been found to reduce cocaine seeking after cocaine self-administration. As repeated drug dosing can have differential effects and is more clinically relevant than acute dosing, in the current study we examined the effects of repeated SB-334867 on cocaine self-administration, extinction, and reinstatement to cocaine seeking in Sprague–Dawley rats. We found that repeated SB-334867 (10 mg/kg/day) had no effect on established cocaine self-administration. Repeated SB-334867 (both 10 and 20 mg/kg) attenuated cocaine seeking during extinction; however, this effect was only observed when animals had no prior experience with SB-334867 and when SB-334867 was administered prior to, but not after, daily extinction sessions. Notably, daily treatment with SB-334867 (10 mg/kg) during extinction increased subsequent cue-induced reinstatement, whereas repeated SB-334867 (20 mg/kg) administration during extinction enabled acute SB-334867 to reduce cue-induced reinstatement. Repeated SB-334867 treatment (10 or 20 mg/kg) failed to affect reinstatement induced by priming injections of cocaine (10 mg/kg). These results show that repeated inhibition of OX1R-mediated signaling exerts a lasting and specific role in mediating environmentally activated cocaine seeking.     

Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats

 Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/ injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D₂ receptor antagonist, eticlopride, or to the selective dopamine D₁ receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing. Received: 4 December 1997 / Final version: 2 July 1998