EEG and behavioral effects of Δ9-Tetrahydrocannabinol in combination with stimulant drugs in rabbits

In rabbits, ⁹-tetrahydrocannabinol (THC) at 0.5 mg/kg, i.v., was challenged with i.v. methamphetamine (0.1 mg/kg), cocaine (1 mg/kg), apomorphine (1 mg/kg), or caffeine (12.5 mg/kg), and observations were made on quantified EEG and behavior. Cortical and hippocampal alterations produced by THC were antagonized by methamphetamine, cocaine, and caffeine and only briefly by apomorphine. Postural and activity behaviors were reversed by methamphetamine and caffeine but only briefly by cocaine and apomorphine. Additionally, stereotypy resulted from the combination of THC with methamphetamine, cocaine, or apomorphine. These data indicate that the effects of THC were antagonized by stimulant drugs of which caffeine was the most effective. However, novel toxicity also resulted from the interaction of THC with catecholaminergic drugs.     

Alpha-methyltyrosine blocks the expression of rotation classically conditioned with apomorphine.

Rats with unilateral 6-hydroxydopamine lesions of substantia nigra rotate (circle) when placed, undrugged, in the environment in which they have previously been treated with apomorphine. This conditioned rotation, like the unconditioned rotation which acutely follows the administration of apomorphine, is directed away from the side with the lesion, i.e., the rotation is contralateral. Here, rats that had been administered apomorphine weeks earlier were tested, in a crossover design, for the expression of conditioned rotation following treatment with saline and with alpha-methyltyrosine. When administered four hours prior to testing, 100 mg/kg alpha-methyltyrosine significantly antagonized the expression of classically conditioned rotation. In a second group of animals, alpha-methyltyrosine had no effect on the unconditioned rotation induced by 0.05 mg/kg apomorphine.     

One trial conditioning with apomorphine is blocked by cycloheximide

Rats with unilateral 6-hydroxydopamine lesions of substantia nigra were treated with 0.05 mg/kg apomorphine and observation of their circling behavior was made. Twenty minutes after the apomorphine treatment they were injected with saline or 2 mg/kg cycloheximide. Two weeks after drug treatment, control animals exhibited rapid contralateral rotation in response to being placed in the rotation environment. This conditioned rotation was not observed in cycloheximide-treated animals. After the first test trial animals received a second apomorphine administration, this time followed by saline injection in both groups. Subsequent to the second apomorphine treatment both groups showed conditioned rotation.     

Differential effects of 7-OH-DPAT on the development of behavioral sensitization to apomorphine and cocaine

The primary objective of this study was to determine whether concurrent treatments with a low dose of the dopamine D(3)-preferring receptor agonist 7-OH-DPAT would attenuate the development of behavioral sensitization to the indirect dopamine receptor agonist, cocaine, or the direct dopamine receptor agonist, apomorphine. In two experiments, male Wistar rats (250-350 g) were given seven daily injections of 7-OH-DPAT (0.05 mg/kg sc) or vehicle in combination with either cocaine (15 mg/kg ip), apomorphine (1.0 mg/kg sc), or vehicle. After the injections, the rats were tested for activity in photocell arenas for 40 min, and three measures of motor behavior (distance traveled, rearing, and stereotypy) were recorded at 10-min intervals. A total of 24 h after the last preexposure session, all rats were given a challenge injection of either cocaine (10.0 mg/kg ip, Experiment 1) or apomorphine (1.0 mg/kg sc, Experiment 2) and tested for activity. Major findings were as follows: (a) 7-OH-DPAT treatments alone suppressed all measures of locomotor activity and did not affect subsequent behavioral sensitivity to either cocaine or apomorphine; (b) cocaine treatments acutely increased all measures of activity, and repeated treatments produced behavioral sensitization to the horizontal locomotor-activating effects of cocaine; (c) apomorphine treatments alone increased horizontal activity and stereotypy but completely abolished rearing behavior; (d) like cocaine, repeated treatments with apomorphine induced behavioral sensitization; (e) concurrent treatments of 7-OH-DPAT with cocaine acutely attenuated cocaine-induced increases in motor behavior but enhanced the development of behavioral sensitization to cocaine; and (f) concurrent 7-OH-DPAT treatments did not significantly affect either the acute or chronic effects of apomorphine. It is evident from these results that concurrent treatment with 7-OH-DPAT does not block the development of behavioral sensitization to either cocaine or apomorphine. Moreover, the differential acute and chronic effects of 7-OH-DPAT on cocaine- and apomorphine-induced hyperactivity appear to be mediated by dopamine autoreceptor stimulation.     

Evidence for dopaminergic involvement in tolerance to the discriminative stimulus properties of cocaine

Rats were trained to discriminate cocaine, 10.0 mg/kg, in a two-lever operant procedure. Dose-effect data for generalization to cocaine and substitution of apomorphine for the cocaine stimulus were determined. Subsequently, training was halted and either apomorphine, 2.5 mg/kg per 8 h, or cocaine, 20 mg/kg per 8 h, was administered for 7-9 days. During chronic administration, the efficacy of cocaine and apomorphine as discriminative stimuli was decreased. These data suggest that dopaminergic mechanisms may mediate tolerance to the discriminative stimulus properties of cocaine.     

Behavioral sensitization to apomorphine in adult rats exposed to cocaine during the preweaning period: a preliminary study.

Sixty-day-old rats treated with cocaine (50 mg/kg SC) during postnatal days (PND) 11-20 received daily injections of apomorphine (2.0 mg/kg SC) for 10 consecutive days to examine the development of sensitization to a direct dopamine agonist. Behavior was monitored on days 1, 5, and 10, using a photobeam system, and on day 10 using the videotape assessments as well. Locomotor sensitization to apomorphine developed in the preweaning vehicle-treated males only. Neither the cocaine-treated males nor any females exhibited locomotor sensitization to repeated apomorphine injections at 2 mg/kg. There were no other treatment-related effects except for grooming, which showed an interaction between treatment and gender. Overall, every behavior analyzed showed significant apomorphine effects, except rearing. Margin time (wall hugging), grooming, and quiet were significantly decreased by apomorphine, while locomotion and the duration of sniffing were increased. In summary, these data indicate that with respect to locomotor activity, the development of sensitization to apomorphine at 2.0 mg/kg is prevented by preweaning cocaine administration in males. These data further suggest that developmental cocaine exposure produces long-term alterations in DA D1 receptor-mediated responses in male rats.     

Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.     

Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats

Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two alternatives is correct, we investigated the occurrence of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats. We have recently shown that under specific environmental conditions (challenged-not habituated to the environment-as measured by distance travelled) apomorphine susceptible rats consistently self-administer more cocaine than apomorphine unsusceptible rats do. As conditioned place preference allows the assessment of the rewarding value of cocaine, we investigated the expression of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats under the same conditions as the self-administration experiments in order to establish whether the rewarding value of cocaine is greater or smaller in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats. The data clearly showed that challenged apomorphine susceptible rats had a preference for the cocaine-paired compartment with lower doses of cocaine (10 mg/kg) than challenged apomorphine unsusceptible rats. Apomorphine unsusceptible rats expressed conditioned place preference only with the highest dose tested (20 mg/kg). On the basis of these data, we concluded that the rewarding value that cocaine has in challenged apomorphine susceptible rats is greater than that in challenged apomorphine unsusceptible rats. It is suggested that challenged apomorphine susceptible rats self-administer more of a lower dose of cocaine than challenged apomorphine unsusceptible rats do, because the rewarding value of cocaine is greater in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats.     

Cocaine cue in rats as it relates to subjective drug effects: A preliminary report

Using a food-reinforced two-lever operant method, rats (n = 5) could be trained to discriminate 10 mg/kg cocaine from saline. Stimulus generalization experiments with lower doses (0.31–5.0 mg/kg) revealed that the cocaine cue is a dose-related phenomenon. Neuroleptic drugs were found relatively ineffective as possible antagonists of the cocaine cue, and no antagonistic effect whatsoever was obtained with dibenamine, propranolol, cyproheptadine and methysergide. Amphetamine (1.25 mg/kg) and apomorphine (0.31 mg/kg) were generalized with cocaine, and a dopaminergic involvement is discussed.     

Transient hypersensitivity to apomorphine-induced gnawing after termination of acute effects of a single high dose of cocaine

Physical dependence on cocaine has not been fully characterized or definitively identified. Since behavioral changes are typically not observed after cocaine withdrawal in animal studies, we sought to amplify or reveal any such changes in behavior by administration of the dopamine agonist apomorphine. C57BL/6J mice were tested for behavioral effects (climbing, gnawing, and locomotor activity) of apomorphine at various times after acute administration of cocaine. When tested at a time when most of the administered cocaine had disappeared from brain and when behavioral effects of cocaine had dissipated, at 2 and 4h post cocaine administration, effects of apomorphine on gnawing were increased 4-fold. This dopaminergic hypersensitivity was induced by acute treatment with doses of 15mg/kg cocaine and higher. Effects of apomorphine were not enhanced at later time periods (6 to 24h after cocaine), indicating a rapid waning of the dopaminergic hypersensitivity. Hypersensitivity to apomorphine was not further augmented by 8 days of daily cocaine injections. Cocaine did not influence climbing and hypomotility induced by apomorphine 4h after its injection, demonstrating selectivity in the behavioral expression of the dopaminergic hypersensitivity. Further, cocaine did not induce sensitization to its own effects indicating that the hypersensitivity to apomorphine was not due to a typical sensitization phenomenon. The results of these experiments demonstrate a short-lived dopaminergic supersensitivity after termination of the acute effects of a single high dose of cocaine, the implications of which remain to be discovered.     

Altered activity of midbrain dopamine neurons following 7-day withdrawal from chronic cocaine abuse is normalized by D2 receptor stimulation during the early withdrawal phase.

Using in vivo single-unit recording in rats, we compared the effects of continuous cocaine infusion via minipump or single daily injections (both 40 mg/kg/d x 14 days, S.C.) on the activity of putative dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA). On days 1-5 after cocaine withdrawal, animals were further treated with single daily injections of DA agonists. On withdrawal day 7 continuous cocaine caused a reduction in spontaneously active neurons in the SNC and reduced bursting in the VTA. In contrast, intermittent cocaine resulted in an increase in the number of active neurons in the VTA. These changes were all reversed by apomorphine or quinpirole given during the first 5 withdrawal days. The D1 antagonist SCH 39166 did not antagonize the effects of apomorphine in either region. The role of D2 receptors in modulating baseline DA activity during intermediate cocaine withdrawal is discussed.     

On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization

Rationale Psychostimulant drugs exert their behavioral effects primarily through enhancement of monoaminergic neurotransmission. Augmented dopamine activity is thought to play a critical role in the psychomotor stimulant effects of amphetamine and cocaine, as well as in the development of long-term behavioral sensitization evoked by repeated exposure to amphetamine. However, despite the fact that brain dopamine and noradrenaline systems are closely interconnected, the extent to which noradrenergic transmission contributes to these behavioral effects of psychostimulants is a relatively unexplored issue. Objectives By inhibiting noradrenergic neurotransmission with the α₂-adrenoceptor agonist clonidine, the α₁-antagonist prazosin and the β-antagonist propranolol, we investigated the involvement of noradrenaline neurotransmission in the psychomotor stimulant and long-term sensitizing effects of d-amphetamine and cocaine in rats. Methods Clonidine (0.003–0.1 mg/kg), prazosin (0.1–3.0 mg/kg) and propranolol (1.0–3.0 mg/kg) were administered prior to d-amphetamine (1.0 mg/kg), cocaine (15 mg/kg) or apomorphine (1.0 mg/kg) and psychomotor activity was measured. In separate studies, clonidine (0.03 mg/kg), prazosin (1.0 mg/kg) or propranolol (3.0 mg/kg) were co-administered with d-amphetamine (2.5 mg/kg) or cocaine (30 mg/kg) for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results The psychomotor stimulant effect of d-amphetamine, but not that of cocaine or apomorphine, was dose-dependently inhibited by clonidine and prazosin, and enhanced by propranolol. Clonidine, prazosin, and propranolol did not influence the induction of sensitization by amphetamine or cocaine. Conclusions Enhancement of synaptic noradrenaline concentrations contributes to the psychomotor stimulant effect of d-amphetamine, but not cocaine or apomorphine. In addition, noradrenergic neurotransmission is not critically involved in the induction of psychostimulant sensitization.     

A conditioned anti-parkinsonian drug effect in the hemi-parkinsonian rat

In two separate experiments contralateral rotation was classically conditioned in hemi-Parkinsonian rats. In the first experiment, ten rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, which produced ipsiversive circling, were given five daily injections of the dopamine receptor agonist apomorphine (0.5 mg/kg) to induce circling contralateral to the lesion hemisphere. One half of the rats (the conditioning group) were placed in a novel environment for 15 min during each apomorphine treatment. Subsequently, when placed into this environment 3, 10, 17, and 24 days after the final apomorphine injection, the conditioning group spontaneously rotated contalateral to the lesion hemisphere, whereas a similarly drug-treated non-conditioned group spontaneously rotated ipsilateral to the lesion hemisphere. On day 26, all rats were given a 2.0 mg/kg injection of d-amphetamine, which generated ipsilateral rotation in all rats in their home environment, but when placed in the conditioning environment, the conditioned group rotated contralateral whereas the non-conditioned group rotated ipsilateral. In the second experiment, eight rats with unilateral destruction of dopamine neurons were given differential conditioning in two novel environments. In every case, environments associated with 0.5 mg/kg apomorphine treatment induced contralateral rotation when the rats were tested without drug but ipsilateral rotation in environments not associated with apomorphine. These findings suggest a role for respondent or Pavlovian conditioning in the pharmacological management of Parkinsonism. Offprint requests to: R. Carey     

Antiparkinson-like effects of a novel neurotensin analog in unilaterally 6-hydroxydopamine lesioned rats.

Parkinson's disease is a neuropathological disorder involving the degeneration of dopamine neurons in the substantia nigra, with the resultant loss of their terminals in the striatum. This dopamine loss causes most of the motor disturbances associated with the disease. One animal model of Parkinson's disease involves destruction of the nigrostriatal pathway with a neurotoxin (6-hydroxydopamine) injected into this pathway. In unilaterally lesioned animals, injection of D-amphetamine causes rotation towards the lesioned side, while injection of apomorphine acting upon supersensitive postsynaptic dopamine receptors causes rotation away from the lesioned side. In this study, we tested the effects of acute and subchronic injection of a neurotensin analog (NT69L) on the rotational behavior induced by D-amphetamine (5 mg/kg) or apomorphine (600 microg/kg) in unilaterally 6-hydroxydopamine lesioned rats. Pretreatment of animals with intraperitoneal injections of NT69L (1 mg/kg) resulted in a significant reduction of apomorphine-induced contralateral rotation and D-amphetamine-induced ipsilateral rotation in these lesioned rats with an ED(50) of 40 and 80 microg/kg, respectively. After three daily injections of NT69L, its effects on this rotational behavior were unchanged, suggesting that no tolerance develops to this effect of NT69L.     

Sensitization of rotation behavior in rats with unilateral 6-hydroxydopamine or kainic acid-induced striatal lesions

Following unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra or unilateral kainic acid (KA) lesions of the striatum rats displayed rotation behavior in response to apomorphine (0.25 mg/kg SC or 1 mg/kg SC for the 6-OHDA- and KA-lesioned rats respectively). Three to five days following the initial apomorphine challenge rats were challenged under identical conditions with the same dose of apomorphine received previously. Both 6-OHDA- and KA-lesioned rats demonstrated a significant increase in the total number of rotations. Following a subsequent challenge with apomorphine, rats showed further increases in the total number of rotations. With the second and the subsequent apomorphine challenges there were significant increases in the maximal number of rotations, a significant decrease in the time of onset of rotation behavior and in some cases an increase in the duration of the rotation behavior. These increases in rotation behavior following repeated challenges with apomorphine indicate a supersensitivity to dopamine receptor agonists distinct from that elicited by lesions and chronic antagonist treatments. Furthermore, the utility of the rotation behavior model for testing the efficacy of dopaminergic agonists might be compromised if repeated challenges in individual animals are employed.     

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.     

Discriminative stimulus properties of cocaine in pigeons

The present study was designed to assess the discriminative stimulus properties of cocaine in pigeons. Six pigeons were trained to discriminate IM injections of cocaine (2 mg/kg) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. Cocaine, d-amphetamine, and l-cathinone substituted completely for the training dose of cocaine in all pigeons. When nicotine (0.25–4.0 mg/kg), apomorphine (0.03–1.0 mg/kg), procaine (4–32 mg/kg), and lidocaine (4–16 mg/kg) were substituted, both partial substitutions and individual differences between pigeons were observed. Oxazepam (0.5–4.0 mg/kg) and pentobarbital (2–8 mg/kg) failed to substitute for the training dose of cocaine. Discriminative stimulus control by cocaine was greatest when the drug was administered 10–40 min prior to the session and the effects disappeared after 2 h. The substitution results indicate drug class specificity of the cocaine cue but, in addition, suggest its multidimensional nature.     

Apomorphine fails to inhibit cocaine-induced behavioral hypersensitivity

The subchronic administration of cocaine will induce a behavioral sensitization to challenge doses of the drug administered several days after cessation of treatment. This sensitization is similar behaviorally to that observed for other stimulants such as amphetamine. Similarities and differences in the sensitization induced by cocaine and amphetamine (which are though to have different mechanisms of actions although common behavioral outcomes) have not been thoroughly studied. The purpose of the present experiment was to examine the effects of these two drugs on basic horizontal locomotion and changes occurring subsequent to their subchronic administration in mice. Cocaine and amphetamine were administered acutely in various doses to compare time and dose responses in the behavioral paradigm used (infrared detection of horizontal locomotion). Subsequently, cocaine (10 mg/kg) or amphetamine (2.5 mg/kg) were administered twice a day for 5 days and the animals challenged 3 days after the last treatment with the same doses received subchronically. Two other groups of mice received the same subchronic treatment and in addition were administered 80 micrograms/kg apomorphine (5 to 15 min after each dose of the stimulant) and then tested for their response to challenge doses of the stimulants 72 hours after the last pretreatment dose. Acutely, cocaine produced a maximum locomotor activity that was significantly lower than that of amphetamine and the former had a much shorter duration of action than the latter. After subchronic administration, both stimulants induced sensitization, however, apomorphine inhibited the sensitization induced by amphetamine but failed to do so in the cocaine-treated animals. Possible mechanisms for these differences are discussed.     

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5–64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.The facilities in which the mice were maintained are fully accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC), and the studies described here were conducted in accordance with the Guide for Care and Use of Laboratory Animals provided by the NIH and adopted by NIDA.     

Opiate antagonists reduce cocaine but not nicotine self-administration

Rats were trained to self-administer cocaine in 1-h sessions on a fixed ratio 5 (FR5) schedule of reinforcement. Acquisition was carried out at a unit dose of 0.3 mg/kg and responding was then stabilized at cocaine doses of 0.1, 0.3, and 1.0 mg/kg/infusion. Pretreatments with naltrexone (0.1-10 mg/kg, SC) 20 min prior to the start of self-administration sessions resulted in decreases in cocaine self-administration at doses of 0.1 and 0.3 mg/kg/infusion, but not at 1.0 mg/kg/infusion. Decreases depended on the dose of naltrexone used, with greater decreases in self-administration occurring at higher antagonist doses. In addition, treatment with the opiate antagonist naloxone also reduced cocaine self-administration at a unit dose of 0.3 mg/kg. A group of rats trained to self-administer nicotine at a dose of 0.03 mg/kg/infusion on the same schedule of reinforcement was unaffected by naltrexone treatment. These results may indicate that an endogenous opiate system plays a role in cocaine reinforcement.