Opioid mediation of cocaine-induced hyperactivity and reinforcement.

The mechanisms by which cocaine produces hyperactivity and reinforcement remain poorly understood. Since reinforcement is also a property of other drugs of abuse including opiates, we examined the possible mediation of these cocaine-induced behaviors by endogenous opioid peptides. In this study, we have confirmed reports that cocaine increases locomotor activity and conditioned place preference in rats. We have also demonstrated that opioid receptor blockade with naloxone antagonizes completely the locomotor-activating effect of cocaine and attenuates the strength of the place preference conditioning produced by cocaine. These data support the thesis that endogenous opioids are involved in mediation of cocaine-induced behavior.

Opiate antagonists and self-stimulation: extinction-like response patterns suggest selective reward deficit.

The present study investigated the response decrement patterns produced by opiate antagonists on intracranial self-stimulation behavior, in order to determine if these drugs affect the reinforcement value of the stimulation or interfere with the ability of the animal to respond. Male rats lever-pressed in 60-min sessions on a continuous reinforcement schedule for self-stimulation of the nucleus accumbens. Naloxone (2.0 and 20 mg/kg) and naltrexone (2.0 and 20 mg/kg) suppressed self-stimulation only after a significant delay, in an extinction-like response decrement pattern, mimicking the effects of reductions in current intensity (75% and 50% of baseline). The increasing behavioral effects characteristic of the extinction pattern were observed despite the fact that testing began after the time point at which maximal suppression of self-stimulation occurs with these drugs, and when brain concentrations of these drugs were declining. Since normal responding was observed for several minutes after the beginning of the session, the results may explain why long sessions are necessary to observe suppression of self-stimulation by opiate antagonists. The extinction-like pattern produced by these drugs suggests that opiate antagonists suppress self-stimulation by reducing the reinforcement value of the stimulation, rather than by interfering with the ability of the animal to respond. These findings are consistent with a role for endogenous opioid peptides in brain stimulation reward.

Caffeine elevates reinforcement threshold for electrical brain stimulation: tolerance and withdrawal changes.

Caffeine dose-dependently increased the reinforcement threshold for electrical self-stimulation of the brain in rats, which is opposite to the effect of other behavioral stimulants. Tolerance to this effect of caffeine developed rapidly with daily drug administration. Abrupt cessation of daily drug treatment was followed by decreases in reinforcement threshold and response rate lasting 24-48 h, changes consistent with a drug withdrawal phenomenon. Because caffeine has the characteristics of a drug of abuse, these results question the generality of hypotheses relating the abuse potential of a drug to its ability to sensitize brain reward systems.

Ethanol with small doses of morphine establishes a conditioned place preference.

Conditioned place preference (CPP) testing is a way of indexing the reinforcing efficacy of drugs among rats. CPP testing involves using an alley with two distinctive sides. Typically, rats have drug experiences on one side and placebo experiences on the other. At testing, without drugs, their preference for side is tabulated. Rats' (6 groups of 12 each) place preferences were assessed before and after they were placed, once a day for 9 days, in the putative side of conditioning, and on 3 interspersed days, in the other side. During putative conditioning, one group received saline prior to being placed in both sides (a control group). Two groups had either morphine (2.0 mg/kg) or ethanol (0.5 g/kg) with the putative side of conditioning and saline with the other side. Three groups received morphine plus ethanol before being placed in the putative side of conditioning and either saline, morphine, or ethanol in the other side. At testing, rats that received morphine plus ethanol on side of putative conditioning showed a strong CPP whereas others did not. Results are compatible with the idea that ethanol's reinforcing effect is enhanced when there is a surfeit of opioidergic activity.

Relationship between minimum reinforcing doses and injection speed in cocaine and pentobarbital self-administration in crab-eating monkeys.

The relationship between minimum reinforcing doses and injection speed was investigated by using 2 levels of speeds in experiments on self-administration of cocaine or pentobarbital in 2 crab-eating monkeys each. The experiments were conducted under a fixed ratio (FR) 1 schedule with 30-min time-out after each drug injection, wherein the drugs and saline were made available for alternate 5-day periods. The minimum reinforcing doses at each injection speed were determined by the titration procedure in which the presence or absence of reinforcing effect at a particular drug dose was judged based on comparison of the self-administration rate at that dose with the rate in the preceding saline period. The results showed that the minimum reinforcing doses of cocaine and pentobarbital tended to be higher in inverse proportion to the injection speed of the drugs.

Behavioral deficits induced by low doses of apomorphine in rats: evidence for a motivational and cognitive dysfunction which discriminates among neuroleptic drugs.

In order to further assess the alterations (motor, motivational or cognitive) that might underlie animal behavioral deficits associated with a reduced dopamine transmission, the effects of apomorphine at doses thought to stimulate dopaminergic autoreceptors were studied on rat operant behavior. Apomorphine (30 micrograms/kg SC) decreased the number of food rewards obtained, when rats trained on a continuous reinforced schedule were shifted to schedules of fixed ratio higher than 2:FR3, FR4, and FR8. In rats shifted to a FR4 schedule, apomorphine (7.5, 15, 30, 60 micrograms/kg SC) dose-relatedly reduced the number of rewards obtained. In rats subjected to previous extinction sessions, apomorphine (30 micrograms/kg) did not affect lever pressing reinstated on presentation of primary reinforcers but inhibited responding renewed on presentation of secondary reinforcers. Under a FR(3 + 1) schedule where the last (rewarded) response was distinct from the initial (non-rewarded) responses, the detrimental effect of apomorphine on response rates was considerably weaker than under a conventional FR4 schedule. The reward deficits caused by apomorphine under the FR4 schedule were dose-dependently and completely reversed by amisulpride (0.125, 0.25, 0.5, 1 and 2 mg/kg), pimozide (0.125 mg/kg), sulpiride (8, 16, 32 and 64 mg/kg), but not by conventional neuroleptics (namely chlorpromazine, fluphenazine, haloperidol, metoclopramide and thioridazine). It is suggested that behavioral deficits associated with a reduced dopamine transmission such as that caused by low doses of apomorphine involve motivational and cognitive dysfunctions rather than motor impairments. In account of its differential sensitivity to neuroleptic drugs, apomorphine-induced deficit might have some relevance for a further delineation of the mechanisms of action of these compounds.

Performance deficit induced by low doses of dopamine agonists in rats. Toward a model for approaching the neurobiology of negative schizophrenic symptomatology?

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.

Amphetamine-haloperidol discrimination: effects of chronic drug treatment.

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.

Pimozide and amphetamine have opposing effects on the reward summation function.

The reward summation function is the plot of self-stimulation performance as a function of the number of pulses in a train of fixed duration. It has previously been shown that drugs that impair performance compress this curve but do not shift it laterally; whereas when the reinforcing efficacy is reduced by reducing current intensity, the curve shifts laterally. The amount of the shift is a measure of the magnitude of a drug's effect upon reinforcing efficacy. We report here that pimozide shifts the curve to the right in a dose-dependent manner, indicating an impairment of reinforcing efficacy, while amphetamine shifts it to the left, indicating an enhancement of reinforcing efficacy. When the two drugs are given together their effects on the reward summation function cancel out. These results are consistent with the hypothesis that pimozide and amphetamine exert their effects on reinforcing efficacy via one and the same set of dopaminergic synapses.

Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination.

In rats, conditioned place preferences are produced by morphine and conditioned place aversions produced by naloxone. In the present studies, several issues concerning the demonstration and interpretation of place conditioning findings were examined in a two-compartment (black and white) tilt box: (1) the responses of naive rats to testing, (2) place conditioning in rats with strong unconditioned biases to one of the sides, and (3) modifications of the testing situation so that naive rats respond to the black and white sides with a minimum of initial bias. Experiments involving manipulation of the conditions of training and testing, use of pentobarbital, and use of a three-compartment test box helped to control for morphine's ability to produce state dependent learning as an explanation of its conditioned place preference. In addition, we examined previous place conditioning studies that failed to show aversive effects of naloxone. These negative findings were suggested to be due to the use or procedures insensitive to aversive stimuli and to the IP administration of naloxone. Finally, in the course of the experiments, novel data on general parameters of the place conditioning were provided. Dose-response curves for subcutaneous (SC) morphine (0.04-5.0 mg/kg) and naloxone (0.02-5.0 mg/kg) were established. Conditioned preferences were also shown to occur after at three pairings of SC drug, and they were retained for at least 1 month.

Ethanol reinforced responding in the rat: relation of ethanol introduction to later ethanol responding.

Rats, maintained on ad lib food and water, were trained to lever press on a concurrent schedule using water and sucrose (10% w/v) as the fluids presented contingent on responding. Each fluid was associated with a lever and available on a fixed ratio eight (FR8) response requirement. The lever with which each fluid was paired was alternated daily. When stable responding occurred, ethanol was substituted for water, first at low concentrations, and then slowly increased to 5% (v/v). When stable sucrose-ethanol responding was reached, the response requirement for sucrose was altered to fixed ratio requirements of either FR32 or FR64. Moderate, but unstable increments in the number of ethanol responses occurred during the increased sucrose response requirements. Following the sucrose response requirement manipulation, water was substituted for the sucrose. Ethanol responding was found to fall to or below prior baseline levels. Weight reduction by food restriction failed to increase ethanol responding. The levels of ethanol responding resulting from this introduction procedure were always much lower independent of body weight than previously reported levels found in rats trained to respond for ethanol using a different procedure of initial ethanol introduction.

Simultaneous modulation of hippocampal cholinergic activity and extinction by intraseptal muscimol.

The relationship between regulation of acetylcholine metabolism in the septal-hippocampal pathway and extinction of a food reinforced lever press response was investigated by comparing the turnover rate of acetylcholine (TRACh) in the rat hippocampus with the amount of responding during extinction after intraseptal injection of the gamma-aminobutyric acid receptor agonist muscimol. Doses (0.3-3.0 nmol) which decreased the TRACh in the hippocampus also increased the responding during extinction over that of saline controls. Responding during the continuous reinforcement schedule before extinction was also increased, but to a lesser extent. Higher doses (10-30 nmol) further decreased the TRACh in the hippocampus, decreased it in the cortex and were accompanied by irregular responding and sedation. The TRACh in the hippocampus was also measured in drug-free rats undergoing extinction after training on a continuous reinforcement or variable interval 60 sec reinforcement schedule. Although the variable interval 60 sec reinforcement schedule rats responded more than the continuous reinforcement rats during extinction, there were no differences between the TRACh in the hippocampus. The present results indicate that the decrease in the hippocampal TRACh which is produced by intraseptal muscimol is accompanied by an increase in the response rate during extinction, but that operantly induced differences in this behavior are not accompanied by detectable changes in hippocampal TRACh.

Increasing the work requirements lowers the threshold of naloxone for reducing self-stimulation in the midbrain of rats.

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes in the midbrain central gray area. The effects of naloxone (0.1-30.0 mg/kg, SC) on a continuous reinforcement (CRF) schedule were determined. Rats were then re-trained on higher fixed-ratio (FR) schedules, and naloxone was re-tested at FR: 5, 10, 15 and 20. Only moderate reductions in lever-pressing rates were obtained at the highest dose of naloxone under CRF and FR: 5 schedules. In contrast, pronounced, dose-dependent reductions in ICSS rates occurred at FR: 10, 15 and 20. The time-course for this reduction at FR: 20 was consistent with an opiate-antagonistic action of naloxone. The modest decrease in locomotor activity produced by naloxone in a matched group of control rats was not sufficient to account for the effects on ICSS. The threshold of naloxone for reducing the rate of ICSS lever-pressing was lowered by increasing the effort and/or time requirement for each reinforcement.

The effects of naloxone, diprenorphine, and diazepam on responding suppressed by pre-shock and pre-food stimuli.

The lever-pressing of rats was reinforced with food according to a variable-interval 1-min schedule. In one group, occasional illumination of cue lights for 30-sec periods was followed by a brief electric shock; responding was suppressed during these periods. Naloxone (0.01-10 mg/kg) did not change the degree to which responding was suppressed during the pre-shock stimulus. Diprenorphine (0.1-10 mg/kg) slightly attenuated suppression, and diazepam (1.0-3.0 mg/kg) increased responding during the stimulus to normal levels. These results confirm that opiate antagonists do not always enhance the effects of shock on behavior. In a second group, occasional illumination of the cue lights for 20-sec periods was followed by delivery of free food pellets. Responding was also suppressed during the pre-food stimulus. Neither naloxone nor diprenorphine had any effect on response rate during this stimulus. In contrast to the results of earlier studies using benzodiazepines, diazepam (1.0-3.0 mg/kg) produced a marked attenuation of response suppression during the pre-food stimulus.

Behavioral tolerance to stimulating effects of pentobarbital: a within-subject determination.

Squirrel monkeys were trained to press a lever under a multiple schedule of food presentation. In one stimulus condition responses that terminated interresponse times greater than 28 sec were followed by food presentation. In the other stimulus condition, an interval schedule of food presentation was presented that provided approximately the same frequency and distribution of food delivery as that observed under the interresponse-time schedule. Except when it was administered for the first time, 5.6 mg/kg sodium pentobarbital produced reliable increases in responding during the interresponse-time schedule. Behavioral tolerance to the rate-increasing effect was assessed in individual subjects by first administering the drug daily following each session, and then giving it daily before each session. Following post-session drugging, the effects of 5.6 mg/kg were not changed, but tolerance developed when the drug was administered pre-session. The way in which tolerance developed was consistent with the reinforcement-loss hypothesis.

Cyclazocine disruption of operant behavior is antagonized by naloxone and metergoline.

Male Sprague-Dawley rats were trained to press a lever on a fixed ratio-40 (FR-40) schedule for food reinforcement. Doses ranging from 0.5 to 16 mg/kg of the mixed narcotic agonist-antagonist cyclazocine (30-min pretreatment) resulted in a dose-dependent decrease in the number of reinforcements obtained and a reciprocal increase in "pausing" (IRT's greater than 10 sec). A 5-min pretreatment with 4 mg/kg of the narcotic antagonist naloxone attenuated the cyclazocine disruption. The 5-HT antagonist metergoline (1 mg/kg; 180-min pretreatment) also blocked cyclazocine effects to approximately the same degree as did naloxone. However, the shift of the dose response pattern of cyclazocine was not parallel for either antagonist. A greater degree of attenuation of the cyclazocine effects was observed when naloxone (4 mg/kg) and metergoline (0.1 mg/kg) were given together, indicating that cyclazocine disruption may be antagonized by either a narcotic antagonist or a 5-HT antagonist, and that these antagonists may operate synergistically. Thus, the behavioral effects of cyclazocine may relate to both opioid and serotonergic components.

Effects of ethanol on enforced spatial variability in the 8-arm radial maze.

Previous work has indicated that ethanol is a potent stereotypy-inducing agent. At least this is the case for spontaneously emitted instrumental behavior. The present experiments were undertaken to determine if spatial variability could be generated by drugged rats when it was enforced by reward contingencies. With a reward nonreplacement rule in force, four arms of an 8-arm radial maze were baited on every trial. Rats injected with 0, 0.75, 1.5, or 2.0 g/kg ethanol were required to run to the same set of arms from trial-to-trial and session-to-session. Efficient performance depended upon their running to the correct set of arms as well as meeting a "win-shift" demand which proscribed returning to previously visited arms during a given trial. Although all groups were eventually able to run to the correct set of arms, alcohol, especially at higher doses, promoted repetition. The inability to refrain from reentering arms prevented many alcohol-injected animals from obtaining the four rewards in the allotted time. In Phase 2 of Experiment 1, the baited arms were rotated 45 degrees. Now the formerly empty arms contained pellets and rewards were withdrawn from the previously correct arms. Adjustment to this shift was rapid for 0 and 0.75 g/kg groups, but an increasingly severe perseveration was observed across the higher ethanol groups. Experiment 2 reproduced the results of Experiment 1 under different circumstances. While trained as before to run to a specific set of four arms in Phase 1, Phase 2 presented the rats with rewards in all eight arms of the maze. With higher doses of alcohol an increasing persistence in running to the original four arms was observed. Saline-injected animals, on the other hand, rapidly doubled the number of pellets taken. Taken together, and in view of earlier findings, the results suggest that alcohol interacts with previous training as well as recent choices with the result that spatial dispersion is restricted in spite of explicitly opposing reward contingencies.

Effects of antianxiety and antipsychotic drugs on DRL responding for brain stimulation.

Satiated rats could be trained to give stable rates of responding for rewarding stimulation of the lateral hypothalamus delivered on differential reinforcement of low rate (DRL) schedule requiring 2 to 8 sec interresponse intervals for reinforcement (DRL-2 to 8). The performance on a DRL-8 schedule was tested 30 min after the oral administration of benzodiazepines. Diazepam (5 and 10 mg/kg) and meprobamate (200 mg/kg) caused significant increases in response rates during the first 5 min of a session, but not thereafter. Bromazepam (1 and 5 mg/kg) also caused a significant increase in the rates during the first and second 5 min. On the other hand, chlorpromazine (20 mg/kg) caused no effect in the first 5 min but decrease in second and third 5 min. These results indicate that DRL schedules with a brain stimulation reward provided a useful tool for evaluation of antianxiety drugs. The advantage of the brain stimulation reward over food reward is that the possible effects of the drugs on hunger motivation need not be considered.