Gerald J. Schaefer

Changes in response rates and reinforcement thresholds for intracranial self-stimulation during morphine withdrawal

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus and were trained in an auto-titration brain self-stimulation paradigm. When response rates and reinforcement thresholds were stable, the animals were implanted with subcutaneous osmotic minipumps (Alzet, 2ML1) which continually delivered morphine (1.2 mg/kg/hr as the base, n = 16) or saline (10.0 microliter/hr, n = 11). After one week the pumps were removed, and the animals were again tested in the auto-titration paradigm following the daily administration of either saline (spontaneous withdrawal) or 1.0 mg/kg naloxone (precipitated withdrawal). During the eight-day withdrawal phase there was a decrease in the rate of lever-pressing for the morphine dependent animals and this was greatest on the first day. The magnitude of the decrease was greater in the precipitated withdrawal group than in the spontaneous withdrawal group and an increase in the reinforcement threshold occurred only with precipitated withdrawal. Animals in both groups lost weight when measured each morning, but the precipitated group showed greater weight loss during the day. In addition, animals in the precipitated withdrawal group had diarrhea and showed a higher incidence of withdrawal signs than both the non-dependent (control) and spontaneous withdrawal groups. These experiments provide a detailed account of opiate withdrawal following the continuous subcutaneous infusion of a small dose of morphine for one week.

Acute effects of neuroleptics on brain self-stimulation thresholds in rats

The acute effects of 5 neuroleptic drugs were tested in rats implanted with stimulating electrodes in the medial forebrain bundle and trained in a brain selfstimulation threshold procedure. Haloperidol (0.01–0.10 mg/kg) and loxapine (0.03–0.56 mg/kg) produced increases in reinforcement thresholds accompanied by reductions in response rates. Chlorpromazine (0.10–3.0 mg/kg) did not significantly alter reinforcement thresholds, but did produce dose-dependent reductions in response rates. Pimozide (0.1–1.75 mg/kg) was similar to chlorpromazine and significantly increased the reinforcement threshold only at the highest dose, although a graded decrease in response rates occurred over a wide dose-range. Clozapine (0.1–1.75 mg/kg) increased reinforcement thresholds without producing any significant changes in response rates, but when 3.0 mg/kg was administered, a marked disruption of behavior occurred. The results suggested that a distinction can be made between the effects of neuroleptics on motor behavior and on central reinforcement thresholds, and this may help in the interpretation of the relation between the chemical and clinical potency of antipsychotic drugs.

Opiate antagonists and rewarding brain stimulation

This review examines the literature on the effects of opiate antagonists on brain stimulation (ICSS) reward. Antagonists should have predictable effects if endogenous opioids modulate ICSS. Naloxone is the antagonist most often used, and it has produced inconsistent results in some ICSS paradigms. When schedules of intermittent reinforcement are used, however, naloxone reliably reduces the rate of responding. It reverses the effects of opiate agonists on ICSS behavior, and it also attenuates the effects of psychomotor stimulants, such as amphetamine. The results produced by naloxone are consistent with a modulatory effect of endogenous opioid systems on reward, and suggest that the opiate and dopamine systems together exert significant control over ICSS. Further research is needed to characterize better the actions of the antagonists on ICSS behavior, and productive research directions are proposed. Data obtained in future studies might suggest how the endogenous opioid systems modulate both natural and brain stimulation reward.

Free-operant and auto-titration brain self-stimulation procedures in the rat: A comparison of drug effects

Rats were implanted with bipolar stimulating electrodes aimed at the medial forebrain bundle of the lateral hypothalamus, and trained to press a lever in one of two different procedures in order to receive electrical stimulation through the electrodes. In a free-operant procedure, each response produced a 200 msec train of electric pulses at a suprathreshold current, the intensity of which remained constant throughout the session. In an auto-titration procedure, each response produced an electrical stimulus which was initially set at a suprathreshold intensity. Every 15th response reduced the stimulation current by 3 muA. The animal could reset the current to its initial intensity at any time by pressing a second lever in the test chamber. The average current at which the animal pressed the reset lever was defined as the reinforcement threshold. Dose-response functions were determined for d- and l-amphetamine, alpha-methyltyrosine, and haloperidol. The reinforcement threshold was decreased by both d- and l-amphetamine, increased by haloperidol, and not changed by alpha-methyltyrosine. These effects on reinforcement threshold were not consistently related to the drug-induced changes in response rate in either procedure. The auto-titration procedure may be useful for distinguishing between drugs which cause nonspecific changes in the rate of ongoing behavior and those which specifically modify the reinforcement efficacy of brain stimulation.

Threshold differences for naloxone and naltrexone in the hypothalamus and midbrain using fixed ratio brain self-stimulation in rats.

Rats were implanted with stimulating electrodes aimed either at the medial forebrain bundle-lateral hypothalamus (MFB-LH) or the midbrain-central gray (MID-GG), and were trained to lever-press for brain self-stimulation on a fixed ratio: 15 schedule of reinforcement. The dose-dependent effects of morphine (0.1–3.0 mg/kg), naloxone (0.1–30 mg/kg), and naltrexone (0.1–30 mg/kg) were then determined during 1 h test sessions. Both naloxone and naltrexone decreased the rate of responding in the MFB-LH as well as in the MID-CG. However, decrements in response rates were produced in the MID-CG by both naloxone and naltrexone at one tenth the doses required to produce similar decrements with electrodes in the MFB-LH. Dose-dependent decreases in response rates produced by morphine occurred at the same doses in the two electrode sites. At both sites, the decreases in response rates produced by the highest dose of morphine were antagonized completely by a low dose of naloxone (0.1 mg/kg). At an intermediate dose of naloxone (1.0 mg/kg), antagonism occurred in the MFB-LH but not in the MID-CG. At a high dose of naloxone (10 mg/kg), a depression in lever-pressing occurred at both sites in the morphine-treated animal indicating that the depressive action predominated over antagonism. These data explain the lack of consistency of the effects of naloxone on brain self-stimulation previously reported by different laboratories, and demonstrate that the use of partial reinforcement schedules in a rational approach to the evaluation of opioid effects on brain self-stimulation behavior.

Interactions between alcohol and nicotine on intracranial self-stimulation and locomotor activity in rats

These studies were aimed at investigating interactions between alcohol and nicotine on operant behavior and on locomotor activity. Independent groups of rats with electrodes in the lateral hypothalamus were trained to lever press for intracranial self-stimulation (ICSS) on either a fixed-ratio 15 (FR 15), FR 30, fixed-interval 15-second (FI 15-s) or FI 30-s schedule of reinforcement. In the FI 15-s experiment, nicotine increased and alcohol decreased responding. This also happened in the FI 30-s experiment; however, when the two drugs were combined, an increase in lever pressing occurred which was greater than that produced by nicotine alone. Nicotine increased rates in the FR 15 schedule but, when combined with alcohol, did not reverse the decrease in rates produced by alcohol. In the FR 30 schedule, nicotine also increased response rates, but did not reverse the decrease produced by alcohol in this paradigm. A separate group of animals was tested in a locomotor activity apparatus following administration of nicotine, alcohol or their combination. Nicotine increased locomotor activity and alcohol depressed it. However, when 0.10 or 0.17 mg/kg nicotine was combined with 0.3 g/kg alcohol, an increase greater than that produced by nicotine alone occurred. We have found that alcohol and nicotine together can produce a potentiation of nicotines stimulatory effects depending upon the dose and the requirements of the task.

Morphine-like stimulus effects in the monkey: opioids with antagonist properties.

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.

Interactions of naloxone with morphine, amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.

Ethanol and Current Thresholds for Brain Self-Stimulation in the Lateral Hypothalamus of the Rat

Two groups of animals were implanted with stimulating electrodes in the lateral hypothalamus for intracranial self-stimulation (ICSS). Following surgery these animals were trained in the auto-titration, brain self-stimulation procedure which measured both the rate of responding and the reinforcement threshold for electrical stimulation. When behavior was stable, one group was given saline or ethanol (0.1-1.7 g/kg) administered intraperitoneally (IP) either 15 or 60 min before testing. The other group was given saline or ethanol (1.0-4.5 g/kg) administered intragastrically (IG) 15 or 60 min before testing. With IP administration, there was a graded decrease in lever-pressing at 15 min but the effect was less obvious at 60 min. There were no changes in threshold except at the highest dose when behavior was disrupted. With IG administration, a reduction in the rate of responding occurred at 15 min only. No changes in thresholds were observed at any dose level or injection-test interval. Thus, administration of ethanol either by the IP or IG route did not affect the reinforcement thresholds for ICSS in the lateral hypothalamus, and these results contrasted with those of other drugs of abuse such as amphetamine or morphine.

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.