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Biomedical subjects

G J Schaefer

Publications and source records attributed to G J Schaefer.

At least 37 records · Page 2Linked to original sources
PubMed1983

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.

Animals↗
PubMed1983

Morphine withdrawal produces differential effects on the rate of lever-pressing for brain self-stimulation in the hypothalamus and midbrain in rats.

Rats were implanted with stimulating electrodes either in the medial forebrain bundle-lateral hypothalamus (MFB-LH) or the midbrain-central gray area (MID-CG), and were trained to lever-press for electrical brain self-stimulation (ICSS). The animals were made tolerant to morphine (15 mg/kg) by twice daily injections for a four-day period. Withdrawal was then induced either by substituting saline (spontaneous withdrawal) or by administering naloxone (1.0 mg/kg) (precipitated withdrawal). Changes in body weight, in the incidence of diarrhea, and in rates of lever-pressing for ICSS were recorded during the five-day withdrawal period. In both the MFB-LH implanted and the MID-CG implanted groups, the duration and magnitude of changes in lever-pressing were greater when withdrawal was precipitated than when it was spontaneous. Independently of the type of withdrawal, however, the behavioral disruption was greater for animals implanted in the MFB-LH than for animals implanted in the MID-CG. The changes in body weight were similar for both electrode sites and both types of withdrawal. Diarrhea only occurred in the precipitated withdrawal group and its incidence was similar for animals implanted in the two sites. Three additional groups of animals were implanted in the MFB-LH, made tolerant to morphine, and given naloxone as above. They were administered clonidine (10, 30 or 100 micrograms/kg) 30 min prior to naloxone to attenuate the effects of withdrawal. The 30 micrograms/kg dose of clonidine produced maximal attenuation of the disruption in lever-pressing. None of the doses of clonidine attenuated weight loss, but all three doses reduced the incidence of diarrhea. The ICSS procedure demonstrated that the behavior during withdrawal can be related to the brain area that is stimulated.

Animals↗
PubMed1982

An easily constructed biphasic constant-current stimulator for intracranial self-stimulation.

This paper describes a biphasic, constant-current stimulator that is appropriate for intracranial self-stimulation (ICSS) studies. The stimulator is made from components that are readily available in electronic supply stores at low cost. A printed circuit board has also been designed for the stimulator which facilitates its production. The device has proven extremely reliable in various ICSS paradigms.

Animals↗
PubMed1981

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 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.

Animals↗
PubMed1981

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.

Animals↗
PubMed1980

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 self-stimulation 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.

Animals↗
PubMed1979

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.

Amphetamine↗
PubMed1978

Discriminative effects of cyclazocine in the squirrel monkey.

In order to characterize the discriminative stimulus properties of cyclazocine squirrel monkeys were trained to discriminate between intramuscular injections of 0.1 mg/kg of cyclazocine and drug vehicle in a discrete-trial avoidance paradigm in which a response on one of two levers would prevent or terminate the delivery of a mild electric shock to the tail. Behavior was considered to be under stimulus control when the monkeys completed at least 22 trials of a 25-trial session on the appropriate choice lever after they received cyclazocine or vehicle. Stimulus generalization (i.e., dose-response) curves were then determined for a variety of drugs over a broad range of doses. The following analgesics with narcotic antagonist properties produced stimulus control of behavior comparable to that produced by 0.1 mg/kg of cyclazocine: ketocyclazocine (0.1 mg/kg), butorphanol (1.0 mg/kg), oxilorphan (3.0 mg/kg) and levallorphan (3.0 mg/kg). Time course experiments revealed that the duration of complete stimulus control was relatively short: 1 hour after 0.1 mg/kg of cyclazocine and 3.0 mg/kg of oxilorphan and 0.5 hour after 0.1 mg/kg of ketocyclazocine. Naloxone produced a dose-related antagonism of the stimulus control by cyclazocine and butorphanol which was complete at 1.0 mg/kg. In contrast, as much as 10 mg/kg of naloxone only partially blocked stimulus control by ketocyclazocine and failed to modify stimulus control by oxilorphan and levallorphan. The monkeys showed partial generalization to other drugs with activity as narcotic agonists, antagonists or both (e.g., morphine, naloxone, pentazocine, nalbuphine, nalmexone and nalorphine), but little or no generalization to the nonopioid psychoactive drugs, d-amphetamine, mescaline, pentobarbital and scopolamine. This discrimination paradigm appears to have potential as a model for the quantitative assessment of the discriminative stimulus properties of narcotic antagonist analgesics.

Animals↗
PubMed1977

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat.

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0-30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1-3.0 mg/kg), meperidine (1.0-30 mg/kg), oxymorphone (0.03-1.0 mg/kg), and d-amphetamine (0.1-3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0-30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for selt-stimulation responding were: oxymorphone greater than levorphanol greater than methadone greater than morphine greater than meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for selt-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.

Analgesics, Opioid↗
PubMed1977

Discriminative effects of morphine in the squirrel monkey.

Squirrel monkeys were trained in a two-choice discrete trial avoidance task to discriminate between intramuscular injections of saline and 3.0 mg/kg of morphine. Morphine (0.1-10 mg/kg) produced a dose-related increase in the number of trials completed on the morphine-appropriate lever. The stimulus control produced by the discriminative effects of morphine met the following criteria for classification as a specific narcotic effect: 1) morphine-like stimulus control was produced by all other narcotic analgesics tested (fentanyl, oxymorphone, levorphanol, methadone and meperidine); 2) in so doing, these drugs spanned a 900-fold potency range relative to morphine; 3) stimulus control was blocked by the specific narcotic antagonist naloxone; and 4) stereospecificity was a requirement for stimulus control--levorphanol produced stimulus control equivalent to 3.0 mg/kg of mrophine but its optical isomer dextrorphan did not. The time course of the stimulus control produced by 3.0 mg/kg of morphine showed that the animals continued to respond on the morphine-appropriate lever up to 14 hours after morphine administration. In contrast, monkeys administered 0.01 mg/kg of fentanyl responded on the morphine lever for only as lone as 1/2 hour after fentanyl administration. Naloxone, d-amphetamine and pentobarbital all failed to substitute for morphine, Thus, this study has extended previous observations of the discriminative properties of morphine in rats by demonstrating that qualitatively similar data are produced in a second species, the squirrel monkey.

Analgesics, Opioid↗
PubMed1971

Pouring a denture.

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Denture, Complete↗