Biomedical subjects

G J Schaefer

Publications and source records attributed to G J Schaefer.

At least 19 recordsLinked to original sources

PubMed1992

Effects of amphetamine and nomifensine on intracranial self-stimulation discrimination behavior in rats.

Rats implanted with electrodes in the medial forebrain bundle-lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation [intracranial self-stimulation (ICSS)]. When animals reached a high level of accuracy (95% correct) in the discrimination task, testing was begun. In the first experiment, we compared the effects of saline and 0.3 mg/kg d-amphetamine when the intertrial interval (ITI) was 1, 5, 10, and 15 s. In the second experiment, animals were tested either with saline, 0.3 mg/kg d-amphetamine, or 1, 3, or 10 mg/kg nomifensine and the ITI was held constant at 5 s. Increasing the ITI from 1-15 s did not produce a drug-induced change in the discriminative stimulus properties of ICSS, although it did produce changes in total numbers of lever presses and numbers of intertrial lever presses. In the second experiment, neither d-amphetamine nor nomifensine altered the discriminative stimulus properties of ICSS, but a dose-response increase occurred in the time to complete the test session and in total number of lever presses and in presses on the initiating lever. Under conditions known to increase extracellular dopamine (DA) levels in brain, both amphetamine and nomifensine produced large increases in locomotor activity, but neither drug produced changes in the detection threshold for ICSS. Results indicated that the internal cues produced by ICSS are different from those produced by these psychomotor stimulant drugs.

Amphetamine↗

PubMed1992

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 nicotine's stimulatory effects depending upon the dose and the requirements of the task.

Animals↗

PubMed1992

Schedule-controlled brain self-stimulation: has it utility for behavioral pharmacology?

We review evidence that schedule-controlled intracranial self-stimulation (ICSS) has properties in common with conventional reinforcements, such as food and water, but unlike the latter, animals will respond for ICSS for long periods of time at a near-constant rate. Schedule-controlled ICSS has proven to be more sensitive to drug-induced changes than has ICSS on a continuous reinforcement schedule, and it permits a more fine-grained analysis of the pattern of responding that results in the reinforcement. Evidence is accumulating that the schedule of ICSS itself leads to neurochemical changes in areas of the brain, such as the nucleus accumbens, in which reward processes occur. Results obtained from schedule-controlled ICSS would complement those obtained by drug self-administration studies which generally use intermittent reinforcement. A systematic examination of ICSS schedules at different brain sites would greatly facilitate our interpretation of drug effects and this would have utility for behavioral pharmacology.

Animals↗

PubMed1991

Housing conditions alter the acquisition of brain self-stimulation and locomotor activity in adult rats.

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus (MFB-LH). After recovery from surgery, they were assigned to one of two groups equalized for body weight. One group was housed four animals to a cage and animals in the other group were housed individually. After four weeks in these housing conditions, animals were tested during the fifth week for locomotor activity in five daily 15-min sessions, and their reactivity to handling was also measured. During the sixth and seventh weeks, animals were allowed to self-train for brain stimulation (ICSS) during daily 15-min sessions. Animals housed in groups had higher levels of locomotor activity and were less reactive to handling than were animals housed individually. When tested for the acquisition of ICSS, animals housed as a group made more responses than did animals housed individually. These results indicate that, within the time frame of a few weeks, the housing conditions of adult animals caused differences in both unconditioned behavior, such as locomotor activity, and in the acquisition of a highly reinforcing brain self-stimulation task.

Animals↗

PubMed1990

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 plus d-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) plus d-amphetamine attenuated the graded increase in response rates produced by d-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.

Amphetamine↗

PubMed1989

Interactions between RO 15-4513 and ethanol on brain self-stimulation and locomotor activity in rats.

Experiments were conducted to elucidate the behavioral effects of RO 15-4513, a putative alcohol antagonist, when administered alone or in combination with alcohol. Two groups of animals were trained to lever-press for brain self-stimulation (ICSS) on either a fixed ratio:15 or a fixed interval:15 second schedule of reinforcement. RO 15-4513 (0.1-3.0 mg/kg) reduced the rate of lever-pressing for ICSS in both groups. RO 15-4513 (1.0 mg/kg) further reduced rates when combined with alcohol (0.1-1.7 g/kg), and this effect was especially marked in the fixed ratio paradigm. Other groups of animals were tested in a locomotor activity apparatus. In contrast to the depression of lever-pressing in the ICSS experiments, RO 15-4513 produced a graded increase in locomotor activity. When combined with alcohol (0.1-1.7 g/kg), 1.0 mg/kg RO 15-4513 also increased locomotor activity. Thus, the depression in schedule-controlled behavior was not associated with a generalized behavioral depression. These results demonstrated that RO 15-4513 has potent behavioral effects of its own that are consistent with its classification as an anxiogenic compound.

Animals↗

PubMed1989

Interactions of diazepam and pentobarbital with RO 15-4513 on intracranial self-stimulation discrimination behavior in rats.

Rats implanted with electrodes in the lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation. When a high level of accuracy (95% correct) was attained in the discrimination, testing with vehicle, RO 15-4513, diazepam (1.0-10 mg/kg), diazepam plus RO 15-4513 (1.0 mg/kg), pentobarbital (1.0-17.5 mg/kg) and pentobarbital plus RO 15-4513 began. Diazepam, at 10 mg/kg, disrupted the discrimination behavior, and it also decreased the total number of lever-presses and increased the time to complete the session. These effects were blocked by the coadministration of 1.0 mg/kg RO 15-4513. Pentobarbital produced effects similar to those of diazepam, but these effects were only reversed to a limited extent by RO 15-4513. By itself, however, RO 15-4513 also decreased the total number of lever presses and increased the time to complete the session. Results were consistent with our previous findings with alcohol and RO 15-4513, and supported the notion that diazepam and alcohol have some similar effects at the GABA-benzodiazepine receptor complex.

Animals↗

PubMed1988

Naloxone and diprenorphine reduce responding for brain self-stimulation in a fixed-ratio schedule in rats.

Rats were implanted with bipolar stimulating electrodes in the midbrain-central gray area (MID-CG) and trained to lever-press for intracranial self-stimulation (ICSS) on a continuous reinforcement schedule (CRF). When behavior was stable, animals were tested in 30 min ICSS sessions following the administration of either naloxone or diprenorphine, both over the dose-range 0.001-10 mg/kg, or with vehicle. Following testing on the CRF schedule, animals were re-trained on a fixed-ratio:30 (FR:30) schedule. When behavior had again stabilized, testing with naloxone, diprenorphine and vehicle was repeated. In the CRF tests, neither naloxone nor diprenorphine had any effects on response rates over the 10,000-fold dose-range used. In the FR:30 tests, however, both drugs significantly reduced response rates at the 10 mg/kg dose, and the reduction produced by naloxone was significantly greater than that produce by diprenorphine. These results suggested that diprenorphine is qualitatively similar to naloxone in altering the rate of responding maintained by ICSS, but is less potent than the prototypical opioid antagonist in this paradigm.

Animals↗

PubMed1988

An analysis of the effects of amphetamine on brain self-stimulation behavior.

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus, and trained in one of two brain self-stimulation (ICSS) procedures. One group of animals was trained in the auto-titration procedure which measured response rates and reinforcement thresholds for ICSS. When trained, the animals were tested with D-amphetamine (0.03-1.0 mg/kg) and saline. The second group of animals was trained in a procedure which established the discriminative properties of brain stimulation and which also measured the detection threshold for ICSS. When trained, the animals were tested with D-amphetamine and saline, and were subsequently tested with amphetamine and saline in an activity monitor. A graded decrease in mean reinforcement thresholds was produced by D-amphetamine. The two lower doses (0.03, 0.10 mg/kg) increased the rate of lever-pressing, but the highest dose (1.0 mg/kg) decreased it. No reliable changes in detection threshold occurred, although at the 0.3 mg/kg dose reductions were seen in two of five animals. Animals also showed a graded increase in motor activity with dose as well as increases in several performance measures. These results demonstrated that although amphetamine lowers reinforcement thresholds, it does not reliably alter detection thresholds, suggesting that the motivation to respond for ICSS is changed without any corresponding changes in the capacity to detect the presence of the stimulus.

Animals↗

PubMed1988

Brain self-stimulation, locomotor activity and tissue concentrations of ethanol in male rats.

These studies were aimed at correlating the effects of ethanol on operant behavior and on locomotor activity with its distribution in selected tissues in the body. One group of male rats was trained on a continuous reinforcement schedule for intracranial self-stimulation (ICSS) with electrodes in the lateral hypothalamus. Another group was studied in a locomotor activity apparatus, and both groups were given ethanol intraperitoneally over the dose-range 0.3-1.7 g/kg. Urine was collected 15 min and 60 min after ethanol administration and samples of blood, brain, heart, lung, liver, muscle and testis were obtained at both time points. Depressions of ICSS and of locomotor activity occurred, and these changes in behavior were correlated with increasing concentrations of ethanol in blood, urine and tissue. Thus, the disrupting effects of ethanol on behavior which occurred shortly after its acute administration were closely linked to its concentrations throughout the body.

Animals↗

PubMed1988

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.

Animals↗

PubMed1987

Self-training for brain stimulation in the medial forebrain bundle of rats: a comparison of saline with amphetamine.

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus (MFB-LH). Following recovery from surgery, they were placed in 3 groups prior to brain self-stimulation training. This consisted of one 15-min session on each of 5 consecutive days. Animals in the first group (controls) were placed in a conventional, single lever operant chamber without any additional manipulation. There were no priming stimuli, there was no experimenter intervention of any kind, and no exteroceptive cues in the chamber to indicate the availability or otherwise of the reinforcement. Animals in the second group (saline-injected) were treated similarly to the first group except that they were weighed and injected subcutaneously with saline (1 ml/kg) immediately before being placed in the chamber. Animals in a third group (D-amphetamine-injected) were weighed and administered D-amphetamine (0.5 mg/kg in saline) immediately before being placed in the chamber. The number of lever-presses made per 15-min session was recorded. In addition, the time taken to achieve a lever-pressing rate of 10 presses per min was recorded. There were no significant differences between groups in the number of presses per 15-min session. Animals administered D-amphetamine reached the rate of 10 presses per min significantly more rapidly than animals administered saline, but the latter did so significantly more rapidly than controls. These results demonstrated that the simple manipulation, and perhaps the mild stress, associated with a saline injection strongly affected the acquisition of a brain self-stimulation task.

Animals↗

PubMed1986

Task-specific effects of nicotine in rats. Intracranial self-stimulation and locomotor activity.

The acute effects of nicotine (0.03-1.0 mg/kg) were studied in a locomotor activity procedure and in a series of intracranial self-stimulation (ICSS) paradigms. Nicotine produced a dose-dependent decrease in locomotor activity. When animals were trained to lever-press for intracranial self-stimulation on a continuous reinforcement schedule (CRF), the drug was ineffective except at the 1.0 mg/kg dose, which produced a moderate decrease in the rate of responding. However, when animals were tested in a fixed-ratio:15 (FR:15) paradigm, nicotine produced a steep, biphasic dose-response curve. At the 0.1 mg/kg dose, the response rates were increased to approx. 60% above baseline, while at the 1.0 mg/kg dose, response rates were decreased to approx. 90% below baseline values. The effects of nicotine were also studied in an auto-titration procedure which measured the rewarding value of the stimulus. There was a decrease in performance at larger doses similar to that observed in the continuous reinforcement procedure, but there were no significant changes in the threshold for reinforcement. Nicotine did not produce any change in the detection threshold for stimulation of the brain. In acute studies, therefore, nicotine produced both stimulation and disruption of behavior, effects that were brought to light by the fixed-ratio schedule of reinforcement, and this may relate to the rewarding effects of nicotine.

Animals↗

PubMed1986

An automatic device for measuring speed of movement and time spent at rest: its application to testing dopaminergic drugs.

We describe a device to measure speed of movement and time at rest for use with a commercially available infrared photobeam activity monitor. This system is a reliable substitute for a human observer and provides additional measures of activity that can help in interpreting how psychoactive drugs alter behavior. The effects of graded doses of d-amphetamine, haloperidol and (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine, (-)-3-PPP, were studied with the device, and the results confirmed that these drugs differentially alter speed of movement and time at rest.

Animals↗

PubMed1986

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.

Animals↗

PubMed1985

The discriminative stimulus properties and detection thresholds of intracranial self-stimulation: effects of d-amphetamine, morphine, and haloperidol.

A two-choice discrimination task was used to evaluate the effects of psychoactive drugs on the discriminative stimulus properties of brain self-stimulation in rats. In these experiments, brain stimulation served both as a discriminative stimulus and as a reinforcing stimulus, but the two effects were manipulated separately. Animals were trained to a criterion of 95% correct in choosing between two levers, and when this level of accuracy was reached, the ability to choose correctly remained stable over an 8-month period. Increasing the current strength of the discriminative stimulus from zero to 100% of the training current produced a graded increase in the number of trials completed on the appropriate lever. The discriminative effects produced by brain stimulation were evaluated pharmacologically by using three prototypical psychoactive drugs in an attempt to change the detection threshold for the discriminative stimulus. Morphine, d-amphetamine, and haloperidol, drugs that reliably alter reinforcement thresholds for brain stimulation, failed to change detection thresholds. These results demonstrated that: brain stimulation produces potent and reliable discriminative effects and the effects of psychoactive drugs on detection thresholds can be dissociated from their effects on reinforcement thresholds for brain stimulation.

Animals↗

PubMed1985

Effects of opioid antagonists and their quaternary derivatives on locomotor activity and fixed ratio responding for brain self-stimulation in rats.

Rats were implanted with stimulating electrodes aimed at the midbrain-central gray area (MID-CG) and trained to lever press for brain stimulation (ICSS) on a fixed ratio:30 (FR:30) schedule of reinforcement. When response rates were stable, animals were administered either naloxone hydrochloride, naltrexone hydrochloride, naloxone methobromide or naltrexone methobromide in a dose range of 0.1-30 mg/kg. Fifteen minutes after the subcutaneous administration of either drug or vehicle, animals were tested for 45 min in the ICSS procedure and changes in response rates following drug administration were compared with those following vehicle administration. Both naloxone and naltrexone hydrochloride produced graded decreases in responding over the entire dose range, while naloxone and naltrexone methobromide did not alter response rates at any dose level. In a separate testing procedure, 30 mg/kg naloxone and naltrexone hydrochloride produced modest reductions in motor activity, while the methobromide derivatives did not. These results demonstrated that the fixed ratio procedure was sensitive to changes in responding for ICSS produced by opioid antagonists, and this effect depends upon the entry of these opioid antagonists into the brain.

Animals↗

PubMed1984

Drug interactions on spontaneous locomotor activity in rats. Neuroleptics and amphetamine-induced hyperactivity.

The locomotor activity of female rats was recorded during 10-min sessions in a circular open-field apparatus after the administration of vehicle or drug. Dose-response curves were obtained for seven neuroleptic drugs both alone (spontaneous activity) and in combination with 1.0 mg/kg of d-amphetamine. Haloperidol, pimozide, loxapine, thiothixene, molindone and chlorpromazine all produced graded decreases in spontaneous locomotor activity. Haloperidol, pimozide, loxapine, thiothixene and molindone also produced graded reversals of the hyperactivity produced by d-amphetamine, while chlorpromazine did not. Clozapine neither altered spontaneous activity nor reversed the hyperactivity produced by d-amphetamine. The data indicate that measures of locomotor activity provide important additional information about the actions of neuroleptics and do not necessarily mirror the actions of these drugs on other measures of performance such as lever-pressing for brain stimulation.

Animals↗