Marianne E. Olds

Effects of d-amphetamine, scopolamine, chlordiazepoxide and diphenylhydantoin on self-stimulation behavior and brain acetylcholine

The effects of d-amphetamine (0.25–8), scopolamine (0.25–8), chlordiazepoxide (2.5–40), and diphenylhydantoin (25–75), given i.p. or s.c. on a mg/kg basis, were studied on self-stimulation behavior in the male albino rat. The dose-effect relationships, the role of baseline rates of responding and their effects on brain acetylcholine (ACh) were determined in rats trained to self-stimulate for electrical reward in the lateral posterior hypothalamus. The effects of d-amphetamine were both dose and baseline-rate dependent. Low-moderate doses (0.5–2.0 mg/kg inclusive) facilitated self-stimulation and larger doses (2.0 to 8.0 mg/kg) depressed responding. Baseline rates before d-amphetamine administration were extremely important in the effect observed. Low rates of responding were facilitated and high rates were depressed by this agent. The effects of scopolamine in a wide range of dosage were less consistent. A small dose (0.5 mg/kg) facilitated only transiently self-stimulation and larger doses (1–8 mg/kg) tended to depress this behavior. Baseline rate effects were less important but high-rate responders were usually depressed by scopolamine.The effects of chlordiazepoxide were dose-dependent. A dose of (5 mg/kg) caused facilitation but larger doses (10–40 mg/kg) produced depression of selfstimulation irrespective of baseline rates. However, high-rate stimulators showed the most dramatic increases with 5 mg/kg of chlordiazepoxide. In contrast, diphenylhydantoin (25–75 mg/kg) usually depressed self-stimulation. Low rate self-stimulators showed the most marked depressant effects.Brain ACh was progressively reduced by handling of naive animals, injection of saline, and 1/2 h of self-stimulation and escape behavior. Animals not allowed to self-stimulate but given d-amphetamine (2.0 mg/kg), scopolamine (2.0 mg/kg) showed a significant decrease in brain ACh. Self-stimulation, in addition to medication with the various drugs, showed a trend for further reduction in brain ACh but the differences were not statistically significant.

Effects of anxiety-relieving drugs on unit discharges in hippocampus, reticular midbrain, and pre-optic area in the freely moving rat

Summary-The effects on unit discharges of various doses of the compounds chlordiazepoxide, meprobamate, sodium pentobarbital, and diazepam were studied in the unanesthetized, unrestrained rat. Recordings of action potentials were made simultaneously in hippocampus, pre-optic region, and the reticular formation of the midbrain. The doses of chiordiazepoxide were 5,10,20 and 40 mgfkg; 5,lO and 20 mg/kg of sodium pentobarbitaf ; 80,100 and 120 mg/kg of meprob~ate, and finally 5,lO and 20 mg/kg of diazepam. In the hippo~mpus, chlordiazepoxide depressed spont~eous activity at every dose used. The reduction ranged from 30 to SO%, but in no case was there inhibition of al1 discharges. Diazepam also had substantial depressing effects on the activity in this region of the brain. In contrast, sodium pentobarbital had relatively minor effects in the lower dose range, but significant depressing effects at the higher doses. Meprobamate also had comparatively small effects in the hippocampus. In the pre-optic area, chlordiazepoxide and meprobamate depressed spontaneous activity at the higher dose range. There were small effects in the lower dose range. Sodium pentobarbital also had minor depressing effects at all doses. Diazepam caused less depression even at the higher doses than either chlordiazepoxide or meprobamate, and these effects were transient. In the midbrain reticular formation, meprobamate caused substantial depression of spontaneous activity even at the lower doses. Sodium pentobarbital similarly depressed activity, but the onset of effect was less delayed than with meprobamate. Chlordiazepoxide at low doses caused less depression of reticular midbrain neurons than of hippocampal or pre-optic region ones. At high doses, the effect was similar to that of meprobamate. The data suggest the possibility of a mode of action of chlordiazepoxide and diazepam which implicates the hippocampus, whereas in the case of sodium pentobarbital and meprobamate, the mode of action appears to implicate the midbrain reticular area. Such a view is based upon comparison of effects at low doses on spontaneous activity of the three regions investigated. CLINICAL studies suggest that chlordiazepoxide may sedate through increasing the wellbeing of the patient rather than depressing him. Studies on animal behavior also report an increase in the animal’s willingness to endure punishment to obtain food or water after chlordiazepoxide (Special Report, 1965). This compound may thus be enhancing positive drives rather than reducing anxiety.

PHARMACOLOGICAL PATTERNS IN SUBCORTICAL REINFORCEMENT BEHAVIOR.

Abstract By means of intercurrent hypothalamic positive reinforcement and tegmental negative reinforcement tests, drug actions on two different brain-stimulated behaviors were assessed simultaneously. Chlorpromazine at 2 mg/kg was effective in antagonizing both hypothalamic positive reinforcement behavior; however, it did produce sustained reduction of tegmental negative but it regularly caused a greater percentage deficit in hypothalamic positive behavior. Meprobamate at 100 mg/kg did not regularly produce lasting reduction of hypothalamic positive reinforcement behavior; however, it did produce sustained reduction of tegmental negative reinforcement behavior. In the case of meprobamate, therefore, there was regularly a greater percentage deficit in tegmental negative behavior. While the imbalanced action of chlorpromazine against positive reinforcement may be explained by aspects of the testing procedure (such as the widely different speeds of the two behaviors) and have no relation to the difference in emotional sign, the opposite imbalanced action of meprobamate makes it quite clear that the two chemicals have quite different modes of action in relation to these brain and behavior tests. The findings with LSD and amphetamine were less informative; LSD had regularly a brief suppressing effect on hypothalamic behavior; amphetamine augmented the slow tegmental negative behavior but often slowed the rapid hypothalamic positive behavior.

Effects of meprobamate, chlordiazepoxide, diazepam, and sodium pentobarbital on visually evoked responses in the tectotegmental area of the rat.

The effects of meprobamate, chlordiazepoxide, diazepam and sodium pentobarbital on sensory input to the boundary area between the dorsal midbrain tegmentum and ventral tectum of the rat have been investigated in order to find out whether effects obtained with these compounds in the hypothalamus can also be observed at the mesencephalic level. The following results have been obtained. (1) At a dose of 2·5 mg/kg i.p., chlordiazepoxide had no effect; at 5, 10, 15, and 20 mg/kg, this compound decreased the amplitude of the initial components of the visually evoked responses in the rat. There was an increased effect at higher doses. (2) Diazepam had effects similar to those produced by administration of chlordiazepoxide. The evoked responses were of smaller amplitude after injection of 5, 10, and 20 mg/kg i.p. At the highest dose, diazepam caused larger reductions in amplitude than chlordiazepoxide at 20 mg/kg. (3) Meprobamate at 40, 80 and 100 mg/kg i.p. increased the amplitude of the evoked responses. There was more individual variation with this compound than with chlordiazepoxide, and more waxing and waning of the effects, but little difference in the magnitude of facilitation at the various doses. At a dose of 120 mg/kg, the size of the evoked responses decreased. (4) At doses of 5, 10, and 20 mg/kg i.p., sodium pentobarbital caused increases in the amplitude of the evoked responses. Only at a dose of 20 mg/kg was there a slight decrease in amplitude, lasting only 25 min after drug administration. Thereafter, responses to this dose were larger than control responses, but not as large as responses to the two smaller doses. The significance of these results is discussed in the context of earlier data on the effects of these compounds and the barbiturates on sensory input to the midbrain reticular formation. A difference in mode of action, at low doses, is shown by the data. A relationship between the effects of meprobamate and the barbiturates on sensory input in the rat finds support in these results.

Subcortical lesions and Maze Retention in the Rat

With intracranial electric shock in the posterior hypothalamus as the source of positive reinforcement, eleven rats were trained to run and “count” in an operant version of the Lashley III maze. In seven animals, bilateral lesions were made in anterior medial forebrain bundle regions; in four animals bilateral lesions were made in anterior thalamic and caudate regions. In earlier experiments anterior medial forebrain bundle lesions had failed to abolish a simple Skinner box behavior rewarded by electric stimulation in the posterior hypothalamus. The possibility was raised that if the response were more complex, lesions in anterior medial forebrain bundle, severing connections between paleocortex and hypothalamus, might cause deficits. The data confirmed this supposition. Four weeks after lesions in anterior medial forebrain bundle, there was almost total deficit in maze and counting behavior. Thirteen weeks after lesions some recovery had occurred, but counting still showed large deficits. Independent Skinner box tests showed that most of these rats were still reinforced by the hypothalamic stimulation. Lesions in thalamic and caudate areas caused minor and temporary deficits. The conclusion was drawn that paleocortical-hypothalamic connections are important when hypothalamic stimulation is used to reinforce behaviors which are complex in character in the sense of drawing upon memory or integrative factors.

Effects of electrical stimulation and electrocoagulation in cortex and thalamus on delayed response in monkeys.

Abstract Eighteen brain points in prefrontal and thalamic areas of each of three adult male macaques were tested for the effects of electrical stimulation and coagulation during the delayed response test. During the delay period, stimulation of prefrontal areas and dorsomedial thalamus caused severe impairment in two subjects. Stimulation caused less impairment during the baiting period than during the delay period; continuous stimulation throughout the test caused less impairment than intermittent stimulation; intermittent stimulation throughout the test was the most effective mode of stimulation. Distraction tests produced the same standard of performance achieved during control tests; peripheral shocks produced a slightly impaired performance. Even aversive peripheral stimuli did not produce as many errors as did central stimuli which produced no behavioral effects. Prefrontal lesions had more disruptive and longer-lasting effects than did thalamic lesions, but the order in which the lesions were made had no effect on performance. The results substantiate previous conclusions that electrical stimulation of points along the banks of the principal sulcus can impair the delayed response performance of overtrained subjects, but, on the other hand, stimulation of dorsomedial nucleus of thalamus has the same effect.

Relation of rat brain acetylcholine levels to duration of self-stimulation and escape behavior

Total brain acetylcholine (ACh) was assayed in groups of animals after various periods of operant responding maintained by electrical stimulation of the lateral posterior hypothalamus or of escape behavior induced by electrical stimulation of the midbrain tegmentum. Different groups of trained rats were placed in identical Skinner boxes for periods of 1 to 24 hr. The following groups were studied: controls, self-stimulators receiving electrical stimulation, escapers from brain stimulation or peripherally applied aversive stimulation, self-stimulators not receiving electrical stimulation prior to decapitation, tubocurarine-paralyzed respired rats with electrodes in the posterior-lateral hypothalamus not receiving stimulation, and a group of tubocurarine-paralyzed, respired rats receiving electrical stimulation automatically. It was found that brain stimulation decreased total brain ACh, regardless of whether the stimulation was positive, as during self-stimulation behavior, or negative, as during escape behavior. Animals that receivied positive stimulation while being paralyzed showed similar decreases in total brain ACh, but the change in ACh was smaller. No changes occurred in animals that were paralyzed that recieved no electrical stimulation. It is concluded that brain usage produced by electrical stimulation of discrete functional pathways causes a reduction of total ACh, but this is unrelated to the specific motivational properties of the electrical stimuli.