Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food.

The effect of intraventricular infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), was examined in rats trained on a progressive ratio schedule for either IV cocaine or food reinforcement. Animals in the 5,7-DHT treatment group responded to significantly higher breaking points than vehicle-injected control animals, regardless of whether food or cocaine was used as the reinforcing stimulus. Analysis of the regional brain amines indicated that depletions of mesencephalic 5-HT correlated with postsurgical alterations in responding. These findings suggest that depletion of forebrain 5-HT produces a general effect on responding rather than a specific alteration in the reinforcing effects of psychomotor stimulant drugs.

Structural correlates of neurological signs in Huntington's disease: a quantitative approach.

Huntington's disease (HD) is a genetically transmitted disorder associated with atrophy of the basal ganglia. Studies of the neuroanatomical correlates of HD have focused primarily on the anterior areas of the basal ganglia and on establishing an association between structural changes resulting from the presence and course of the illness. The objective of the present study was to assess the value of measurements of the third ventrical and lentiform regions. Computed tomographic (CT) brain scan measures of the basal ganglia of patients in the "early" and "late" stages of the disease were correlated with scores on a quantified neurological examination (QNE) and compared with scans of age-matched control groups. Basal ganglia atrophy was assessed by two conventional "anterior" measures: the maximal distance between the frontal horns of the lateral ventricles (FH) and the minimum distance between the caudate nuclei (CC), and two measures of more "posterior" regions: the width of the third ventricle (3V), and a measure of the lentiform regions (LENTI). In the group of patients with HD, CT scan measures were strongly correlated with disease duration. Further, in the "late" group, all CT measures were significantly correlated with QNE scores, with the two "posterior" measures being equally, if not more strongly correlated with QNE scores than the conventional "anterior" measures. Separate correlations of the CT indices of atrophy and QNE scores in the "early" and "late" HD groups revealed relationships between basal ganglia atrophy and motor abnormality consistent with earlier reports.

Evaluation of response perseveration of rats in the radial arm maze following reinforcing and nonreinforcing drugs.

The behavioral effects of three drugs with high abuse potential (amphetamine, heroin, and nicotine) and two substances with low abuse potential (haloperidol and scopolamine) were evaluated in an eight-arm radial maze. Rats were trained to explore the maze for the food reward. Unlike most radial arm maze paradigms, a food pellet was made available every time the rat entered an arm; thus, no external restrictions were placed upon rats' exploratory pattern. Following 3 days of drug-free training, rats were injected prior to testing with one of the five drugs. Analysis of the sequences of arm entries demonstrated that the variability of the search strategy was significantly decreased by amphetamine, heroin, and nicotine. In contrast, scopolamine and haloperidol either decreased or had no effect on preservation. These data, along with previous data on ethanol and diazepam, lead to the speculation that drugs of abuse may share the common property of reducing behavioral variability.

Clozapine increases breaking points on a progressive-ratio schedule reinforced by intravenous cocaine.

The effect of the atypical neuroleptic clozapine on cocaine self-administration reinforced on a progressive-ratio schedule in rats was examined. The rat's first response on a lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each infusion until the frequency of responding on the lever fell below a criterion level. The final ratio completed was defined as the breaking point. Doses of 5 and 20 mg/kg clozapine produced either no effect or a nonspecific disruption in responding. Rats pretreated with 10 mg/kg clozapine responded to significantly higher breaking points, indicating an increased motivation to self-administer cocaine.

Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin.

The effect of intracerebral injections of 5,7-dihydroxy-tryptamine (5,7-DHT) on cocaine self-administration behavior was assessed. Rats were tested on a progressive ratio (PR) schedule for cocaine reinforcement. The first response on the lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed was defined as the breaking point. Bilateral injections of 5,7-DHT into either the medial forebrain bundle (MFB) or amygdala (AMY) significantly increased the breaking points on the PR schedule compared to vehicle-injected control animals. We interpret these data to indicate that depletion of forebrain serotonin increases the incentive value of cocaine.

Reduced behavioral variability in extinction: effects of chronic treatment with the benzodiazepine, diazepam or with ethanol.

Extinction of a food reinforced habit results in an increase in the variability of the response learned in acquisition and in the appearance of previously suppressed competing responses. The purpose of the present study was to examine the effects of chronically administered diazepam (0.0, 1.5, 3.0, or 6.0 mg/kg, IP, -30 min) or 10% ethanol (0.0, 1.0, 1.5, or 2.0 g/kg, IP, -15 min) on such behavioral variability in the extinction of radial maze performance. Eight groups of food deprived rats (n = 6) were given one of the forementioned doses for 2 sessions of baseline, 18 sessions of acquisition, and 5 sessions of extinction. In acquisition, eight rewards of two food pellets were obtained on each of three trials in each session. The food well at the end of each arm was rebaited when emptied by the animal, consequently an entry into any arm was reinforced. In baseline and extinction no food was available in the maze. Each session consisted of three 10-min trials. In extinction, compared to treatment with vehicle, both diazepam and ethanol treatments decreased the rate of the instrumental response, arm entry, and increased the variability of the instrumental response and of competing responses. Only the effects of the drugs on the competing responses in extinction were greater than those observed in acquisition. It was concluded that the interference-reduction model of drug action best described the magnitude of the drug effects and the variability-reduction model best predicted the direction of the effects.

Rats treated chronically with the benzodiazepine, diazepam or with ethanol exhibit reduced variability of behavior.

The hypothesis that chronic treatment with diazepam or with ethanol reduces behavioral variability, was tested on rats in a radial maze. Eight groups (n = 6) of male Sprague-Dawley rats were given one of eight treatments of diazepam (0.0, 1.5, 3.0 or 6.0 mg/kg, IP, -30 min) or of 10% ethanol (0.0, 1.0, 1.5, or 2.0 g/kg, IP, -15 min) for 2 sessions of baseline and 18 sessions of acquisition. Each session consisted of 3 trials of 8 rewards each. Emptied food wells were immediately rebaited so that an entry into any arm produced a reward of 2 food pellets. Both diazepam and ethanol produced a dose-dependent reduction in the variability of arm choice, reduction in the variability of angle of turn between arms, and reduction in the variability of goal-directed behavior. Correlations between these measures suggested they were not independent. The implications of these reductions in behavioral variability for other effects of anxiolytic drugs are described.

Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment.

Intravenous cocaine self-administration behavior in rats was investigated using a progressive ratio (PR) schedule of reinforcement. The first response on the lever each day produced a drug infusion, whereupon the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed each day was found to be relatively stable, sensitive to changes in dose, and drastically reduced by pretreatment with haloperidol (0.05 mg/kg). We conclude that self-administration behavior of rats reinforced on a progressive ratio schedule can provide useful information about changes in the reinforcing efficacy of specific drugs.