Inhibition of nitric oxide (NO) production selectively impairs learning and memory in the rat.

Animals administered the nitric oxide (NO) synthase inhibitor N-w-nitro-L-arginine methyl ester (NAME) for five days exhibited severe deficits in acquisition of a place-navigation learning task. The effect of NAME was selective to place-navigation learning. NAME had no effect on sensorimotor or motivational processes in a related task. These results are consistent with the view that NO participates in learning and execution of memory tasks.

CGS 8216 treatment decreases central-type benzodiazepine receptors in rat brain.

Central- and peripheral-type benzodiazepine receptors were analyzed in several brain areas of rats (n = 8-9) that had been treated for five days with CGS 8216 (20 mg/kg per day). Twenty-four hours after cessation of drug treatment a significant decrease of central-type benzodiazepine receptors as labeled by [3H]beta-carboline-3-carboxylate ethyl ester ([3H]beta CCE) and [3H]flunitrazepam ([3H]FNZ), but not of peripheral-type benzodiazepine receptors as labeled by [3H]RO 5-4864 could be observed in the animals treated with CGS 8216.

Differential effects of benzodiazepine receptor ligands on isotonic saline and water consumption in water-deprived rats.

Water-deprived male rats were adapted to a 30 min test of water or saline drinking in a single-bottle acceptance test. The potent benzodiazepine agonist, clonazepam, produced significant increases in both water and saline consumption. Increases in the consumption of both were also obtained with the non-benzodiazepine agonist, zopiclone (a cyclopyrrolone), but not with the pyrazoloquinoline agonist, CGS 9896. Hence, some, but not all, benzodiazepine receptor agonists enhance drinking responses. The benzodiazepine receptor antagonists, Ro15-1788 and CGS 8216, had no significant effect on the intake of either isotonic saline or water. In contrast, the beta-carboline FG 7142, which has been described as an inverse agonist acting at benzodiazepine receptors, reduced both saline and water drinking at 10 and 20 mg/kg. Although the baseline level of saline drinking was considerably higher than that of water, there was no general indication that any drug effect on consumption interacted with the type of fluid in the drinking test. However, in the case of agonist-induced increases in consumption, peak effects occurred at different doses; they were lower for saline- than for water-drinking.

Benzodiazepine receptor-mediated effect of CGS 8216 on milk consumption in the non-deprived rat.

The pyrazoloquinoline CGS 8216, which binds with high affinity to central benzodiazepine recognition sites, produced a highly significant reduction in the consumption of familiar, sweetened milk by non-deprived male rats, when administered in a dose of 20 mg/kg, IP. The anorectic effect was present during the first 5 min period of a 20-min drinking test, and remained in evidence throughout the remainder of the test. The benzodiazepine receptor antagonist Ro15-1788, administered 15 min before the consumption test, produced a dose-related (10-40 mg/kg, IP) reversal of the anorectic effect of CGS 8216, during the first 10 min of the test. Injection of Ro15-1788 alone had no significant effect on milk ingestion. This experiment shows that the reduction in the consumption of a palatable liquid food by CGS 8216 can be attributed to an action at benzodiazepine receptors. The result is consistent with the characterization of CGS 8216 as a weak benzodiazepine receptor inverse agonist.

Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors.

Drugs which are agonists at benzodiazepine receptors produce many interesting behavioural effects, and amongst these are the stimulation of food, water and salt intake. This review examines the evidence for benzodiazepine effects on these forms of ingestion, and makes tentative proposals about their modes of action. The recent advent of putative benzodiazepine antagonists and inverse agonists provides important new pharmacological tools for the analysis of factors which control ingestion. Preliminary data on examples of such drugs are considered. Anorectic effects of inverse agonists are described. It is clear, though, that the categorization of a drug in one test situation may not apply to another. For example, the compound Ro15-1788 appears as a specific antagonist in one test, a partial agonist in another, and apparently lacks effect in a third. We are not yet sufficiently forward in our understanding of drug actions at benzodiazepine receptors, and their interactions with particular test circumstances, to predict and account for divergent effects of this kind.

Effects of chlordiazepoxide and of valproate on hyponeophagia in rats. Evidence for a mutual antagonism between their anxiolytic properties.

The effects of chlordiazepoxide (0,2.5 and 7.5 mg/kg), of valproate (0,100 and 300 mg/kg), and of combinations of these drugs, on hyponeophagia in rats, were studied using a food preference test. Chlordiazepoxide alone reduced the latency for eating, and also enhanced the time of eating and the amount of familiar food eaten at the smaller dose, and of novel food eaten at the larger dose. Valproate alone reduced the latency of eating and enhanced time of eating and the amount of novel food eaten, especially at 300 mg/kg. However, valproate antagonised the effects of chlordiazepoxide on all behavioural measures. These findings are discussed in the context of the GABA hypothesis of the actions of benzodiazepines, with the conclusion that valproate has an atypical pharmacological profile amongst putative GABA agonists, and may have partial agonist activity at the proposed benzodiazepine/GABA receptor complex.

Anxiolytic actions of chlordiazepoxide determine its effects on hyponeophagia in rats.

The effects of chlordiazepoxide (0, 5, 15 mg/kg) on eating latency, eating time and amount eaten of familiar and novel foods by rats were assessed. Familiarity with the test apparatus and procedure increased feeding but reduced responsivity to chlordiazepoxide (5 mg/kg). Food deprivation increased feeding and responsivity to 5 mg/kg chlordiazepoxide but attenuated some sedative effects of 15 mg/kg chlordiazepoxide. Preference for familiar food was shown only by food-deprived, test-experienced rats. The time devoted to eating novel food, but not the amount eaten, was increased by chlordiazepoxide. These findings are discussed in the context of anxiolytic and appetitive interpretations of benzodiazepine effects on hyponeophagia , with the conclusion that reduction in apparatus neophobia largely accounts for the results observed.