David N. Johnson

A fully automated light/dark apparatus useful for comparing anxiolytic agents

The effects of known anxiolytic agents and putative anxiolytic agents were assessed in mice in a fully automated 2-compartment light/dark test. Significant increases in lit area activities (e.g., time spent in the lit area, locomotor activity, rearing behavior) were used as possible indicators of anxiolytic-like action. The measurement found most consistent and useful for assessing antianxiety-like activity was the time mice spent in the lit area. The benzodiazepine, diazepam; the 5-HT1A agent, ipsapirone; and the 5-HT3 receptor antagonist, ondansetron, produced significant anxiolytic-like activity between doses of 1.0 to 10.0 mg/kg, 17.8 to 31.6 mg/kg, and 0.0001 to 1.0 mg/kg respectively. The 5-HT1A receptor agonist, 8-OH DPAT, also exhibited anxiolytic-like action between doses of 0.0005 to 3.16 mg/kg. In contrast, the peripheral 5-HT3 receptor agonist, N-phenylbiguanide; the antidepressant, imipramine; the neuroleptic, chlorpromazine; and the CNS stimulant, S(+)-amphetamine, did not display antianxiety-like activity. The positive results obtained for the three types of compounds (benzodiazepine, 5-HT1A, and 5-HT3) indicate that this fully automated light/dark apparatus may be useful for identifying known and putative anxiolytic agents.

Effect of diazepam on food consumption in rats

Diazepam significantly increased milk consumption in rats that had never been exposed to this food before but not in rats trained to drink milk. Diazepam failed to increase lever-pressing for food reward except when this behavior had been previously suppressed by the simultaneous administration of electric shock. These data suggest that diazepam does not alter appetite, but enhances the expression of motivation suppressed by instinct or training.

Anxiolytic-like activity of R(+)- and S(−)-zacopride in mice

The effects of the optical isomers of zacopride were assessed in mice in a fully automated two-compartment light/dark apparatus. A significant increase in time spent in the lit area was used as an indication of anxiolytic-like action. Intraperitoneal (i.p.) doses of R(+)-zacopride from 0.00001 to 10.0 mg/kg and S(-)-zacopride from 0.01 to 1.0 mg/kg produced significant anxiolytic-like activity. Oral (p.o.) doses of the R(+) isomer from 0.00001 to 10.0 mg/kg and S(-)isomer from 0.1 to 1.0 mg/kg also generated antianxiety-like action. In addition, R(+)-zacopride (0.0001 mg/kg) was evaluated for time course effects after i.p. and p.o. administration. By either route of injection, the onset to action of R(+)-zacopride was 0.5 h, while the duration of effect was greater than or equal to 16 h. It was concluded that R(+)-zacopride is a potent and long-acting drug and that it is principally responsible for the anxiolytic-like activity of racemic zacopride.

Effects of fenfluramine on sleep-wakefulness in cats.

Five cats were prepared with chronically implanted electrodes for recording sleep-wakefulness patterns. Four of these animals received fenfluramine at each of three dose levels and data was recorded for the following 12 hours. Percent of time in paradoxical sleep was significantly reduced by 2.5 and 7.5 mg/kg, but not by 0.5 mg/kg, of fenfluramine. The higher doses also increased slow-wave sleep and, at 7.5 mg/kg (an anorexigenic dose), total sleep time was significantly increased. Under similar conditions amphetamine, at an anorexigenic dose of 1 mg/kg, significantly suppressed both paradoxical sleep and slow-wave sleep in three cats.Rebound of paradoxical sleep after suppression induced by 2.5 mg/kg of fenfluramine was not seen in either of two cats studied when sleep patterns were recorded for 48 hours. After 7.5 mg/kg of the drug, however, rebound was seen on days 3 and 4 after suppression of paradoxical sleep which lasted for over 26 hours. In two animals, daily administration of 2.5 mg/kg of fenfluramine for 16 consecutive days, followed by saline administration for three days, indicated that tolerance was developing to the suppression of paradoxical sleep produced by the drug.

Contrasting effects of two 5-hydroxytryptamine-depleting drugs on sleep patterns in cats

Abstract Slow-wave sleep increased in cats after administration of a 5-hydroxytryptamine (5-HT)-depleting dose of fenfluramine while it was decreased by p-chlorophenylalanine (pCPA), another 5-HT-depleting drug. Fenfluramine reversed the reduction in sleeping time resulting from pCPA administration and this reversal was blocked by AHR-3009, a 5-HT antagonist. These data suggest that although brain 5-HT levels may not be involved in the sedative action of fenfluramine, sleep was induced by an action on a tryptaminergic pathway.

Comparative effects of ten anorectic drugs on sleep-wakefulness patterns in cats.

Abstract Sleep patterns in chronically prepared cats were determined after administration of approximately equal anorectic doses of each of ten substituted phenethylamine appetite suppressant drugs. Compared to saline, each agent significantly suppressed the incidence of paradoxical sleep while it increased the latency of this phenomenon during the 12 hr after drug administration. Percent time in slow-wave sleep, however, was significantly increased by one drug (fenfluramine), unaffected by another (chlorphentermine), and suppressed by the others. These data support the hypothesis that it is possible to separate anorectic properties from CNS stimulation by appropriate substitutions on the phenyl ring.

AHR-3219, a new antianxiety agent

Abstract 1. 1. AHR-3219 blocked tonic seizures induced by maximal electroshock or pentylenetetrazol in mice in doses comparable to those of diazepam. 2. 2. The drug produced muscle relaxation in mice or cats in doses comparable to or less than those of diazepam, respectively. 3. 3. The antianxiety activity of AHR-3219, as determined in rats by blockade of natural aversion (disinhibition) or of conditioned suppression (conflict behavior), was similar to that seen after diazepam. 4. 4. Lethality studies suggested that AHR-3219 and diazepam were equally toxic after intraperitoneal administration while AHR-3219 was less toxic after oral administration.

AHR-6646: A new, long-acting neuroleptic

1. AHR-6646 blocked d-amphetamine lethality in mice under aggregated conditions when the pretreatment interval was between one hour and seven days. 2. Conditioned avoidance responding in mice and cats was suppressed by AHR-6646 in doses that did not impair escape behavior. The duration of this effect was markedly prolonged. 3. AHR-6646 produced catalepsy in rats. The onset of this effect was delayed and the duration was prolonged when compared with that of chlorpromazine. 4. Apomorphine-induced pivoting in mice with unilateral lesions of the caudate nucleus was suppressed by AHR-6646. 5. AHR-6646 was a potent antiemetic agent in dogs, with a delayed onset and prolonged duration of action.