Jeffrey B. Malick

Differential antagonism of the anticonflict effects of typical and atypical anxiolytics

Selected benzodiazepine and non-benzodiazepine agents were studied alone or in the presence of benzodiazepine antagonists in the shock-induced suppression of drinking (SSD) procedure in rats. The disinhibitory activity of chlordiazepoxide, CL218,872, zopiclone and CGS 9896 was antagonized by two benzodiazepine antagonists, RO-15-1788 and CGS 8216. In contrast, the disinhibitory activity of fenobam, meprobamate, phenobarbital and tracazolate was not antagonized by either RO 15-1788 and CGS 8216. From these data it is apparent that the anticonflict activity of agents that bind to benzodiazepine receptors is blocked by benzodiazepine antagonists. In contrast, the activity of anxiolytics that are not displacers are unaffected even at higher doses.

The role of serotonergic pathways in isolation-induced aggression in mice.

Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed between potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced aggression is discussed.

Quipazine-induced head-twitch in mice ☆

Quipazine has been reported to be a direct serotonin receptor agonist. In this laboratory, quipazine produced head-twitch in mice similar to that produced by the serotonin precursor, 5-hydroxytryptophan (5-HTP). Three antiserotonergic drugs (methiothepin, methysergide, and cinanserin) antagonized both the 5-HTP and quipazine-induced head-twitch responses. In addition, the quipazine response was significantly potentiated by a monoamine oxidase (MAO) inhibitor, pargyline. Since it is not likely that quipazine itself is metabolized by MAO, these results suggested that quipazine might cause release of endogenous serotonin. Parachlorophenylalanine, a serotonin depletor, significantly antagonized the potentiation of quipazine by the MAO inhibitor but failed to antagonize the head-twitch produced by quipazine itself. The present studies suggest that quipazine influences serotonin receptors in the brain to produce head-twitch by two mechanisms of action: (1) by direct serotonin receptor activation, and (2) indirectly by causing a release of endogenous serotonin.

Effects of age and food deprivation on the development of muricidal behavior in rats

The induction of muricidal behavior in the rat, under various experimental conditions, was studied in order to determine whether mouse killing is a form of predatory aggression that is closely related to feeding behavior. Rats of various ages were socially isolated and subjected to various degrees of food deprivation to determine whether the same laws that govern feeding also govern muricidal behavior. The age of the rat at the beginning of the study (8, 12 or 18 weeks of age) did not appear to significantly affect the induction of muricide by food deprivation. Chronic food deprivation caused non-killer rats to kill mice. In addition, the severity of the food deprivation influenced the induction of mouse killing such that the greater the degree of deprivation, the greater the number of rats that became killers. The effects of food deprivation on the induction of mouse killing were reversed by giving the rats access to food ad lib. Since many of the laws that govern feeding also appear to be the laws which govern mouse killing, the two behaviors may be highly inter-related.

The evaluation of anti-parkinson drugs on reserpine-induced rigidity in rats

The effect of anti-parkinson drugs on reserpine-induced rigidity was examined using a technique which measured rigidity by hind limb palpation. Centrally acting dopaminergic and anti-cholinergic drugs were able to antagonize reserpine-induced rigidity, whereas peripherally acting drugs had no effect. Results are discussed in terms of possible modes of action. Relative potencies of the drugs studied in this model were well correlated with the dose ranges of clinically established anti-parkinson drugs. It is concluded that measurement of reserpine-induced rigidity by hind limb palpation is a rapid and sensitive technique to evaluate potential anti-parkinson drugs.

Selective antagonism of isolation-induced aggression in mice by diazepam following chronic administration.

Benzodiazepines are non-selective (i.e., they only inhibit aggression at doses producing concurrent neuromuscular impairment) antagonists of isolation-induced aggression in mice following acute administration. However, in the present study diazepam was shown to be a selective antagonist of fighting in isolated mice following chronic administration for 5 days. When administered chronically, selective tolerance rapidly developed to the general CNS depression produced by diazepam whereas the antifighting activity was not diminished and, in fact, tended to be enhanced following multiple drug administrations. Thus, the antagonism of fighting in isolated mice by diazepam does not appear to be due solely to general CNS depressant properties.

Pharmacological antagonism of mouse-killing behavior in the olfactory bulb lesion-induced killer rat

Representative agents from all of the major classes of drugs that have been reported to be selective antagonists of spontaneous mouse-killing behavior (i.e., antidepres-sants, antihistamines, anticholinergics, and stimulants) were tested for their ability to antagonize the mouse-killing response in rats that became killers following removal of the olfactory bulbs (O.B. lesion-induced killer rat) and in spontaneous killers. All of the drugs tested selectively antagonized the killing behavior of both spontaneous and lesion-induced mouse-killing rats. Several drugs (i.e., imipramine, amitriptyline, d-amphetamine, and chlorpheniramine) were found to be significantly less potent antagonists of mouse killing in the 0.6. lesioned rat as compared to spontaneous killers. Since all of the drugs that exhibited significant differences in activity between the two models have been shown to possess the ability to elevate norepinephrine levels at receptor sites in the brain, alterations in noradrenergic systems may account for the differences in sensitivity that were observed in this study. The possibility that there may be a common neural substrate for mouse killing in the two models is discussed.

Inhibition of fighting in isolated mice following repeated administration of lithium chloride

Lithium was found to be a selective (i.e., it antagonized aggression at doses that did not produce concurrent neuromuscular impairment) antagonist of isolation-induced aggressive behavior in mice following repeated (subacute) administration for five days. Acute (single dose) administration of lithium failed to inhibit aggression. At atiaggressive doses, lithium did not produce ataxia as measured by the inclined-screen or rotarod procedures. The mechanism of this action is discussed in terms of a possible influence on serotonergic mechanisms.

Differential effects of d- and l-amphetamine on mouse-killing behavior in rats

Muricidal behavior in rats was selectively antagonized by both the d- and the l-isomer of amphetamine. However, d-amphetamine was approximately 8 times as potent as l-amphetamine as an inhibitor of mouse killing. The results of this study suggest that amphetamine antagonizes muricidal behavior in rats primarily via noradrenergic mechanisms. In addition, these results, as well as those in previous reports, imply that agents which modify the level of activity at central noradrenergic receptors may significantly alter the mouse-killing response of rats.

Antagonism of isolation-induced aggression in mice by thyrotropin-releasing hormone (TRH)

TRH was shown to be an extremely potent (ED50 = 0.04 mg/kg, IP) antagonist of isolation-induced aggression in male mice. The antifighting activity of TRH was selective in that it did not produce concurrent neurological impairment or significant alterations in spontaneous locomotor activity at antiaggressive doses. This activity of TRH appeared to be a direct affect on CNS structures since neither triiodothyronine nor any of the constituent amino acids of TRH antagonized aggression in isolated mice. The results are discussed in terms of the recent clinical effectiveness of TRH in some cases of mental illness (e.g., depression and schizophrenia).