Dihydropyridine calcium channel antagonists as antidepressant drugs in mice and rats.

A pharmacological profile of the effects of nimodipine, nifedipine and nitrendipine (2.5-20 mg/kg p.o.) in several models which are indicative of possible antidepressant activity, was tested in mice and rats. These compounds, as well as verapamil (short-lasting effect), but not diltiazem, reduced the hypothermia induced by a large dose of apomorphine in mice. Nimodipine and nifedipine slightly increased the behavioural action of L-DOPA in mice, and nimodipine facilitated the action of imipramine in the L-DOPA test. Nimodipine, nifedipine, verapamil and diltiazem slightly reduced the clonidine-induced hypoactivity in rats. The hypothermia induced by reserpine or clonidine in mice was not changed by these drugs. Various antidepressants (imipramine, amitriptyline, citalopram, mianserin) used in the behavioural despair test in mice, in doses which were not effective by themselves, increased the immobility-reducing effect when given jointly with 1,4-dihydropyridine calcium channel antagonists (5 mg/kg). The above results indicate that the psychopharmacological profile of nimodipine, nifedipine and nitrendipine resembles that of antidepressants in some tests only; moreover, these results support the assumption that concomitant administration of antidepressants and 1,4-dihydropyridine calcium channel antagonists may result in a greater antidepressant efficacy.

Forced swimming test in rats: effect of desipramine administration and the period of exposure to the test on struggling behavior, swimming, immobility and defecation rate.

The effect of desipramine administration and the duration of the daily exposure to forced swimming on some variables has been studied in adult male rats. Desipramine administration (15 mg/kg) significantly increased struggling behavior in the first and second 5-min periods of a single exposure to forced swimming. Swimming was reduced in the first 5 min and remained unchanged thereafter. Immobility was decreased in the second and the third 5-min periods. After a pre-exposure to forced swimming for 15 min the day before, the drug was effective in increasing struggling behavior and reducing immobility during a subsequent 5-min test. Swimming was not modified. Daily exposure to forced swimming for 3 days caused a decline in struggling behavior and swimming, while increasing immobility and the defecation rate. The duration of daily exposure to forced swimming did not alter the changes in the variables measured. The present results indicate that a one-day test can be used to discriminate between saline- and desipramine-treated rats, and that struggling behavior could be a reliable measure of the positive action of antidepressants. The finding that behavioral changes over the 3 days were independent of the duration of exposure to swimming argues against the interpretation of the results which suggest that the responses are caused by the appearance of a behavioral despair state, and suggests that these behaviors might be trait-markers in the rat. In addition, the changes in struggling behavior and immobility over the 3 days cannot be attributed to a behavioral adaptation to the test because the defecation rate increased rather than decreased during successive forced swimming tests.

The effects of tryptophan and manipulations of serotonergic receptors on tonic immobility in chickens.

The effects of serotonergic manipulations on tonic immobility (TI) were examined. Systemic injections of tryptophan enhanced TI duration. This effect was reversed by quipazine, a 5-HT receptor agonist, and p-chloroamphetamine, a 5-HT releaser. Separately, these drugs caused marked reductions in TI duration. Fenfluramine, which promotes 5-HT release, also reduced TI duration. The quipazine attenuation of TI was prevented by pretreatment with the 5-HT receptor blocker cinanserin. The results are discussed in terms of 5-HT receptor mechanisms and the raphe model of tonic immobility.

Tonic immobility in domestic fowl: possible interaction of serotonergic and dopaminergic mechanisms.

Treatment with the dopamine (DA) receptor blocker, haloperidol, enhanced tonic immobility (TI) duration. Fenfluramine, a receptor agonist for serotonin (5-HT), reversed this effect. Tryptophan produced long TI reactions, and is believed to do so due to impaired synaptic transmission of 5-HT following its direct inhibitory effects on 5-HT neurons. DA receptor stimulation by apomorphine prevented the tryptophan potentiation of tonic immobility. The results suggest that serotonergic and dopaminergic systems may interact with respect to tonic immobility.

Immobility test: effects of 5-hydroxytryptaminergic drugs and role of catecholamines in the activity of some antidepressants.

Fenfluramine and m-chlorophenylpiperazine, two drugs purported to enhance central 5-hydroxytryptaminergic transmission, and metergoline, a 5-HT antagonist, did not modify the duration of immobility induced in rats made to swim in a restricted space. Nomifensine, desipramine and amineptine, three antidepressants known to block neuronal catecholamine uptake, significantly reduced the duration of immobility. Penfluridol, a dopamine antagonist at central receptors, counteracted the effect of nomifensine and amineptine but not that of desipramine. Propranolol and phenoxybenzamine respectively reduced the effects of desipramine and nomifensine but did not modify amineptine's effect. Metergoline pretreatment did not counteract the effect of any drug. The results indicate that various antidepressants can reduce the duration of immobility in rats by activating dopaminergic and/or noradrenergic mechanisms in the brain. Either alpha- or beta-noradrenergic receptors could contribute to the anti-immobility effects, depending on the drug used. The immobility test appears to be insensitive to drugs activating or reducing 5-HT-ergic mechanisms in the brain.

The effect of antidepressants on behavioral despair in rats.

A possibility of inducing immobility in rats immersed in a cylinder filled with water from which they cannot escape was confirmed. The period of active attempts to escape from the cylinder was lengthened by injecting the animals with the following antidepressants: imipramine (IMI), amitriptyline (AMI), doxepin (DOS), mianserin (MIA), danitracen (DAN), iprindole (IPR), as well as cyproheptadine (CYP), even if they were administered only once. Femoxetine (FEM) produces no effect,. The swimming activity of rats diminished gradually to ca 15% of the initial value if experiments were repeated during 7-8 consecutive days. A chronic administration of IMI in a dose of 10mg/kg daily counteracted this phenomenon, and when the drug had been given for 10 days before the immersions were started, it presented the decrease in the activity.

Central action of mepiprazole.

Mepiprazole, a phenylpiperazine derivative, strongly antagonizes the behavioral syndromes evolved by 5-hydroxytrypotophan. The drug did not affect the serotonin neurons in the preparation of flexor reflex of the hind paw of the spinal rat: in higher doses it depressed the reflex showing noradrenolytic properties. Mepiprazole antagonized the fenfluramine-induced hyperthermia, depressed spontaneous locomotor activity, produce hypothermia and was inactive in the despair test. The results suggest that mepiprazol may have noradenolytic properties; its possible influence on the serotonergic system is masked by noradrenolytic properties and hence difficult to demonstrate.

Animal model of depression.

A behavioural procedure is described which may provide an animal model for some aspects of human depression. Rats or mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Immobility is reduced by many clinically effective antidepressant treatments suggesting that the immobile behaviour may reflect a state of lowered mood in the animal. If so the method could be useful as a simple experimental tool for research into the biology and therapeutics of depression.

Tonic immobility: effects of dopamine receptor blockade and stimulation.

Blockade of dopaminergic receptors by haloperidol enhanced the duration of tonic immobility in chickens. Apomorphine, a dopamine receptor agonist, produced short durations. Apomorphine also produced an increase in stabilimeter activity. These data suggest dopaminergic involvement in tonic immobility, and support a competing response interpretation of the apomorphine effect.

Classical conditioning of hippocampal theta patterns in the rat.

Electrical stimulation (88 HZ) of the lateral hypothalamus elicited a sustained theta response at hippocampal recording sites of rats immobilized with succinylcholine. By pairing this unconditioned stimulus with a 10-sec presentation of a light, conditioned theta responses were demonstrated in as few as 40 trials. Spectral analysis of hippocampal bioelectric patterns during acquisition, extinction, and reconditioning indicated that the earliest change as a result of conditioning is a loss of power in EEG frequency below 8 HZ, followed by the development of a peak at 8 HZ with further conditioning. Extinction was associated with an increase in power in the frequencies below 8 HZ. When the conditioned rats were tested in the absence of the neuromuscular blocking agent, the conditioned stimulus elicited a theta response that was associated with slow motor activity on 70% of the trials.