E. Mogilnicka

Drugs affecting dopamine neurons and yawning behavior

Drugs stimulating the dopamine (DA) neurons in different ways (apomorphine, piribedil, amphetamine, nomifensine, L-DOPA) given in low doses (not producing behavioral excitation) induced yawning in rats. Blockade of DA receptors with neuroleptics counteracted DA-agonists induced yawning which may indicate a dopaminergic component of this behavior.

Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

The central stimulant effect of cocaine is generally considered related to its potentiating effect on biogenic amines. However, the individual role and significance of the amines involved in various stimulant effects of cocaine are still a controversial topic. Cocaine is a potent inhibitor of noradrenaline uptake (Hertting, Axelrod, and Whitby, 1961; Ross and Renyi, 1967; Langer and Enero, 1974; Azzaro, Ziance, and Rutledge, 1974), dopamine uptake (Fuxe, Hamberger, and Malmfors, 1967; Ross and Renyi, 1967; Harris and Baldessarini, 1973; Heikkila, Orlansky, Mytilineou, and Cohen, 1975), and serotonin uptake (Ross and Renyi, 1969; Friedman, Gershon, and Rotrosen, 1975). High affinity uptake of tryptophan into synaptosomes is also inhibited (Knapp and Mandell, 1972). In vivo studies have shown that cocaine induces a short-lasting uptake inhibition into brain tissues of noradrenaline (Schanberg and Cook, 1972), dopamine (Fuxe, Ham-berger, and Malmfors, 1967), and serotonin (Ross and Renyi, 1969).

Dihydropyridine calcium channel antagonists reduce immobility in the mouse behavioral despair test; antidepressants facilitate nifedipine action

The effect of the calcium channel antagonists nifedipine, nitrendipine, nimodipine, verapamil and diltiazem in the mouse behavioral despair test was investigated. The dihydropyridine calcium channel antagonists nifedipine, nitrendipine, nimodipine (0.1, 1, 10 mg/kg p.o.) but not the non-dihydropyridine compounds verapamil or diltiazem, dose dependently reduced immobility. Various antidepressant drugs (imipramine, mianserin, citalopram, (+)oxaprotiline) and (-)oxaprotiline in combination with nifedipine facilitated its effect.

Effects of chronic administration of antidepressant drugs on aggressive behavior induced by clonidine in mice

The effects of antidepressant drugs on clonidine-induced aggressive behavior were determined in mice. Imipramine, mianserin and iprindole used in a single dose attenuated clonidine-induced aggression. Their chronic administration enhanced it.

The effect of repeated administration of antidepressant drugs on the responsiveness of rats to catecholamine agonists.

The antidepressant drugs, imipramine (10mg/kg s.c.), amitriptyline (10 mg/kg s.c.), mianserin (2 mg/kg i.p.), danitracen (3 mg/kg i.p.) or the vehicle were administered to rats twice a day for 4 or 10 days. Clonidine (0.5 mg/kg s.c.) induced in rats chronically treated with the compounds studied an increase in locomotor activity but, at the same time, did not affect or decreased this activity in rats chronically treated with the vehicle or a single dose of an antidepressant. This refers, in particular, to imipramine, amitriptyline and danitracen which have a similar effect. This effect, an increase in motility, was most pronounced and common for all the three drugs (after a 4- and 10-day treatment) when clonidine was administered 72 hours after the last dose of an antidepressant. Only in a few cases the amphetamine-induced hypermotility was enhanced by a chronic administration of antidepressants (a 4-day amitriptyline treatment, 72 hours after the last injection; a 4-day mianserin or danitracen treatment, 48 hours after the last injection). The results obtained seem to suggest that a chronic administration of the antidepressant drugs may cause a change in the sensitivity of the central noradrenaline receptors.

Chronic treatment with antidepressants: Potentiation of clonidine-induced aggression in mice via noradrenergic mechanism

The chronic (10mg/kg i.p. twice daily, 10 days)-and not the acute-administration of amitriptyline, maprotiline or zimelidine enhances aggressiveness induced by clonidine in mice. An analogous potentiation of clonidine-induced aggressiveness was obtained with chronic administration (the schedule as above) of levomepromazine (2 mg/kg) or thioridazine (5 mg/kg) but not of spiperone (0.2 mg/kg). Fluoxetine (10 mg/kg), atropine (5 mg/kg), propranolol (10 mg/kg) or metergoline (0.5 mg/kg) given chronically (the schedule as above) also had no effect. The enhancement of clonidine aggressiveness induced by prolonged treatment with imipramine (10 mg/kg) was prevented by cycloheximide, an inhibitor of protein synthesis. The results supply further evidence for the previously proposed hypothesis that chronic administration of antidepressants enhances the responsiveness of central postsynaptic noradrenaline receptors.

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.

The effects of acute and repeated treatment with salbutamol, aβ-adrenoceptor agonist, on clonidine-induced hypoactivity in rats

A dose-dependent decrease in exploratory activity of naive rats was observed after 5–20 mg/kg i.p. of salbutamol. This effect was antagonized by the pretreatment with propranolol and yohimbine. Furthermore, in a single dose of 5 mg/kg salbutamol increased clonidine-induced hypoactivity. By contrast to acute effects, repetitive administration of salbutamol (5 mg/kg twice daily for 10 days) failed to change exploratory activity of rats and abolished the clonidine-induced hypoactivity. The results demonstrate differences in the acute and chronic effects of salbutamol on behaviour which may indicate changes in the sensitivity of adrenergic pre- as well as postsynapticα-adrenoceptors. Tentatively, the results could be explained by development ofα 2-adrenoceptor subsensitivity and the involvement ofβ-adrenoceptors in the regulation of their activity.

Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with morphine.

Apomorphine in a very small non-stimulant dose 0.05 mg/kg s.c. antagonized the locomotor stimulant effect of morphine (50 mg/kg) in mice. Apomorphine (0.05 mg/kg) antagonized also the locomotor stimulant effect of a single low dose of morphine (2 mg/kg) in the rat as well as “the late stimulatory effect” seen after a higher dose of morphine (10 or 20 mg/kg). The pretreatment with morphine in increasing doses induced an increasing degree of potentiation of stereotyped behavior induced by high doses of apomorphine (0.5 and 2 mg/kg s.c.) in the rat. The apomorphine stereotyped biting/gnawing activity was found strongly increased by morphine (10–50 mg/kg) during the time interval where morphine given alone induced catalepsy. Our results indicate that the acute treatment with morphine may induce an increase of apomorphine sensitive dopaminergic mechanisms. The inhibitory effect by a very small dose of apomorphine (0.05 mg/kg) of morphine stimulation may be due to a presynaptic dopamine receptor stimulant effect of apomorphine. The antagonism by the serotonin antagonist methergoline of morphine catalepsy and the increase by this drug of “the late morphine excitation” indicate in addition a role of a serotonergic mechanism.

REM sleep deprivation changes behavioral response to catecholaminergic and serotonergic receptor activation in rats

The effects of REM sleep deprivation (REMD) on apomorphine-induced aggressiveness and quipazine-induced head twitches in rats were determined. Forty-eight hr of REMD increased apomorphine-induced aggressiveness, and reduced (immediately after completing of REMD) or increased (96 hr after completing of REMD) quipazine-induced head twitches. Results are discussed in terms of similarity to pharmacological effects of other antidepressive treatments.