Pharmacological studies on the antagonism by antidepressants of the hypothermia induced by apomorphine.

In male Swiss mice, the hypothermia induced by apomorphine (10 mg/kg) was completely blocked by administration of haloperidol and d-butaclamol, but not by l-butaclamol, phenoxybenzamine, clozapine or propranolol. This substantiated the dopaminergic nature of the hypothermia induced by apomorphine. Desipramine, imipramine, chlorimipramine, fluoxetine and mazindol produced a dose-dependent blockade of apomorphine-induced hypothermia, their ED50S being 0.313, 0.733, 1.88, 6.04 and 0.0033 mg/kg, respectively. Iprindole failed to block the hypothermia induced by apomorphine. Because chlorimipramine and fluoxetine, which are relatively more selective and more potent blockers of the uptake of serotonin (5-HT) than is desipramine, were considerably less effective than the latter in antagonizing hypothermia induced by apomorphine, it was concluded that the property of blocking uptake of 5-HT alone does not contribute to the antagonism to apomorphine exhibited by the classical antidepressants. Quipazine, a 5-HT agonist, blocked the hypothermia induced by apomorphine, this effect developed tolerance on repeated administration. However, no cross-tolerance between quipazine and the antidepressants could be demonstrated. This finding provided further support for the non-involvement of 5-HT in the antagonism to apomorphine. No correlation existed between the potencies of these antidepressants to block the reuptake of norepinephrine (NE) in brain and their relative potencies to block the hypothermia induced by apomorphine. Moreover, selective depletion of high affinity binding sites for [3H]desipramine and [3H]-NE, achieved by treatment with DSP-4, failed to reduce the effectiveness of desipramine in blocking the hypothermia induced by apomorphine. Hence, inhibition of uptake of NE does not account for the antagonism by the antidepressants of apomorphine-induced hypothermia. A possibility was considered that certain antidepressants selectively blocked the hypothalamic DA receptors, thereby antagonizing the hypothermic effects of apomorphine, leaving the extra-hypothalamic dopaminergic responses of this DA agonist unaffected.

Evidence for presynaptic antagonism by amantadine of indirectly acting central stimulants.

In mice, amantadine pretreatment (150 mg/kg, but not 10 mg/kg, 2 h prior to testing) markedly inhibited the locomotor stimulation produced by submaximal doses of d-amphetamine, amfonelic acid, methylphenidate, caffeine, memantin, phencyclidine, and cocaine. A 50-mg/kg dose was ineffective in blocking the effects of caffeine and memantin, but blocked the responses to the other five stimulants. Amantadine did not modify the locomotor stimulant effect of apomorphine in reserpinized mice. These results indicate that amantadine acts as a presynaptic antagonist to the above seven stimulants. Even the highest dose of amantadine did not modify the hyperactivity induced in mice by morphine and levorphanol. This result is consistent with evidence showing opiate actions at postsynaptic striatal neurons, sites where presumably amantadine is unable to exert an antagonist effect. Amantadine did not modify the central depressant effects of ethyl alcohol and pentobarbital. Amantadine could be of value as a pharmacological tool in understanding the mode of action of central stimulants, and in the management of stimulant abuse. The present data do not support the currently held view that the antiparkinsonism effect of amantadine results from its ability to potentiate the central effects of dopamine.

Modification of apomorphine hypothermia by drugs affecting brain 5-hydroxytryptamine function.

Intraperitoneal administration of apomorphine caused hypothermia in mice. Pretreatment with the serotonin (5-HT) receptor antagonists methysergide (3 mg/kg), cinanserin (10 mg/kg) or brom-LSD (3 mg/kg) potentiated this response of apomorphine. Brain 5-HT depletion by p-chlorophenylalanine caused similar modification. On the contrary, the 5-HT receptor agonists quipazine (3 mg/kg) and MK-212 (3 mg/kg), significantly blocked apomorphine hypothermia. It was concluded that 5-HT modulates the dopamine (DA)-mediated body temperature changes and that drug-induced alterations in the brain 5-HT function modify apomorphine-induced hypothermia in a predictable manner. One mg/kg dose of lysergic acid diethylamide (LSD) blocked apomorphine hypothermia. The apomorphine-blocking effect of both quipazine and LSD developed tolerance. Moreover, LSD showed cross tolerance with quipazine. It was concluded that the hypothermia-blocking property of LSD resides on its ability to activate the hypothalamic 5-HT receptors.

Serotonergic drugs, benzodiazepines and baclofen block muscimol-induced myoclonic jerks in a strain of mice.

In male Swiss mice, muscimol produced myoclonic jerks. A 3 mg/kg (i.p.) dose induced this response in all of the mice tested and the peak response of 73 jerks per min was observed between 27 and 45 min. Increasing the brain serotonin levels by the administration of 5-hydroxytryptophan (80-160 mg/kg) in combination with a peripheral decarboxylase inhibitor resulted in an inhibition of the muscimol effect. However, in a similar experiment l-dopa (80-160 mg/kg) was without effect. In doses of 3-10 mg/kg, the serotonin receptor agonist MK-212 caused a dose-dependent blockade of the response of muscimol. Of the benzodiazepines, clonazepam (0.1-0.3 mg/kg) was found to be several fold more potent than diazepam (0.3-3 mg/kg) in blocking the myoclonic jerks. While (-)-baclofen (1-3 mg/kg) proved to be an effective antagonist of muscimol, its (+)-isomer (5-20 mg/kg) lacked this property. Considering the fact that 5-HTP and the benzodiazepines have been found to be beneficial in the management of clinical myoclonus, the muscimol-induced myoclonus seems to be a satisfactory animal model that may prove useful for the development of new drug treatments for this condition. Our present study indicated the possible value of MK-212 and (-)-baclofen in the management of clinical myoclonus.

A new method for the evaluation of benzodiazepines based on their ability to block muscimol-induced myoclonic jerks in mice.

A number of clinically used benzodiazepines were tested for their effectiveness in blocking muscimol-induced myoclonic jerks in mice. Their ED50 values were determined from their dose-response curves. These data gave the following relative potencies with respect to diazepam: diazepam = 1, medazepam = 0.24, oxazepam = 1.27, flurazepam = 1.90, lorazepam = 3.01, nitrazepam = 3.93, clonazepam = 33.14, and flunitrazepam = 116.00. Because our earlier studies indicated that muscimol-induced myoclonic jerks probably originate from the spinal cord, the present method may prove to be suitable for quantitatively evaluating the effect of benzodiazepines on the spinal cord. The present results also indicate the possible value of flunitrazepam in the management of neurologic disorders in which preferential action on the spinal cord is desired.