Potentiation by TRH of the effect of antidepressants in the forced-swimming test, involvement of dopaminergic and opioid systems.
1. It has been shown that thyrotropin releasing hormone (TRH) can potentiate the effects of the antidepressant, imipramine, as measured by the mouse forced-swimming test. This potentiation is not associated with an increase of effective levels of noradrenaline in the synaptic clefts, but depends upon the integrity of opioid systems. The present study was designed to investigate: (a) the potentiation by TRH of the effects of other antidepressants, using the same test; (b) the possible involvement of other neuronal systems, such as the 5-hydroxytryptaminergic and dopaminergic systems; (c) the contribution of the opioid and dopaminergic systems to the potentiation of the actions of other antidepressants by TRH. 2. The effects of nortriptyline, amineptine, maprotiline, nomifensine and mianserin, but not that of clomipramine, were potentiated by TRH (2 mg kg-1, i.p.). The inhibitor of 5-hydroxytryptamine synthesis, p-chlorophenylalanine (PCPA), did not prevent the effect induced by imipramine plus TRH. Blockade of dopaminergic systems by gamma-butyrolactone (GBL) (37.5 mg kg-1, i.p.), alpha-methyl-p-tyrosine (AMPT) (125 mg kg-1, i.p.) and apomorphine (0.025 mg kg-1, i.p.) antagonized the effects induced by various antidepressants alone (at high, effective doses) or at lower ineffective doses in association with TRH. The effect induced by imipramine plus TRH was also blocked by sulpiride (16 mg kg-1, i.p.). Pretreatment with the opioid antagonist, naloxone, inhibited the effects induced by nomifensine plus TRH or mianserin plus TRH but not those induced by nortriptyline plus TRH, maprotiline plus TRH or amineptine plus TRH. When high active doses of the antidepressants were used alone, only the clomipramine effect was blocked by naloxone. 3. These data indicate that TRH is able to potentiate the effect not only of imipramine but of other antidepressants in the mouse forced-swimming test, although these other antidepressants act in various ways on cerebral amines. The antagonism of the effects induced by the antidepressants alone or in association with TRH after blockade of dopaminergic systems may indicate a reversal of the effect of the antidepressants by blockade of dopaminergic systems. Hence, the same mechanisms would be involved in the effects induced by antidepressants alone or in association with TRH, with respect to dopaminergic systems. However, different mechanisms of action seem to be responsible for the potentiation of TRH of the effect of the various antidepressants, since the involvement of the opioid systems varies according to the antidepressant tested.
Reny-Palasse
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Unité de Pharmacologie Chimique, INSERM, Paris, France.
Constans
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M
Rips
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R
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology*; D013550:Swimming; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
D000928:Antidepressive Agents; D011957:Receptors, Opioid; D009270:Naloxone; D013973:Thyrotropin-Releasing Hormone; D006916:5-Hydroxytryptophan; D004298:Dopamine