No abstract

The effect of beta-adrenoceptor antagonists, varying in lipophilicity and receptor selectivity, were studied on tremor elicited by L-5-hydroxytryptophan (L-5-HTP) in rats pretreated with a peripherally acting decarboxylase inhibitor and a monoamine oxidase inhibitor, or by the directly acting 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). Plasma levels of the beta-adrenoceptor antagonists were determined simultaneously. The non-selective lipophilic adrenoceptor antagonist propranolol was found to dose-dependently reduce tremor intensity, whereas the non-selective hydrophilic adrenoceptor antagonist sotalol had no effect, indicating a central site of action. Furthermore, beta 1-selective blockade with the adrenoceptor antagonist metoprolol had no effect on tremor intensity, whereas the beta 2-selective antagonist ICI 118,551 dose-dependently suppressed tremor intensity, suggesting that the beta-adrenoceptor subtype involved is of the beta 2-type. These results suggest that blockade of centrally located beta 2-adrenoceptors are able to attenuate the tremor response following 5-hydroxytryptamine receptor activation.

Subchronic (5 mg/kg SC, twice daily for 14 days) but not acute administration of the beta-2-adrenoceptor agonist salbutamol to rats caused a significant increase in the accumulation of 5-hydroxytryptophan in the limbic forebrain, the corpus striatum and the cerebral cortex when measured during 30 min after inhibition of L-amino acid decarboxylase by NSD 1015 (100 mg/kg IP). Simultaneously assayed tryptophan concentrations in the same brain regions were not affected. These results indicate an increase in the in vivo rate of tryptophan hydroxylation in the brain, produced by subchronic salbutamol administration. The effect of salbutamol treatment on brain catecholamine(CA) utilization was estimated by studying the disappearance of CA in the brain after inhibition of tyrosine hydroxylase by alpha-methyltyrosine methyl ester (H 44/68), 250 mg/kg IP, 3.5 h before sacrifice. Subchronically but not acutely administered salbutamol caused both a significant increase in endogenous noradrenaline (NA) levels and an increase NA utilization. Dopamine levels and turnover were, however, not altered by either acute or subchronic treatment. The activation, probably centrally elicited, of brain NA and 5-hydroxytryptamine systems by the subchronic salbutamol regimen supports the concept of beta-adrenoceptor mediated regulation of brain monoamine systems, and could contribute to the clinically reported antidepressant activity of beta-2-adrenoceptor agonists.

Activation of postsynaptic noradrenergic al-receptors may be involved in the mediation of psychomotor activating effects of tricyclic antidepressant (TCA) drugs. On the other hand, the pronounced sedative properties of some TCA drugs seem to be correlated with their u,-receptor blocking capacity. The presynaptic u2-receptors probably mediate the feed, back inhibition of central NE neurons seen after administration of TCA drugs, particularly the secondary amines. Yet other antidepressants such as mianserin are potent antagonists at central a*-receptors, a phenomenon which can even cause activation of brain NE neurons and form a basis for their therapeutic action. &Receptor activation in the brain is also suggested to participate in the therapeutic effect of several drugs, e.g. mianserin and the putative antidepressant agent salbutamol, a Bz-receptor agonist. A reduced central B-receptor activation may, accordingly, contribute to depressive symptoms associated with treatment with Badrenoceptor blocking drugs, both by their action per se as well as by secondary effects on the monoamine systems, which we recently have demonstrated. Facilitation of brain 5-HT neurotransmission seems to be achieved with several TCA drugs not only via inhibition of reuptake but also through sensitization of postsynaptic 5-HT receptors, developing during repeated treatment. In contrast the "presynaptic" 5-HT receptors do not show increased sensitivity during chronic TCA drug treatment.thus allowing for an enhanced synaptic effect of 5-HT induced by TCA drugs.

1 The effects of two P2-adrenoceptor agonists with different lipophilicities were studied on tremor induced by L-5-hydroxytryptophan (L-5-HTP) in pargyline-and carbidopa-pretreated rats. 2 Tremor was recorded and analysed by an objective method based on accelerometry. 3 Clenbuterol, a lipophilic p2-selective agonist, dose-dependently enhanced tremor intensity, whereas the hydrophilic p2-agonist terbutaline had no effect.4 The clenbuterol-induced enhancement of tremor was completely abolished by the P2-selective antagonist ICI 118,551 but unchanged by the pi-selective antagonist metoprolol.5 The results suggest that centrally located P2-adrenoceptors can mediate a modulation of 5-hydroxytryptamine-induced tremor in rats.