Endogenous tetrahydroisoquinolines, such as 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), were tested for their interaction with motor effects of amphetamine and morphine in C57BL/6 mice. TIQ binding to cortical adrenergic alpha1, alpha2 and beta receptors, striatal dopamine D1 and D2 receptors and cortical L-type calcium channels in the Wistar rat was also studied. Both compounds in high doses reduced the mouse locomotor activity, and in doses not affecting activity inhibited the motor stimulation induced by amphetamine, 2 or 3 mg/kg i.p., but facilitated the hyperactivity induced by 10 mg/kg of morphine. TIQ did not displace ligands that are antagonists for several receptor sites (including D1 and D2 receptors), but displaced an agonist of alpha2-adrenoceptor, clonidine. It is proposed that TIQ and salsolinol specifically antagonize the agonistic conformation of dopamine receptor and that endogenous 1,2,3,4-tetrahydroisoquinolines may play a role of natural feedback regulators of the activity of dopaminergic system.
Tetrahydroisoquinolines present in the mammalian brain, 1,2,3,4-tetrahydroisoquinoline (TIQ) and salsolinol, suspected to cause neurodegeneration leading to Parkinson's disease, were investigated to find their possible physiological role. To this aim their behavioral and receptor effects induced after a single dose were tested in mice and rats. Both compounds do not affect significantly the basal locomotor activity, very effectively block hyperactivity induced by apomorphine (rats) and amphetamine (mice), only partially block hyperactivity induced by scopolamine, do not affect locomotor stimulation induced by cocaine, and strongly augment the running fit induced by morphine (mice). They do not produce extrapyramidal symptoms and do not potentiate haloperidol-induced catalepsy (rats). TIQ and salsolinol do not displace antagonists of several receptors (including D(1) and D(2)) from their binding sites, but displace the agonists of Alpha(2)-adrenoceptors, [(3)H]clonidine and of dopamine receptors, [(3)H]apomorphine. The results indicate that salsolinol and TIQ act as specific antagonists of agonistic conformation of dopamine receptors, and owing to that may play a role of endogenous feed-back regulators of the dopaminergic system. Those properties make tetrahydroisoquinolines potential antidopaminergic drugs devoid of extrapyramidal effects, with possible application in substance addiction disorder as anti-craving agents.
Spontaneous locomotor activity has been studied in mice treated with single or repeated doses (five daily injections) of chlordiazepoxide. The repeated administration enhanced the stimulatory action of the lower doses of the drug, while the depressant effect of the higher doses was reduced.
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