BACKGROUND AND PURPOSE:

To address the questions of whether Δ9 -tetrahydrocannabivarin (THCV) can (a) enhance activation of 5-HT1A receptors in vitro and (b) induce any apparent 5-HT1Areceptor-mediated anti-psychotic effects in vivo.

EXPERIMENTAL APPROACH:

In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) of 5-HT1A receptors in membranes obtained from rat brainstem or human 5-HT1A CHO cells, using [35 S]GTPγS and 8-[3 H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated anti-psychotic effects in rats.

KEY RESULTS:

We found that THCV (a) potently, albeit partially, displaced 8-[3 H]-OH-DPAT from specific binding sites in rat brainstem membranes, (b) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of receptors in these membranes, (c) produced concentration-related increases in 8-[3 H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells, and (d) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A receptors. In phencyclidine-treated rats, THCV, like clozapine, (a) reduced stereotyped behavior, (b) decreased time spent immobile in the forced swim test, and (c) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5-HT1A receptor antagonist, WAY100635, or could be produced by the CB1antagonist, AM251.

CONCLUSIONS AND IMPLICATIONS:

Our findings suggest that THCV can enhance 5-HT1Areceptor activation, and that some of its apparent anti-psychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia.
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