The phytocannabinoid, Δ9‐tetrahydrocannabivarin, can act through 5‐HT1A receptors to produce antipsychotic effects. (March 2015)

• Record Type: Journal Article
• Authors: Cascio, Maria Grazia; Zamberletti, Erica; Marini, Pietro; Parolaro, Daniela; Pertwee, Roger G
• Is Part Of: British journal of pharmacology. Volume 172:Number 5(2015:Mar.)
• Page Start: 1305
• Page End: 1318
• Publication Date: 2015-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.13000
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph13000-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>This study aimed to address the questions of whether Δ<sup>9</sup>‐tetrahydrocannabivarin (THCV) can (i) enhance activation of 5‐HT<sub>1</sub><sub>A</sub> receptors <italic>in vitro</italic> and (ii) induce any apparent 5‐HT<sub>1</sub><sub>A</sub> receptor‐mediated antipsychotic effects <italic>in vivo</italic>.</p> </sec> <sec id="bph13000-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p> <italic>In vitro</italic> studies investigated the effect of THCV on targeting by 8‐hydroxy‐2‐(di‐<italic>n</italic>‐propylamino)tetralin (8‐OH‐DPAT) of 5‐HT<sub>1</sub><sub>A</sub> receptors in membranes obtained from rat brainstem or human 5‐HT<sub>1</sub><sub>A</sub> CHO cells, using [<sup>35</sup>S]‐GTPγS and 8‐[<sup>3</sup>H]‐OH‐DPAT binding assays. <italic>In vivo</italic> studies investigated whether THCV induces signs of 5‐HT<sub>1</sub><sub>A</sub> receptor‐mediated antipsychotic effects in rats.</p> </sec> <sec id="bph13000-sec-0003" sec-type="section"> <title>Key Results</title> <p>THCV (i) potently, albeit partially, displaced 8‐[<sup>3</sup>H]‐OH‐DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8‐OH‐DPAT‐induced activation of receptors in these membranes; (iii) produced concentration‐related increases in 8‐[<sup>3</sup>H]‐OH‐DPAT binding to specific sites in membranes of human 5‐HT<sub>1</sub><sub>A</sub> receptor‐transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8‐OH‐DPAT‐induced activation of these human 5‐HT<sub>1</sub><sub>A</sub> receptors. In phencyclidine‐treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5‐HT<sub>1</sub><sub>A</sub> receptor antagonist, WAY100635, or could be reproduced by the CB<sub>1</sub> antagonist, AM251.</p> </sec> <sec id="bph13000-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>Our findings suggest that THCV can enhance 5‐HT<sub>1</sub><sub>A</sub> receptor activation, and that some of its apparent antipsychotic 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.</p> </sec> </abstract>