The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects

Maria Grazia Cascio, Erica Zamberletti, Pietro Marini, Daniela Parolaro, Roger G. Pertwee

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Abstract

Background and Purpose
This study aimed to address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1A receptors in vitro and (ii) induce any apparent 5-HT1A receptor-mediated antipsychotic 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 [35S]-GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats.

Key Results
THCV (i) potently, albeit partially, displaced 8-[3H]-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-[3H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A 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-HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251.

Conclusions and Implications
Our findings suggest that THCV can enhance 5-HT1A 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.
Original languageEnglish
Pages (from-to)1305-1318
Number of pages14
JournalBritish Journal of Pharmacology
Volume172
Issue number5
Early online date13 Feb 2015
DOIs
Publication statusPublished - Mar 2015

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Serotonin 5-HT1 Receptors
Receptor, Serotonin, 5-HT1A
8-Hydroxy-2-(di-n-propylamino)tetralin
Antipsychotic Agents
Membranes
CHO Cells
Brain Stem
Serotonin 5-HT1 Receptor Antagonists
Stereotyped Behavior
Phencyclidine
Neurobehavioral Manifestations
tetrahydrocannabivarin 9
Social Behavior
Clozapine
hydroxide ion
Schizophrenia
Binding Sites

Cite this

The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects. / Cascio, Maria Grazia; Zamberletti, Erica; Marini, Pietro; Parolaro, Daniela; Pertwee, Roger G.

In: British Journal of Pharmacology, Vol. 172, No. 5, 03.2015, p. 1305-1318.

Research output: Contribution to journalArticle

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abstract = "Background and PurposeThis study aimed to address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1A receptors in vitro and (ii) induce any apparent 5-HT1A receptor-mediated antipsychotic effects in vivo.Experimental ApproachIn 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 [35S]-GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats.Key ResultsTHCV (i) potently, albeit partially, displaced 8-[3H]-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-[3H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A 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-HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251.Conclusions and ImplicationsOur findings suggest that THCV can enhance 5-HT1A 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.",
author = "Cascio, {Maria Grazia} and Erica Zamberletti and Pietro Marini and Daniela Parolaro and Pertwee, {Roger G.}",
note = "Funded by: •GW Pharmaceuticals Acknowledgements: The authors wish to thank Mrs Lesley Stevenson for technical support and Dr John Raymond, Dr Keith Parker and Dr Ethan Russo for providing human 5-HT1A CHO cells. This research was supported by a grant from GW Pharmaceuticals to M. G. C. and R. G. P.",
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T1 - The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects

AU - Cascio, Maria Grazia

AU - Zamberletti, Erica

AU - Marini, Pietro

AU - Parolaro, Daniela

AU - Pertwee, Roger G.

N1 - Funded by: •GW Pharmaceuticals Acknowledgements: The authors wish to thank Mrs Lesley Stevenson for technical support and Dr John Raymond, Dr Keith Parker and Dr Ethan Russo for providing human 5-HT1A CHO cells. This research was supported by a grant from GW Pharmaceuticals to M. G. C. and R. G. P.

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N2 - Background and PurposeThis study aimed to address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1A receptors in vitro and (ii) induce any apparent 5-HT1A receptor-mediated antipsychotic effects in vivo.Experimental ApproachIn 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 [35S]-GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats.Key ResultsTHCV (i) potently, albeit partially, displaced 8-[3H]-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-[3H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A 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-HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251.Conclusions and ImplicationsOur findings suggest that THCV can enhance 5-HT1A 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.

AB - Background and PurposeThis study aimed to address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1A receptors in vitro and (ii) induce any apparent 5-HT1A receptor-mediated antipsychotic effects in vivo.Experimental ApproachIn 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 [35S]-GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats.Key ResultsTHCV (i) potently, albeit partially, displaced 8-[3H]-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-[3H]-OH-DPAT binding to specific sites in membranes of human 5-HT1A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT1A 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-HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251.Conclusions and ImplicationsOur findings suggest that THCV can enhance 5-HT1A 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.

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DO - 10.1111/bph.13000

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SN - 0007-1188

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