Altered responses of dopamine D3 receptor null mice to excitotoxic or anxiogenic stimuli: Possible involvement of the endocannabinoid and endovanilloid systems

Vincenzo Micale; Luigia Cristino; Alessandra Tamburella; Stefania Petrosino; Gian Marco Leggio; Filippo Drago; Vincenzo Di Marzo

doi:10.1016/j.nbd.2009.06.015

Altered responses of dopamine D3 receptor null mice to excitotoxic or anxiogenic stimuli: Possible involvement of the endocannabinoid and endovanilloid systems

Neurobiol Dis. 2009 Oct;36(1):70-80. doi: 10.1016/j.nbd.2009.06.015. Epub 2009 Jul 8.

Authors

Vincenzo Micale¹, Luigia Cristino, Alessandra Tamburella, Stefania Petrosino, Gian Marco Leggio, Filippo Drago, Vincenzo Di Marzo

Affiliation

¹ Department of Experimental and Clinical Pharmacology, University of Catania, Medical School, Catania, Italy.

PMID: 19591935
DOI: 10.1016/j.nbd.2009.06.015

Abstract

Dopamine and the endocannabinoids, anandamide and 2-arachidonoylglycerol, interact at several levels in the brain, with the involvement of both cannabinoid CB(1) receptors and transient receptor potential vanilloid type-1 (TRPV1) channels (which are alternative anandamide receptors). Using pharmacological, immunohistochemical and analytical approaches, we investigated the response of dopamine D(3) receptor null (D3R((-/-))) mice in models of epilepsy and anxiety, in relation to their brain endocannabinoid and endovanilloid tone. Compared to wild-type mice, D3R((-/-)) mice exhibited a delayed onset of clonic seizures, enhanced survival time, reduced mortality rate and more sensitivity to anticonvulsant effects of diazepam after intraperitoneal administration of picrotoxin (7 mg/kg), and a less anxious-like behaviour in the elevated plus maze test. D3R((-/-)) mice also exhibited different endocannabinoid and TRPV1, but not CB(1), levels in the hippocampus, nucleus accumbens, amygdala and striatum. Given the role played by CB(1) and TRPV1 in neuroprotection and anxiety, and based on data obtained here with pharmacological tools, we suggest that the alterations of endocannabinoid and endovanilloid tone found in D3R((-/-)) mice might account for part of their altered responses to excitotoxic and anxiogenic stimuli.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analysis of Variance
Animals
Anti-Anxiety Agents / pharmacology
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anxiety / genetics
Anxiety / metabolism*
Anxiety / pathology
Arachidonic Acids / pharmacology
Brain
Cannabinoid Receptor Modulators / genetics
Cannabinoid Receptor Modulators / metabolism*
Capsaicin / analogs & derivatives
Capsaicin / pharmacology
Diazepam / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Endocannabinoids*
Epilepsy / etiology
Epilepsy / genetics
Epilepsy / metabolism*
GABA Antagonists / adverse effects
Male
Maze Learning / drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Picrotoxin / adverse effects
Piperidines / pharmacology
Pyrazoles / pharmacology
Reaction Time / drug effects
Receptor, Cannabinoid, CB1 / antagonists & inhibitors
Receptor, Cannabinoid, CB1 / genetics
Receptor, Cannabinoid, CB1 / metabolism
Receptors, Dopamine D3 / deficiency*
Serotonin / analogs & derivatives
Serotonin / pharmacology
TRPV Cation Channels / agonists
TRPV Cation Channels / genetics
TRPV Cation Channels / metabolism*

Substances

Anti-Anxiety Agents
Anti-Inflammatory Agents, Non-Steroidal
Arachidonic Acids
Cannabinoid Receptor Modulators
Endocannabinoids
GABA Antagonists
Piperidines
Pyrazoles
Receptor, Cannabinoid, CB1
Receptors, Dopamine D3
TRPV Cation Channels
TRPV1 protein, mouse
arachidonoylserotonin
Picrotoxin
Serotonin
AM 251
olvanil
Diazepam
Capsaicin