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The Journal of Neuroscience, July 16, 2008, 28(29):7284-7292; doi:10.1523/JNEUROSCI.5346-07.2008

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Behavioral/Systems/Cognitive
Chronic Psychoemotional Stress Impairs Cannabinoid-Receptor-Mediated Control of GABA Transmission in the Striatum

Silvia Rossi,^1,2 Valentina De Chiara,^1,2 Alessandra Musella,^1,2 Hajime Kusayanagi,^1,2 Giorgia Mataluni,^1,2 Giorgio Bernardi,^1,2 Alessandro Usiello,^3,4 and Diego Centonze^1,2

¹Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy, ²Centro Europeo per la Ricerca sul Cervello/Fondazione Santa Lucia, 00179 Rome, Italy, ³Behavioural Neuroscience Laboratory, Centre of Genetics Engineering–Biotecnologie Avanzate, 80145 Naples, Italy, and ⁴Department of Health Science, Università del Molise, 86100 Campobasso, Italy

Correspondence should be addressed to Diego Centonze, Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Email: centonze{at}uniroma2.it

Exposure to stressful events has a myriad of consequences in animals and in humans, and triggers synaptic adaptations in many brain areas. Stress might also alter cannabinoid-receptor-mediated transmission in the brain, but no physiological study has addressed this issue so far. In the present study, we found that social defeat stress, induced in mice by exposure to aggression, altered cannabinoid CB₁-receptor-mediated control of synaptic transmission in the striatum. In fact, the presynaptic inhibition of GABAergic IPSCs induced by the cannabinoid CB₁ receptor agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol] was reduced after a single stressful episode and fully abolished after 3 and 7 d of stress exposure. Repeated psychoemotional stress also impaired the sensitivity of GABA synapses to endocannabinoids mobilized by group I metabotropic glutamate receptor stimulation, whereas the cannabinoid CB₁-mediated control of glutamate transmission was unaffected by repeated exposure to an aggressor. Corticosteroids released in response to the activation of the hypothalamic–pituitary–adrenal axis played a major role in the synaptic defects observed in stressed animals, because these alterations were fully prevented by pharmacological blockade of glucocorticoid receptors and were mimicked by corticosterone injections. The recovery of stress-induced synaptic defects was favored when stressed mice were given access to a running wheel or to sucrose consumption, which function as potent natural rewards. A similar rescuing effect was obtained by a single injection of cocaine, a psychostimulant with strong rewarding properties. Targeting cannabinoid CB₁ receptors or endocannabinoid metabolism might be a valuable option to treat stress-associated neuropsychiatric conditions.

Key words: cocaine; electrophysiology; glucocorticoid; natural reward; running wheel; sucrose

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Received Dec. 3, 2007; revised May 19, 2008; accepted June 4, 2008.

Correspondence should be addressed to Diego Centonze, Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Email: centonze{at}uniroma2.it

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