1. ¹DBSF, Pharmacology Section, and Neuroscience Center, University of Insubria, Varese, Italy
2. ²Department of Pharmacology, Chemotherapy and Medical Toxicology, Faculty of Sciences, University of Milan, Milan, Italy
3. ³Department of Pharmacology, University of Bologna, Bologna, Italy

Correspondence: Prof D Parolaro, DBSF, Pharmacology Section, and Neuroscience Center, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy. Tel: +39 0331 339417; Fax: +39 0331 339459; E-mail: daniela.parolaro@uninsubria.it

⁴These authors contributed equally to this study.

Received 25 July 2007; Revised 16 November 2007; Accepted 26 November 2007; Published online 2 January 2008.

Abstract

Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of ⁹-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35–45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.