Long-term consequences on cannabinoid CB1 receptor binding of enhanced endocannabinoid signalling during adolescence: interaction with early maternal deprivation

Eva M Marco1, Walter Adriani3, Tiziana Rubino2, Daniela Parolaro2, Maria Paz Viveros1, Giovanni Laviola3. 1Depto. Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain, 2DBSF, Pharmacology Section and Center of Neuroscience, University of Insubria, Busto Arsizio, VA, Italy, 3Unit of Behavioural Neuroscience, Dept of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.

Pharmacological manipulation of the endocannabinoid system has been proposed as a promising tool in the management of a variety of pathological states (Viveros et al., 2005). Despite the forthcoming therapeutical application of cannabinoid compounds, little is known about their long lasting consequences. Maternal deprivation (MD) represents a neurodevelopmental animal model for some aspects of diverse neuropsychiatric disorders (Ellenbroek et al., 1998; Macrì et al., 2004). Adolescence is considered as a critical period for the onset of several neuropsychiatric disorders, and therefore suitable for pharmacological intervention (Adriani et al., 2004). We aimed to study the long-term effects of a cannabinoid-based therapy during adolescence on cannabinoid CB1 receptor binding. Control (NDEP) and maternally deprived (for 24 hours on PND 9, Ellenbroek et al., 1998) (DEP) male Wistar rats, were administered during adolescence (PND 38-43) the fatty-acid amide hydrolase (FAAH) inhibitor URB-597 (0, 0.1 or 0.5 mg/kg/day I.P.) for six days, while tested for impulsive behaviour in the intolerance-to-delay task (for details see Marco et al., 2007). At adulthood, cannabinoid CB1 receptor expression was analyzed using [3H] CP 55,940 autoradiographic binding in prefrontal cortex, nucleus Accumbens (NAcc), caudate-putamen (CPu), hippocampus (Hip), globus pallidus, ventral tegmental area (VTA), hypothalamus (Hypo), medial thalamus, substantia nigra (SN), locus coeruleus (LC), amygdala, periaqueductal grey matter (PAG) and cerebellum. The repeated adolescent administration of the higher dose of URB-597 significantly reduced CB1 receptor binding in the long-term within NDEP animals in NAcc [F2,37 = 5.72, P<0.01], CPu [F2,54 = 4,62, P<0.05], Hip [NDEP, F2,44 = 3.73, P<0.05], and VTA [F2,30 = 4.04, P<0.05]. On contrast, but also within control NDEP animals, URB-597 significantly increased LC CB1 receptor binding [F2,19 = 5.48, P<0.05]. Significant durable effects of MD were also found, particularly an up-regulation of receptor binding in Hypo [F1,21 = 4.90, P<0.05], Hip [F1,32 = 4.33, P<0.05], and SN [F1,20 = 11,77, P<0.01] when compared to control vehicle-treated animals. Surprisingly, within DEP animals, no modifications in CB1 receptor binding were observed on adult animals.

We found that a prolonged enhancement of the endocannabinoid signalling at the still plastic period of adolescence persistently modified brain CB1 receptor expression in control NDEP animals. Moreover, MD appeared to have disrupted developmental patterns producing a long-lasting dysregulation of the endocannabinoid system, and possibly impairments on neural plasticity. Additional investigations on the long-term neurobehavioural consequences of cannabinoid-based therapies are an urgent need.

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