Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide reduces extracellular glutamate levels in primary rat cerebral cortex cell cultures T. Antonelli a , M.C. Tomasini a , M. Tattoli b , T. Cassano c , S. Finetti a , E. Mazzoni a , L. Trabace c , M.R. Carratu ` b , V. Cuomo d , S. Tanganelli a, * , L. Ferraro a a Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy b Department of Pharmacology and Human Physiology, University of Bari, Italy c Department of Biomedical Sciences, University of Foggia, Italy d Department of Pharmacology and General Physiology University ‘‘La Sapienza’’ Roma, Italy Received 8 February 2006; received in revised form 19 April 2006; accepted 27 April 2006 Available online 14 June 2006 Abstract The effects of prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 (0.5 mg/kg s.c.), alone or in combination with carbon monoxide, on extracellular glutamate levels in primary rat cerebral cortical neuronal cultures, were investigated. Dam weight gain, pregnancy length and litter size at birth were not affected by prenatal treatment with WIN 55,212-2 and carbon monoxide alone or in combination. Basal and K + -evoked extracellular glutamate levels were reduced in cortical cultures from pups born to mothers exposed to WIN 55,212-2 and carbon monoxide alone or in combination compared to cultures from rats born to vehicle-treated mothers. In cultures obtained from rats exposed to vehicle or carbon monoxide alone during gestation, WIN 55,212-2 (0.01–100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration–response curve. In cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide the WIN 55,212-2 (1 nM)-induced increase in extracellular glutamate levels was lower than that observed in cultures from rats born to vehicle-treated mothers and similar at those observed at 10 and 100 nM concentrations. The selective CB1 receptor antagonist SR141716A (10 nM) counteracted the WIN 55,212-2-induced increase in extracellular glutamate levels in cultures exposed to vehicle or carbon monoxide during gestation, but failed to antagonise it in cultures from rats born to mothers exposed to WIN 55,212-2 alone or in combination with carbon monoxide. These findings provide evidence that prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 and carbon monoxide, alone or in combination, is associated with an impairment in cortical glutamatergic transmission. It could be speculated that such detrimental effects might be involved in the reported deficit in learning and memory associated with prenatal marijuana exposure. # 2006 Elsevier Ltd. All rights reserved. Keywords: SR141716A; Basal and K + -evoked glutamate levels; Maternal marijuana exposure 1. Introduction Despite remarkable progress during the last years, a clear understanding of the neurobiology of endogenous and exogenous cannabinoids and, in particular, of the molecular and neuro- chemical mechanisms underlying their effects on the central nervous system (CNS) remain undefined. In this context, an understanding of the short and long-term consequences on those offspring born to mothers exposed to marijuana during pregnancy is particularly relevant. Cannabinoids may indeed affect the CNS development when consumed during gestation (Fernandez-Ruiz et al., 2000, 2004; Bernard et al., 2005), because they are transferred from mother to the offspring through placental blood (Hutchings et al., 1989). In addition, the demonstration of cannabinoid receptors in foetal brain (Buckley et al., 1998; Berrendero et al., 1998; Wang et al., 2003) and the presence of brain constituents which selectively bind to cannabinoid receptors (Berrendero et al., 1999; Fernandez-Ruiz et al., 2000; Martinez Orgado et al., 2005) highlight the potential for cannabinoids to target the CNS during development. Such a www.elsevier.com/locate/neuint Neurochemistry International 49 (2006) 568–576 * Corresponding author. Tel.: +39 0532 291212; fax: +39 0532 291205. E-mail address: tgs@unife.it (S. Tanganelli). 0197-0186/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2006.04.012