3). The prefrontal cortex serves a variety of functions, including WM. Our experiments demonstrate that the impairment of spatial WM induced by intracortical injection of the exogenous cannabinoid Δ9-THC is prevented by the dopamine receptor antagonists SCH and CZP. Additionally, the present results also provide evidence that the cannabinoid induces disruption in spatial working memory. It was observed a different

pattern in the three doses of Δ9-THC in the experiments with D1 or D2 antagonists. Besides the fact that the experiments are independent (different animals), the vehicle solution for the drugs was different, being SAL for SCH and HCl for Ganetespib order CZP. This can explain the difference in the effectiveness pattern of Δ9-THC treatment or its VEH between SCH and CZP experiments. Administration of Δ9-THC significantly increased the number of errors in the radial maze task, and this finding is in accordance with published reports of Δ9-THC-induced spatial learning deficits in rats (Nakamura et al., 1991, Lichtman et al., 1995, Lichtman and Martin, 1996 and Silva de Melo et al., 2005). Memory impairment induced by Δ9-THC is mediated directly

through CB1 cannabinoid receptors (Mallet and Beninger, 1998, Varvel et al., 2001 and Varvel and Lichtman, 2002). As there is a high density of these cannabinoid receptors in the PFC (Wedzony and Chocyk, 2009, Eggan et al., 2010 and Mato et al., 2010), they probably mediate the Δ9-THC-induced impairment of WM in this brain area. Briefly, the synaptic Oxalosuccinic acid LDK378 function of cannabinoids is more compatible with a modulatory role than as a classic

transmitter. The frequent, although not exclusive, presynaptic location of CB1 receptors allows cannabinoids to directly influence presynaptic events, such as the synthesis and release of specific neurotransmitters, especially γ-aminobutyric acid (GABA) and glutamate. Indeed, CB1 receptors are frequently located on neurons containing these neurotransmitters (Lafourcade et al., 2007 and Chiu et al., 2010). The combination of numerous pharmacological, electrophysiological, and immunohistochemical studies suggest that cannabinoid receptors function as retrograde signals at the synapse, directly preventing an excess of excitation or inhibition in glutamatergic or GABAergic neurons, respectively (Schlicker and Kathmann, 2001, Piomelli, 2003 and Kano et al., 2009). DA has been frequently linked to the action of cannabinoids within the CNS. Nevertheless, it is generally accepted that DA transmission is not the first target for the action of cannabinoid agonists; rather, the DA effects would be most likely indirect (Fattore et al., 2008 and Lupica et al., 2004). These effects involve a variety of regulatory functions exerted by mesocorticolimbic dopaminergic neurons, such as the control of cognitive processes, learning, and memory.