In the present study, DA antagonists were directly injected into the mPFC in order to assert that output DA neurons of this area would be tested. Accordingly, we found that pre-treatment with both D1-like and D2-like DA antagonists prevented the spatial WM impairment induced by ∆9-THC in rats, suggesting that the impairment is due to excess dopaminergic activation in the mPFC. Since the blockade of DA receptors directly in the mPFC prevented the disruptive effect Alisertib cell line induced by ∆9-THC, we hypothesized in the present study that this disruption is the resultant of an excess of dopaminergic activation in the mPFC. This study provides the first evidence

of dopaminergic involvement in the disruption of spatial WM after ∆9-THC administration into the PFC. DA release occurs in several areas of brain reward circuits after administration of ∆9-THC (Lupica et al, 2004), as does an enhancement of mesolimbic DA neuron firing (Gessa et al, 1998). However, as cited above, these effects of ∆9-THC over DA release are most likely indirect. The connection between DA receptor stimulation and cognitive functions has been examined systematically. Venetoclax price An elegant study designed by Phillips et al. (2004) showed that DA efflux is elevated in the mPFC of rats after an extended delay of 30 min in

a situation in which spatial memory for the correct location of food had to be recalled. The increase in DA efflux in the mPFC was not related to reward but to the accuracy of WM, confirming the correlation of this function with DA activation. Furthermore, several other studies performed with high DA levels support the finding that excess DA release and turnover in the PFC are associated with impairment of spatial WM (Murphy et al., 1996, Zahrt et al., 1997, Seamans and Yang, 2004 and Phillips et al., 2004). Dopaminergic regulation of frontal cortical cognition was studied by Jentsch et al. (1998), who observed that high doses of ∆9-THC

(20 mg/kg/day for 14 days) that seemed nontoxic to mesocortical DA neurons selectively reduced PFC DA metabolism in rats. Methisazone Although the involvement of D1-like receptors in WM is widely recognized, recent studies have demonstrated the involvement of D1- and D2-like DA receptors on WM or executive functions in the PFC, and it has been suggested that when DA levels are high, the prefrontal network is modulated not only by D1 but mainly by D2 receptors (Floresco et al, 2006). Glickstein et al. (2002) observed that mice lacking D2 receptors show WM deficits (2002). Additionally, systemic administration of D2 agonists in humans improved cognitive functions, including WM and executive functions (McDowell et al, 1998), whereas administration of D2 antagonists impaired such functions (Mehta et al, 1999).