2001). The augmented positive place reinforcing effects of METH that we observed following conditioning the bottom-up pathway of the hippocampus-VTA loop in the current study could hypothetically be due to inhibition of baseline firing rate of GABAergic MSN neurons of

the NAc. Consistent with this hypothesis, our preliminary data in addition showed that subjects that were treated with METH and MK801 (METH+MK801) Inhibitors,research,lifescience,medical showed a trend of enhanced CPP learning (data not shown, n = 3). Therefore, unleashing inhibitory GABA tone of the NAc that routes to the VTA could in addition enhance the population activity of spontaneously active VTA DA neurons to report the Inhibitors,research,lifescience,medical delivery or arrival of a reward or any other environmental cues previously paired with the rewarding drug (Berridge

et al. 1989). Decades of investigations on the behavior of LY2157299 in vivo midbrain DA neurons by Schultz and colleagues (Schultz W. 1998) assert that increases in the baseline firing rate of midbrain DA neurons are highly correlated with reward-related behaviors. If the DA hypothesis of reinforcement learning remains intact, Inhibitors,research,lifescience,medical we would have expected that blocking excitatory output of the VHC should have increased the firing rate of MSN neurons of the NAc, diminished the baseline firing rate of VTA DA neurons, and presumably reduced motivational behavior. However, unlike the expected behavioral outcome, rats that were treated with the combination Inhibitors,research,lifescience,medical of

METH and MK801 spent more time in drug-paired chambers (enhanced motivation) as opposed to METH alone group, which implies that drug-seeking behavior can be potentially achieved by attenuating the baseline firing rate of VTA DA neurons. Alternatively, the observed Inhibitors,research,lifescience,medical finding could be MK801-mediated phenomenon rather than DA per se (Brown et al. 2008; Itzhak 2008). Furthermore, the enhanced positive CPP learning in rats that were treated with the combination of METH and MK801 could also be due to an increase in firing rate of MSN neurons medroxyprogesterone of the NAc because of the attenuation of NMDA-mediated excitation followed by a decrease in VTA DA firing rate, which probably may increase the spontaneously active VTA DA neurons without increasing the baseline firing rate. In other words, the strengthening of accumbo-palidal inhibitory tone and attenuation of excitatory hippocampal GLUergic surge may result in the reduction of the firing rate of VTA DA neurons and thereby help recruit more of spontaneously active VTA DA neurons. Therefore, it is hypothesized that increases in the number of spontaneously active VTA DA neurons may subserve as a neural correlate of positive reinforcement learning (Fig. 9).