The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, and opioids on physiology of this system. In addition, this brain nucleus is known to mediate motivational aspects of behavior. For this reason it has been implicated in a variety of psychiatric disorders that involve alterations in mood and motivation, as well as in the process of drug addiction. The NAc medium spiny GABAergic output neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by abused drugs, suggesting that this action may contribute to their rewarding properties. In addition, abused drugs are known to increase NAc dopamine (DA). One role of DA in regulating NAc activity may be to contribute to the long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. However, the precise mechanisms through which such synaptic plasticity develops, and how drugs of abuse, including cannabinoids (CBs), alter such synaptic plasticity, remain poorly understood. To investigate the actions of CBs in the NAc, we are utilizing both electrophysiological and fast scan cyclic voltammetry (FSCV) recording techniques in brain slices. By combining these approaches, we hope to be able to simultaneously monitor changes in DA levels and the development of synaptic plasticity. We are also collaborating with Dr. Bruce Hope investigating the effects of repeated cocaine treatment on synaptic inputs to MSNs. To do this, we are using mice that express green fluorescent protein in only MSNs that are activated during cocaine sensitization. By visualizing these specific neurons in our slice preparation, we can perform electrophysiological recordings from these cells and assess the mechanisms supporting cocaine sensitization. We have also recently investigated the consequences of cannabinoid CB1 receptor deletion in transgenic mice on DA release in the NAc and on locomotor behavior elicited by cocaine. These studies address the role of the NAc in motivated behavior, and the interaction between cannabinoid and DA systems in the NAc. Since the NAc is involved in mediating all motivated behavior these studies should delineate neurochemical systems involved in motivation and learning behavior.