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, opioids, and designer drugs on the physiology of this system, as well as to understand the important brain circuits that connect with the NAc. In addition, this brain nucleus is known to mediate motivational aspects of behavior. For this reason the NAc 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 the release of dopamine (DA)in the NAc. 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 alter such synaptic plasticity, remain poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing electrophysiological and fast scan cyclic voltammetry (FSCV) recording, combined with optogentic techniques in brain slices obrained from transgenic and normal rodents. By combining these approaches, we hope to be able to simultaneously monitor changes in DA levels and the development of synaptic plasticity. Our most recent experiments have involved examining the synaptic properties of excitatory synapses arising from ventral tegmental (VTA)DA neurons in transgenic rats in which cre recombinase is under control of the tyrosine hydroxylase promoter (TH-Cre rats). Therefore, we selectively express the light-activated protein, channelrhodopsin-2 (ChR-2), using an adeno-associated virus containing the ChR-2 construct (AAV-DIO-ChR2). As many tyrosine hydroxylase positive (TH+) VTA neurons also express the vesicular glutamate-2 transporter (VGlut-2) they are capable of co-transmitting DA and glutamate signals to the NAc, as well as to other brain areas targeted by TH+ neurons. In experiments with brain slices, we find that light-activation of ChR2 evokes glutamate-mediated synaptic EPSCs in the NAc shell following virus injections into 3 brain areas containing TH+ neurons. These brain areas include the VTA, as well as the dorsal and medial raphe nuclei. Our current studies are exploring the biophysical properties of these glutamate synapses onto NAc neurons, and we have begun to examine effects of short- and long-term exposure to the psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC) on each of these synapses. Preliminary data suggest that both short-and long-term exposure to THC can increase the strength of synaptic transmission at the VTA to NAc glutamate synapses, and that this is likely accomplished through changes AMPA receptor distribution. Future experiments will evaluate glutamate synapses from the dorsal and medial raphe nuclei following THC exposure, and these results will be compared to those observe following VTA axon terminals in the NAc.
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