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 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 expressed 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 the VTA. In experiments with brain slices, we find that FSCV can detect DA release in the NAc during light-activation (473 nm) of TH+ axons, but not in the lateral habenula (LHb), another brain area receiving TH+ inputs from VTA. However, in contrast to these experiments, we also find that light-activated, glutamate-mediated synaptic EPSCs are readily detected in both brain regions. This suggestes that the mechanisms of DA release in the LHb differ from those in the NAc, whereas the control of glutamate release is distinct. Subsequent experiments examining the properties of glutamatergic EPSCs in both the NAc and LHb demonstrate that the biophysical kinetics of these light-activated synaptic currents differ significantly, with those in the NAc demonstrating much slower decay kinetic than those in the NAc. These data suggest that the ionotropic glutamate receptors targeted by these same TH+ neurons differ in these distinct brain regions. Planned experiments will elucidate the molecular basis for this difference.
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