Effect Of Drugs of Abuse On Synaptic Transmission In Nucleus Accumbens

National Institute On Drug Abuse

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Abstract

The nucleus accumbens (NAc) is a critical brain area involved in motivation and mediates the rewarding and addictive properties of several classes of abused drugs. Additionally, because of its role in motivational processes, the NAc is also implicated in psychiatric disorders that involve alterations in mood, motivation. Therefore, it is necessary to understand the basic function of this brain region, as well as the actions of abused drugs such as marijuana, cocaine, opioids, and designer drugs on this system. The NAc is largely comprised of medium spiny, GABAergic output neurons (MSNs) that receive innervation from other MSNs, glutamate innervation from many additional brain areas, and dopamine innervation from the ventral midbrain. Acutely, both GABA and glutamate synapses onto MSNs are inhibited by several classes of abused drugs, suggesting that this action may contribute to their rewarding properties, and long-term exposure to drugs alters the function of both intrinsic circuits and extrinsic inputs. In addition, abused drugs are known to increase the release of dopamine (DA)in the NAc, and this likely contributes to long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. Although much is known about the contributions of the NAc to behavior, the precise mechanisms in which such synaptic plasticity contributes to behavior, and how abused drugs alter synaptic processes remains poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing electrophysiology and behavioral analyses combined with optogenetic techniques in transgenic and normal rodents. Current experiments involve examining the influence of specific NAc input and output pathways on behavior and changes in these pathways after exposure to abused drugs by self-administration or through experimenter delivery. Optogenetics permits selective expression of the light-activated proteins, such as channelrhodopsin-2 (ChR2), or halorhodopsin (Halo) when an adeno-associated virus (AAV) containing these constructs are used. 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. We find that light-activation of ChR2 evokes glutamate-mediated synaptic EPSCs in the NAc shell following virus injections into several brain regions that send axons to the NAc. These EPSP properties are then compared among pathways targeting the NAc, such as the ventral hippocampus, basolateral amygdala and medial prefrontal cortex, and alterations in their function following exposure to the psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC), on each of these pathways can be compared. Specifically, exposure to THC over a 2 week period causes a significant weakening of prefrontal inputs to the NAc shell, and greatly strengthens inputs arising from the ventral hippocampus and basolateral amygdala. The pattern of changes observed in the inputs to the NAc are consistent with reports in brain imaging studies conducted in human marijuana users, and suggest a loss of cortical control over the NAc and an increase in subcortical control with chronic THC use. This has important implications for cognition and emotional processing in humans, and we hypothesize that the changes we have identified are related to behavioral and psychiatric changes seen in humans that are diagnosed with cannabis use disorder. Additional work includes an examination of the relevance of output pathways of the NAc to impulsive behaviors that are linked to drug use and relapse to drug seeking in humans. In this regard, we are combining retrograde tracing studies with immunohistochemistry to identify pathways targeted by the NAc that are involved in suppression of unwanted behavior. These ongoing studies have developed behavioral assays of impulsive behavior that are increased by disruption of NAc output.