PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes

Project Summary/Abstract
Dysregulation of glutamate signaling is a core component of the pathological basis of drug addiction involving
cocaine and many other substances. Recent progress in neuroscience and other fields clearly establishes that
the molecular and cellular basis of glutamate-encoded signaling is vastly more complex than previously
recognized. In particular, it is becoming increasingly evident that astrocytes, which are among the most
abundant cells in the human brain, release glutamate to produce complex regulation over neural circuit activity.
This novel form of glutamate-encoded intercellular signaling may be critical to understanding the pathological
glutamate produced by long-term drug use since astrocytic glutamate release mechanisms, such as system
xc- (Sxc), are altered by cocaine. While these discoveries raise numerous questions that may be essential in
understanding glutamate signaling in the human brain, this proposal will focus on the question, how do
neurons regulate glutamate release from astrocytes to control neural network activity and behaviors relevant to
cocaine addiction. We will test the hypothesis that this is achieved by the actions of the neuropeptide pituitary
adenylate cyclase-activating polypeptide (PACAP), which we believe to be an unrecognized component of
glutamate signaling in the nucleus accumbens (NAc). In support, we have found that A) PACAP mRNA is
expressed in NAc afferents, B) PACAP receptors are expressed in NAc astrocytes and neurons projecting to
the substantia nigra (SN) but not the ventral pallidum (VP), C) PACAP stimulates glutamate release from
astrocytes by increasing the activity of system xc- (Sxc), D) PACAP application depresses eEPSCs in NAc
medium spiny neurons (MSNs) projecting to the substantia nigra (SN) but not the ventral pallidum, and E)
intra-NAc micro-infusion of PACAP blocks cocaine reinstatement. In this proposal, we will test the hypothesis
that PACAP is a neuropeptide that regulates glutamate release from astrocytes and glutamate receptors on
neurons to provide a novel form of pathway-specific regulation of NAc efferent pathways. In Aim 1, we will
examine the molecular basis of PACAP-induced increases in Sxc activity and determine whether Sxc
regulation is necessary for PACAP to depress eEPSCs in NAc-SN MSNs and block cocaine reinstatement. In
this aim, we will also examine if PACAP increases glutamate from astrocytic release mechanisms other than
Sxc. In Aim 2, we will examine the possibility that the form of astrocyte-neuron signaling triggered by PACAP
require the regulation of neuronal glutamate receptors to produce the relevant changes in physiology that gate
the output of NAc efferents and behavior. We will also explore whether PACAP alters presynaptic glutamate
release. In Aim 3, we will investigate the role of endogenous PACAP to learn whether this neuropeptide is an
unrecognized component of glutamate signaling in the NAc, and whether it is a key determinant of drug-
seeking behavior.

Grant Number: 5R01DA050180-05
NIH Institute/Center: NIH
Principal Investigator: DAVID BAKER