Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Abstract

The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action

“…Similarly, leptin (15, 16, 34 -36, 41), galanin (21,52), neurotensin (6,17,23,30), and CART (29,31,51) have all been associated with the control of reward as well as arousal behavior. Indeed, neurotensin-LepRb neurons modulate the reward system via orexin neurons, although it is still unknown by which mechanisms leptin inhibits orexin neurons (40).…”

Galanin – 25 years with a multitalented neuropeptide

“…Local administration of galanin into the cerebral ventricle attenuates the rewarding effect of morphine in the mouse as measured by the place preference paradigm by shifting the dose response curve such that threshold doses are no longer rewarding in animals receiving galanin [1]. Consistent with the possibility that galanin signaling opposes opiate reward, galanin knockout mice showed increased sensitivity to a low dose of morphine in the place preference paradigm compared to their wild-type controls [11]. The effect of galanin on morphine-induced locomotion and morphine place preference occurred at very different doses, since at the threshold dose for morphine place preference (0.25 mg/kg), no locomotor activation was seen.…”

“…Indeed, inhibition of ERK phosphorylation in the VTA blocks the rewarding effects of morphine [58]. Morphine induces a significant increase in the activity of ERK in the VTA, NAc and amygdala of both galanin wild-type and knockout animals, but the increase is significantly greater in knockout mice lacking the galanin peptide [11]. In the VTA, galnon administration decreased morphine-induced ERK phosphorylation in both wild-type and galanin knockout mice, suggesting that activation of galanin receptors in the VTA can attenuate activity of DA neurons and decrease signaling related to opiate reward; however, the decrease in P-ERK by galnon was not complete, suggesting that morphine also regulates ERK activity independent of the galanin system.…”

“…This compound has been useful for determining whether behavioral changes in galanin knockout mice are due to adaptation to the loss of the peptide during development or acute effects of galanin in the adult behaving animal. Galnon administration was able to reverse the morphine-induced increase in locomotor activation seen in galanin knockout mice, suggesting that even in the absence of galanin signaling throughout development, replacement of galanin action in adulthood could normalize morphine-induced locomotor activation [11]. Conditioned place preference is a contextual task that is thought to measure drug reward and drug seeking [14].…”

“…Thus, locomotor activation can provide a behavioral measure of sensitivity to drugs of abuse. Interestingly, knockout mice lacking the galanin peptide show increased locomotor responses to morphine across a number of doses compared to their wild-type controls [11]. Galnon is a non-peptide galanin receptor agonist that can cross the blood-brain barrier [12,13].…”