Glycyl-glutamine reduces ethanol intake at three reward sites in P rats

Abstract

Abstractβ-endorphin, implicated in modulation of ethyl alcohol reward, has neuron terminals in several reward sites. Alcohol consumption was reduced after ventricular or site specific injections into the nucleus accumbens of an opioid-derived dipeptide, glycyl-glutamine. The current study examined the effects of this dipeptide after site specific injections into additional reward sites. Alcohol preferring (P) rats, stereotaxically implanted with bilateral guide cannulae into the nucleus accumbens, ventral tegmental area, and the central nucleus of the amygdala were given 30% alcohol and water in a 24 h voluntary 2-bottle choice paradigm. Upon achieving stable baseline intakes, glycyl-glutamine (GQ) doses were injected bilaterally, and the alcohol and water intakes and body weight recorded for the response and recovery. The data show reduced alcohol intake by 32 to 49.5% after 100 pmol glycyl-glutamine into reward sites (nucleus accumbens, ventral tegmental area, and central nucleus of the amygdala), but not after injections into control sites dorsal to reward sites. The order of sensitivity to the 1 fmol dose was amygdala ≥ ventral tegmental area > accumbens. GQ was effective in reducing ethanol intake at reported β-endorphin terminal regions in each of the three reward sites tested. The effective doses were similar to reported endogenous GQ levels, consistent with the notion that it may function as part of an endogenous counter regulatory mechanism and represent a "stop drinking" signal in the high drinking, alcohol preferring P rats at these three reward sites.

A liquid chromatography–tandem mass spectrometry assay for detection and quantitation of the dipeptide Gly-Gln in rat brain

“…Gly-Gln is a known inhibitor of voluntary ethanol drinking in rats acting within the nucleus accumbens, and has also been shown to inhibit the reward benefiting effects of morphine and nicotine [3; 4; 5; 6; 7; 8; 9]. An assay for Gly-Gln would be of great utility for further investigation of this effect and in efforts to exploit this effect for the development of novel anti-addictive agents.…”

“…Two cleavage products of β-endorphin 1-31 – β-endorphin1-27 and Gly-Gln (β-endorphin 30-31) – are implicated in reduction of ethanol intake [1; 2; 3; 4; 5; 6]. β-endorphin1-27 and Gly-Gln act in different ways.…”

“…The 27 residue peptide and classical opioid antagonists act by blocking mu and delta receptors, whereas Gly-Gln does not significantly bind to opioid receptors, does not displace naltrexone bound to mu or delta receptors, and does not bind to other known neurotransmitter receptors or transporters [7]. It apparently acts by a unique and as yet undefined mechanism [5]. Along with inhibition of voluntary alcohol consumption activity, Gly-Gln has also been shown to inhibit the reward benefiting effects of morphine and nicotine [8; 9; 10].…”

High specific activity tritium labelling of biologically active small peptides and a related analogue

“…Glycyl-L-glutamine (2) is an endogenous dipeptide that is biosynthesized from beta-endorphin . Interest in this small peptide has emerged in part because of its potential use for inhibiting addiction to a number of substances including alcohol [12] morphine [13] and nicotine [14]. It has also been investigated for its role as a cardioprotective agent [15].…”