Glycyl-l-Glutamine Injected Centrally Suppresses Alcohol Drinking in P Rats

Simpson, Charles W.; Resch, Garth E.; Millington, William R.; Myers, R.D.

doi:10.1016/s0741-8329(97)00167-5

Cited by 9 publications

(17 citation statements)

References 38 publications

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“…The Bonferonni for saline vs. GQ is P < 0.0001, in NAC, CeM, and VTA. The data also show the mean % change in drinking after saline vehicle control injections were not significant, and in this respect, were similar to aCSF vehicle controls (Simpson et al, 1998) and saline vehicle controls (Resch et al, 2005) in previous work.…”

Section: Resultssupporting

confidence: 87%

“…Communication, WR Millington). Second, this finding supports our initial observation that GQ reduced drinking over 48 h following an injection protocol of GQ twice-a-day for 3 days icv (Simpson, et al, 1998). Finally, third, the data (Fig.…”

Section: Characteristics Of Gq Actionsupporting

confidence: 86%

“…The data also show that the required dose is significantly lower than the 100 nmol dose used in our previous reports (Simpson et al, 1998;Resch et al, 2005). Further, the data showed that GQ elicited no response from dorsal control sites.…”

Section: Discussionsupporting

confidence: 56%

“…Ethanol was introduced to P rats in their home cages using a series of increasing concentrations from 3% to 30% as previously reported (Myers, 1971;Resch et al, 2005;Simpson et al, 1998). Briefly, rats were provided continuous access (24 h/day) free-choice of 2 bottles, one containing water and the other the graded sequence of ethanol concentrations.…”

Section: Ethanol Preference Determinationmentioning

confidence: 99%

“…β-endorphin-(1-27), both reduces ethanol intake (Resch et al, 2005) and acts as a partial agonist reducing the β-endorphin-(1-31) induced release of dopamine in NAC (Spanagel et al, 1991). However, the co-produced dipeptide GQ, which also antagonizes ethanol intake (Simpson et al, 1998) appears to utilize different mechanisms to exert its effects in brain. From a NOVA screen (NIMH/NovaScreen Drug Discovery and Development Program, unpublished data) it is clear that GQ does not significantly bind to opioid receptors or to other known neurotransmitter receptors or transporters.…”

Section: Introductionmentioning

confidence: 99%

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

Resch¹,

Simpson²

2008

Alcohol

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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.

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Section: Resultssupporting

confidence: 87%

Section: Characteristics Of Gq Actionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 56%

Section: Ethanol Preference Determinationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Resch¹,

Simpson²

2008

Alcohol

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Glycyl-glutamine (β-endorphin30-31) inhibits morphine-induced dopamine efflux in the nucleus accumbens

Başaran

Büyükuysal

Millington

et al. 2010

Naunyn-Schmied Arch Pharmacol

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Glycyl-glutamine (Gly-Gln) is an endogenous dipeptide that is synthesized from beta-endorphin post-translationally. Previously, we showed that Gly-Gln prevents acquisition of morphine-conditioned place preference, a behavioral test of morphine reward, but does not interfere with morphine analgesia. In this study, we tested the hypothesis that Gly-Gln inhibits morphine reward by blocking morphine-induced dopamine efflux in the nucleus accumbens (NAc). Extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were sampled by microdialysis and analyzed by high-performance liquid chromatography with electrochemical detection. Guide cannulas were implanted in the right NAc and left lateral ventricle of male Sprague-Dawley rats stereotaxically. Approximately 24 h later, a microdialysis probe was inserted into the NAc and perfused at 1 microl/min. Gly-Gln (1, 3, 30, or 100 nmol/5 microl) or saline was administered intracerebroventricularly, morphine (2.5 mg/kg) was injected intraperitoneally (i.p.) 2 min later, and extracellular dopamine and DOPAC were sampled at 20-min intervals. Morphine administration increased extracellular dopamine concentrations by approximately 600% within 40 min. Gly-Gln pretreatment inhibited the rise in extracellular dopamine in a dose-related manner; the lowest significantly inhibitory dose was 1 nmol. Gly-Gln also inhibited the morphine-induced rise in extracellular DOPAC concentrations but did not affect extracellular dopamine or DOPAC in control animals. Gly-Gln (100 nmol/5 microl) prevented morphine-induced dopamine efflux in rats treated with morphine chronically (10 mg/kg, i.p. twice daily for 6 days), although it did not affect DOPAC concentrations significantly. These data support the hypothesis that Gly-Gln abolishes the rewarding effect of morphine by inhibiting the ability of morphine to stimulate dopamine release in the NAc.

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

Bobba

Resch

Gutheil

2012

Analytical Biochemistry

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The enzymatic cleavage products of β-endorphin (β-endorphin1-27 and Gly-Gln) reduce voluntary alcohol consumption in alcohol preferring P rats. Gly-Gln also inhibits the reward benefiting effects of morphine and nicotine. It would be useful for the investigation of this effect to have an analytical method suitable for Gly-Gln detection and quantitation. Given the now widespread availability of LC-MS/MS instruments, the development of an LC-MS/MS-based approach seemed a viable option. An LC-MS/MS method for Gly-Gln quantitation was developed based on derivatization with Marfey’s reagent. The Marfey’s adduct of Gly-Gln (Mar-Gly-Gln) was chromatographically resolved and readily detected and quantitated by LC-MS/MS. Precursor/product positive ions of 456.2/366.2, 456.2/237.2, 456.2/147.0 were used for detection and quantitation. This method shows good linearity from 1 to 500 pmole of Mar-Gly-Gln (R2 >0.99). The assay also demonstrated good accuracy and precision, with an average percent standard deviation for Gly-Gln over the range of the assay of <5%. A combination of MRM fragment ratio normalization and chromatographic peak shifting were used to ensure that the LC-MS/MS peak for Mar-Gly-Gln was free from possible isobar interferences. This assay was then demonstrated for the determination of in vivo Gly-Gln levels in P and Sprague-Dawley rat cortex and nucleus accumbens samples.

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Glycyl-l-Glutamine Injected Centrally Suppresses Alcohol Drinking in P Rats

Cited by 9 publications

References 38 publications

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

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

Glycyl-glutamine (β-endorphin30-31) inhibits morphine-induced dopamine efflux in the nucleus accumbens

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

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