Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats

Olsson, Yasmin; Lidö, Helga Höifödt; Danielsson, Klara; Ericson, Mia; Söderpalm, Bo

doi:10.1007/s00702-020-02284-x

Cited by 7 publications

(14 citation statements)

References 37 publications

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“…The accumbal dopamine response for each individual rat was scrutinized to investigate whether a subpopulation of animals presented elevated extracellular dopamine levels of more than 10%, a heterogenous response that has previously been observed following glycine administered i.p. or locally into the nAc (Molander and Soderpalm, 2005a , Olsson et al 2020 ). As depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…of either isomer (Han et al 2018 ). In this explorative study, we chose also to include a 10- and 100-fold higher dose in which the latter dose approximately corresponds to a molar content of glycine that upon systemic administration produces a trend for raised accumbal glycine levels between 50 and 150% (Olsson et al 2020 ). Ethanol (95%; Kemetyl AB, Sweden) was diluted in 0.9% NaCl to a concentration of 15% for i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Extracellular glycine and dopamine measurements over time ( t = 0–120 min) from in vivo microdialysis were evaluated by a two-way ANOVA followed by Dunnett’s multiple comparison test whereas area under the curve (AUC) data were analyzed using one-way ANOVA. In the microdialysis study, rats were classified as dopamine responders if dopamine was elevated more than 10% compared to baseline within the first hour after injection, in line with previous subdivision for rats that received local (into the nAc) or systemic treatment with glycine (Molander and Soderpalm, 2005a, Olsson et al 2020 ). Baseline glycine and dopamine levels and peak glycine levels for dopamine responders vs non-responders were compared using an independent samples t test.…”

Section: Methodsmentioning

confidence: 99%

“…Attempts to precisely delineate the neurobiological underpinnings of alcohol reward are currently ongoing and evidence from animal studies suggests that alcohol enters the mesolimbic reward pathway by targeting GlyRs in the nAc, among other receptor populations (Molander and Söderpalm 2005b , Spanagel 2009 ; Soderpalm et al 2017 ). Accordingly, both local (into the nAc) and systemic treatment with the endogenous GlyR agonist glycine or glycine-transporter-1(GlyT-1)-inhibitors, that regulate CNS glycine levels, elevate basal dopamine levels in a sub-population of rats denoted dopamine responders, attenuate the alcohol-induced dopamine elevation and robustly reduce alcohol intake in the rat (Molander and Söderpalm, 2005b , Molander et al 2007 ; Lidö et al 2009 , 2012 ; Vengeliene et al 2010 , 2018 ; Olsson et al 2020 ). Thus, compounds that elevate central glycine levels and target the GlyR appear to interfere with the reinforcing properties of alcohol and may represent a new pharmacologic treatment principle for AUD (Soderpalm et al 2017 ; Olsson et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, treatment protocols for glycine, utilizing either glycine’s agonistic effect on the GlyR in AUD animal models or its co-agonistic effect on the NMDA-receptor in human studies for the treatment of schizophrenia, require impractically large doses of glycine (Heresco-Levy et al 1999 ; Buchanan et al 2007 ; Olsson et al 2020 ). In addition, serum and brain glycine levels as measured by magnetic resonance spectroscopy (MR-S) vary considerably between subjects after intravenous glycine treatment (Kaufman et al 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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The glycine-containing dipeptide leucine-glycine raises accumbal dopamine levels in a subpopulation of rats presenting a lower endogenous dopamine tone

et al. 2022

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Interventions that elevate glycine levels and target the glycine receptor (GlyR) in the nucleus Accumbens (nAc) reduce ethanol intake in rats, supposedly by acting on the brain reward system via increased basal and attenuated ethanol-induced nAc dopamine release. Glycine transport across the blood brain barrier (BBB) appears inefficient, but glycine-containing dipeptides elevate whole brain tissue dopamine levels in mice. This study explores whether treatment with the glycine-containing dipeptides leucine-glycine (Leu-Gly) and glycine-leucine (Gly-Leu) by means of a hypothesized, facilitated BBB passage, alter nAc glycine and dopamine levels and locomotor activity in two rodent models. The acute effects of Leu-Gly and Gly-Leu (1–1000 mg/kg, i.p.) alone or Leu-Gly in combination with ethanol on locomotion in male NMRI mice were examined in locomotor activity boxes. Striatal and brainstem slices were obtained for ex vivo HPLC analyses of tissue levels of glycine and dopamine. Furthermore, the effects of Leu-Gly i.p. (1–1000 mg/kg) on glycine and dopamine output in the nAc were examined using in vivo microdialysis coupled to HPLC in freely moving male Wistar rats. Leu-Gly and Gly-Leu did not significantly alter locomotion, ethanol-induced hyperlocomotor activity or tissue levels of glycine or dopamine, apart from Gly-Leu 10 mg/kg that slightly raised nAc dopamine. Microdialysis revealed no significant alterations in nAc glycine or dopamine levels when regarding all rats as a homogenous group. In a subgroup of rats defined as dopamine responders, a significant elevation of nAc dopamine (20%) was seen following Leu-Gly 10–1000 mg/kg i.p, and this group of animals presented lower baseline dopamine levels compared to dopamine non-responders. To conclude, peripheral injection of glycine-containing dipeptides appears inefficient in elevating central glycine levels but raises accumbal dopamine levels in a subgroup of rats with a lower endogenous dopamine tone. The tentative relationship between dopamine baseline and ensuing response to glycinergic treatment and presumptive direct interactions between glycine-containing dipeptides and the GlyR bear insights for refinement of the glycinergic treatment concept for alcohol use disorder (AUD).

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The glycine-containing dipeptide leucine-glycine raises accumbal dopamine levels in a subpopulation of rats presenting a lower endogenous dopamine tone

et al. 2022

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The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats

Olsson,

Lidö,

Ademar

et al. 2023

J Neural Transm

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Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.

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Alcohol and the dopamine system

Söderpalm,

Ericson

2024

International Review of Neurobiology

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Effects of systemic glycine on accumbal glycine and dopamine levels and ethanol intake in male Wistar rats

Cited by 7 publications

References 37 publications

The glycine-containing dipeptide leucine-glycine raises accumbal dopamine levels in a subpopulation of rats presenting a lower endogenous dopamine tone

The glycine-containing dipeptide leucine-glycine raises accumbal dopamine levels in a subpopulation of rats presenting a lower endogenous dopamine tone

The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats

Alcohol and the dopamine system

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