Anna Molander1, Bo Söderpalm. 1. Institute of Physiology and Pharmacology, Section of Psychiatry, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
Abstract
BACKGROUND: The mesolimbic dopamine (DA) system seems to be centrally involved in regulating reward-related behavior and consequently has been implicated in addictive processes, such as alcoholism and drug addiction. This DA system has also been implicated in psychosis and in regulating hedonia/anhedonia, important components of mania and depression. Given the potentially great importance of the mesolimbic DA system for several psychiatric disorders, it is of major interest to delineate the mechanisms and dynamics underlying DA regulation and release. Recently strychnine-sensitive glycine receptors (GlyR) have attracted some interest in this matter. METHODS: Western blot and in vivo microdialysis (couplied to high-pressure liquid chromatography with electrochemical detection), as well as reversed microdialysis, in awake, freely moving, adult male Wistar rats. RESULTS: Here we demonstrate by means of Western blot that alpha GlyR subunit proteins are expressed in the rat nucleus accumbens (nAc), a major target of the mesolimbic DA system. We further show that reversed microdialysis of the competitive GlyR antagonist strychnine into the nAc concentration-dependently (2-200 microM) and in a reversible manner decreases accumbal extracellular DA levels. Conversely, reversed microdialysis of the agonist glycine increases accumbal DA levels in some rats but not others. The strychnine-induced depression of the accumbal DA levels is antagonized by simultaneous local perfusion of glycine. CONCLUSIONS: The present results indicate that GlyRs in the nAc are tonically activated and of importance for regulating extracellular DA levels. The possibility of pharmacologically interfering with GlyRs to combat psychiatric disorders, in which the mesolimbic DA system is implicated, such as alcoholism, drug addiction, and psychosis, should be explored.
BACKGROUND: The mesolimbic dopamine (DA) system seems to be centrally involved in regulating reward-related behavior and consequently has been implicated in addictive processes, such as alcoholism and drug addiction. This DA system has also been implicated in psychosis and in regulating hedonia/anhedonia, important components of mania and depression. Given the potentially great importance of the mesolimbic DA system for several psychiatric disorders, it is of major interest to delineate the mechanisms and dynamics underlying DA regulation and release. Recently strychnine-sensitive glycine receptors (GlyR) have attracted some interest in this matter. METHODS: Western blot and in vivo microdialysis (couplied to high-pressure liquid chromatography with electrochemical detection), as well as reversed microdialysis, in awake, freely moving, adult male Wistar rats. RESULTS: Here we demonstrate by means of Western blot that alpha GlyR subunit proteins are expressed in the rat nucleus accumbens (nAc), a major target of the mesolimbic DA system. We further show that reversed microdialysis of the competitive GlyR antagonist strychnine into the nAc concentration-dependently (2-200 microM) and in a reversible manner decreases accumbal extracellular DA levels. Conversely, reversed microdialysis of the agonist glycine increases accumbal DA levels in some rats but not others. The strychnine-induced depression of the accumbal DA levels is antagonized by simultaneous local perfusion of glycine. CONCLUSIONS: The present results indicate that GlyRs in the nAc are tonically activated and of importance for regulating extracellular DA levels. The possibility of pharmacologically interfering with GlyRs to combat psychiatric disorders, in which the mesolimbic DA system is implicated, such as alcoholism, drug addiction, and psychosis, should be explored.
Authors: Braulio Muñoz; Scarlet Gallegos; Christian Peters; Pablo Murath; David M Lovinger; Gregg E Homanics; Luis G Aguayo Journal: Addict Biol Date: 2019-03-18 Impact factor: 4.280