GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

Abstract

Deficits in N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABAB receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC–EC in freely moving rats. Infusion of the GABAB receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABAB agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABAB receptors on DA terminals, with both GABAB ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.

Neurochemical and molecular characterization of ketamine-induced experimental psychosis model in mice

“…increased glutamate and dopamine release in the limbic striatal regions (Gass et al, 1993;Moghaddam et al, 1997;Duncan et al, 1998;Gao et al, 1998;Lorrain et al, 2003;Balla et al, 2009;Hons et al, 2010). Our results tend to corroborate these findings (Fig.…”

Astrocytes Express N-Methyl-D-Aspartate Receptor Subunits in Development, Ischemia and Post-Ischemia

“…Abel Lajtha and his group recently have reported the deficits in NMDA-R mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia [38]. However, studies on NMDA-R were mainly limited to neurons.…”

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

“…The site of action of GlyT-1 inhibitors to reduce striatal dopamine release may be the GABAergic neurons, which receive NMDA receptormediated glutamatergic innervation from the cerebral cortex, and their recurrent axon collaterals terminate on nigrostriatal dopaminergic nerve endings [36]. It is possible that GlyT-1 inhibitors decrease dopamine release in the striatum indirectly as these drugs were shown to facilitate GABA release, which then in turn inhibits dopamine efflux [35,37]. The decrease in dopamine release after Org-24461 can be attributed to effects on NMDA receptors as this compound, in contrast to risperidone, does not exhibit significant binding affinity to D 2 dopamine receptors.…”