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 GABA(B) 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 GABA(B) receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA(B) 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 GABA(B) receptors on DA terminals, with both GABA(B) 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.

Fig. 1

The locations of the microdialysis probes were confirmed histologically in Nissl stained sections. The locations of sampling in the PFC (A) were medial and rostral to the anterior forceps of the corpus callosum (arrow). Striatal sampling sites (B) were in the rostral caudoputamen (arrow). Scale bar = 1 mm.

Fig. 2

Shows the effect of the GABA_B agonist SKF97541 on extracellular dopamine levels in the presence and absence of the antagonist CGP52432 following local administration into prefrontal cortex (A) or striatum (B) at indicated doses. (A) Baseline DA levels for control group 1.92 ± 0.41 pg/10 µl (n = 6), for the SKF97541 group 1.95 ± 0.56 pg/10 µl (n = 10), for the CGP52432 group 1.55 ± 0.35 pg/10 µl (n = 9) and for the SKF97541 + CGP52432 group 1.56 ± 0.37 pg/10 µl (n = 6). (B) Baseline DA levels for control group 10.30 ± 2.15 pg/10 µl (n = 8), for the SKF97541 group 10.63 ± 1.43 pg/10 µl (n = 8), for the CGP52432 group 8.06 ± 1.13 pg/10 µl (n = 8) and for the SKF97541 + CGP52432 group 7.35 ± 1.71 pg/10 µl (n = 5).

Fig. 3

Represent the effect of local administration of the GABA_B agonists on AMPH-induced DA release (1 and 5 mg/kg) in PFC (A, B) and in STR (C, D) at indicated doses. (A) Baseline DA levels for control group getting 1 mg/kg AMPH injection 1.33 ± 0.19 pg/10 µl (n = 10), for SKF97541+1AMPH group 1.22 ± 0.12 pg/10 µl (n = 5). (B) Baseline DA levels for group getting 5 mg/kg AMPH injection 1.17 ± 0.19 pg/10 µl (n = 12), for SKF97541+5AMPH group 1.49 ± 0.41 pg/10 µl (n = 7) and for the Baclofen+5AMPH group 1.34 ± 0.24 pg/10 (n = 7). (C) Following baseline DA levels were detected: in control group getting 1 mg/kg AMPH injection 11.70 ± 2.00 pg/10 µl (n = 15) and for SKF97541 +1AMPH group 13.52 ± 1.27 pg/ 10 µl (n = 9). (D) Baseline DA levels for control group getting 5 mg/kg AMPH injection 13.13 ± 1.12 pg/10 µl (n = 14), for SKF97541 +5AMPH group 10.90 ± 1.20 pg/10 µl (n = 7) and for the Baclofen + 5AMPH group 10.50 ± 1.99 pg/10 µl (n = 9).

Fig. 4

Effect of subchronic administration of GLY on AMPH-induced DA (5 mg/kg) DA release in PFC (A) or STR (B) in the absence or presence of the GABA_B antagonist CGP52432 infused locally through the microdialysis probe. Inset: each bar represents a mean ± SEM value (percent of baseline) of the 150–210 min time period after AMPH administration. (A) Baseline DA values for control group receiving 5 mg/kg AMPH 1.17 ± 0.19 pg/10 µl (n = 12), for CGP52432 + 5AMPH group 0.96 ± 0.18 pg/10 µl (n = 11), for the GLY-treated group receiving 5 mg/kg AMPH injection 1.08 ± 0.21 pg/10 µl (n = 14) and for GLY-treated group receiving CGP52432 + 5AMPH 0.94 ± 0.21 pg/10 µl (n = 6). (B) Baseline DA values for control group receiving 5 mg/kg AMPH 13.13 ± 1.12 pg/10 µl (n = 14), for CGP52432 + 5AMPH group 11.06 ± 2.60 pg/10 µl (n = 9), for the GLY-treated group receiving 5 mg/kg AMPH injection 8.11 ± 1.29 pg/10 µl (n = 10) and for GLY-treated group receiving CGP52432 + 5AMPH 6.10 ± 1.03 pg/10 µl (n = 6).