Modulation of stimulated dopamine release in rat nucleus accumbens shell by GABA in vitro: Effect of sub‐chronic phencyclidine pretreatment

Abstract

Dopamine signaling in nucleus accumbens (NAc) is modulated by γ‐aminobutyric acid (GABA), acting through GABA‐A and GABA‐B receptors: dysregulation of GABAergic control of dopamine function may be important in behavioral deficits in schizophrenia. We investigated the effect of GABA‐A (muscimol) and GABA‐B (baclofen) receptor agonists on electrically stimulated dopamine release. Furthermore, we explored whether drug‐induced changes were disrupted by pretreatment with phencyclidine, which provides a well‐validated model of schizophrenia. Using brain slices from female rats, fast‐scan cyclic voltammetry was used to measure electrically stimulated dopamine release in NAc shell. Both muscimol and baclofen caused concentration‐dependent attenuation of evoked dopamine release: neither effect was changed by dihydro‐β‐erythroidine, a nicotinic acetylcholine receptor antagonist, or the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐type glutamate receptor antagonist, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), precluding indirect mechanisms using these transmitter systems in the GABAergic actions. In slices taken from rats pretreated with phencyclidine, the attenuation of evoked dopamine release by baclofen was abolished, but the attenuation by muscimol was unaffected. Since phencyclidine pretreatment was followed by drug‐free washout period of at least a week, the drug was not present during recording. Therefore, disruption of GABA‐B modulation of dopamine is due to long‐term functional changes resulting from the treatment, rather than transient changes due to the drug's presence at test. This enduring dysregulation of GABA‐B modulation of accumbal dopamine release provides a plausible mechanism through which GABA dysfunction influences accumbal dopamine leading to behavioral changes seen in schizophrenia and may provide a route for novel therapeutic strategies to treat the condition.

Attenuation of Stimulated Accumbal Dopamine Release by NMDA Is Mediated through Metabotropic Glutamate Receptors

“…We extended this by testing whether blockade of GABA-B receptors affected the NMDA-induced attenuation. As with DHβE, the GABA-B antagonist CGP 54626 (1 μM) caused a marked increase in stimulated dopamine release when applied alone, consistent with previous reports, and therefore required the extended (18 stimulus) protocol to establish a new baseline release in the presence of the antagonist, before applying NMDA. In these conditions, NMDA continued to reduce stimulated dopamine release, even in the presence of the GABA-B antagonist.…”

“…Neither the nicotinic AChR antagonist DHβE (1 μM) nor the muscarinic AChR antagonist scopolamine (1 μM), at concentrations previously shown to be effective at blocking cholinergic actions, affected the NMDA-evoked attenuation. Similarly, the GABA-B receptor antagonist CGP 54626 (1 μM), at a concentration known to block the GABA-B function, did not reverse the NMDA-evoked attenuation. However, the broad-spectrum (group I/II/III) mGluR antagonist MCPG (100 μM) and the specific group II mGluR antagonist LY 341495 (1 μM) completely reversed the effect of NMDA.…”

“…Previous studies have shown that the GABA-A receptor antagonist picrotoxin does not diminish the attenuation of stimulated dopamine release caused by NMDA; 14 therefore the current experiments focused on GABA-B receptors. As with DHβE and consistent with previous experiments, 36 the GABA-B receptor antagonist CGP 54626 caused an increase in stimulated dopamine release when applied alone. We therefore used the extended protocol, where a new baseline was established in the presence of the antagonist before application of the NMDA, facilitating dissociation of the effects of the two drugs.…”

“…Therefore, GABA-B receptors do regulate accumbal dopamine release, but whether this mediates the effect of NMDA remains unclear. Moreover, the effect of pretreatment with the noncompetitive NMDA receptor antagonist, phencyclidine, on the GABA-B mediated modulation of stimulated dopamine release 36 is consistent with a potential role of GABA-B mechanisms mediating the attenuating effect of NMDA on stimulated dopamine release, although this is not equivocal and warrants further investigation.…”

“…However, GABA-B receptors provide another mechanism through which the attenuation of dopamine release by NMDA may occur, − particularly as there is evidence for GABA-B heteroreceptors on accumbal dopamine terminals . GABA-B agonists decrease accumbal dopamine release in vivo and in rat and mouse brain slices in vitro . Therefore, GABA-B receptors do regulate accumbal dopamine release, but whether this mediates the effect of NMDA remains unclear.…”