Electrical stimulation of the prefrontal cortex increases dopamine release in the nucleus accumbens of the rat: Modulation by metabotropic glutamate receptors

Abstract

In vivo microdialysis was used to assess the effects of electrical stimulation of the prefrontal cortex (PFC) on dopamine (DA) release in the nucleus accumbens (NAC) of awake, unrestrained rats. The PFC was stimulated bilaterally for 20 min at parameters previously shown to support intracranial self-stimulation in this structure. Stimulation at 50 μA evoked a 38% increase in DA release while 100 μA produced a 69% increase. Thus, phasic activation of the PFC increases DA release in the NAC. Additional experiments were performed to establish whether glutamate receptors in the NAC mediated these effects. The noncompetitive NMDA antagonist dizocilpine maleate (MK- 801) and the broad spectrum competitive antagonist kynurenic acid were each applied locally to the NAC via reverse dialysis alone or in combination with electrical stimulation of the PFC (100 μA). Both MK-801 (10 μM) and kynurenic acid (5 mM) increased DA release when administered alone. When a 'subthreshold' concentration (i.e., the highest concentration employed that did not itself increase DA release) of either compound was administered together with PFC stimulation, neither kynurenic acid (1 mM) nor MK-801 (1 μM) attenuated the effect of stimulation on DA release, thereby indicating that this effect is not mediated by ionotropic glutamate receptors located within the NAC. To examine the possible role of metabotropic glutamate receptors in regulating DA release, the metabotropic glutamate agonist trans(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) was employed. When applied locally to the NAC, ACPD had a dose-dependent effect on DA release with a high concentration (1 mM) causing an increase and a lower concentration (100 μM) causing a small decrease. The latter concentration blocked PFC stimulation (100 μA)-induced increases in DA release in the NAC. To determine whether this finding reflected a general inhibitory effect of ACPD on stimulated DA release, ACPD was also applied during electrical stimulation (20 μA) of the ventral tegmental area, the origin of the mesoaccumbens DA projection. Again, ACPD (100 μM) blocked the stimulation- induced increase in DA release. These findings demonstrate that (1) phasic activation of the PFC increases DA release in the NAC, (2) this effect is not mediated by ionotropic glutamate receptors in the NAC, and (3) local metabotropic receptors serve to inhibit stimulation-induced increases in transmitter release from mesoaccumbens DA terminals. These results provide further evidence for functional interactions between metabotropic glutamate receptors and DA in the limbic striatum.