Repeated exposure to cocaine alters the modulation of mesocorticolimbic glutamate transmission by medial prefrontal cortex Group II metabotropic glutamate receptors

Abstract

Repeated cocaine exposure enhances glutamatergic output from the medial prefrontal cortex to subcortical brain regions. Loss of inhibitory control of cortical pyramidal neurons may partly account for this augmented cortical glutamate output. Recent research indicated that repeated cocaine exposure reduced the ability of cortical Group II metabotropic glutamate receptors to modulate behavioral and neurochemical responses to cocaine. Thus, experiments described below examined whether repeated cocaine exposure alters metabotropic glutamate receptor regulation of mesocorticolimbic glutamatergic transmission using in vivo microdialysis. Infusion of the Group II metabotropic glutamate receptor antagonist LY341495 into the medial prefrontal cortex enhanced glutamate release in this region, the nucleus accumbens and the ventral tegmental area in sensitized animals, compared to controls, following short-term withdrawal but not after long-term withdrawal. Additional studies demonstrated that vesicular (K(+)-evoked) and non-vesicular (cystine-evoked) glutamate release in the medial prefrontal cortex was enhanced in sensitized animals, compared to controls, that resulted in part from a reduction in Group II metabotropic glutamate receptor modulation of these pools of glutamate. In summary, these findings indicate that the expression of sensitization to cocaine is correlated with an altered modulation of mesocorticolimbic glutamatergic transmission via reduction of Group II metabotropic glutamate receptor function.

Figure 1

Motor stimulant response to cocaine in animals that had previously received daily repeated saline or cocaine injections for microdialysis studies in Experiment 1 following (a) 1 day, (b) 7 days or (c) 30 days of withdrawal. Data represented as mean ± SEM photocell counts. *p< 0.05 compared to saline.

Figure 2

The effects of the intra-mPFC infusion of LY341495 (0.1, 1 and 10 μM) on extracellular glutamate levels within the mPFC (a) 1 day, (b) 7 days or (c) 30 days following repeated saline or cocaine exposure. *p < 0.05 compared to saline animals and ⁺p < 0.05 compared to baseline.

Figure 3

The effects of the intra-mPFC infusion of LY341495 (0.1, 1 and 10 μM) on extracellular glutamate levels within the nucleus accumbens (a) 1 day, (b) 7 days or (c) 30 days following repeated saline or cocaine exposure. *p < 0.05 compared to saline animals and ⁺p < 0.05 compared to baseline.

Figure 4

The effects of the intra-mPFC infusion of LY341495 (0.1, 1 and 10 μM) on extracellular glutamate levels within the VTA (a) 1 day, (b) 7 days or (c) 30 days following repeated saline or cocaine exposure. *p < 0.05 compared to saline animals and ⁺p < 0.05 compared to baseline.

Figure 5

Motor stimulant response to cocaine in animals that had previously received daily repeated saline or cocaine injections for microdialysis studies in Experiment 2 following (a) 1 day or (b) 7 days withdrawal from repeated cocaine exposure. Data represented as mean ± SEM photocell counts. *p < 0.05 compared to saline.

Figure 6

The effects of infusion of KCl (80 mM) into the mPFC on extracellular glutamate levels within this region (a) 1 day or (b) 7 days following repeated saline or cocaine exposure. *p < 0.05 compared to saline animals, ⁺p < 0.05 compared with baseline and ^#p < 0.05 compared with comparable saline treatment.

Figure 7

The effects of the infusion of cystine (50 μM) into the mPFC on extracellular glutamate levels within this region (a) 1 day or (b) 7 days following repeated saline or cocaine exposure. *p < 0.05 compared to saline animals, ⁺p < 0.05 compared with baseline and ^#p < 0.05 compared with comparable saline treatment.

Figure 8

Representative photomicrographs of dialysis probe sites in the a) mPFC, b) nucleus accumbens and c) VTA. fmi= forceps minor corpus callosum, ac= anterior commissure, PBP= parabrachial pigmented nucleus, PN= paranigral nucleus and SN= substantia nigra.