THE MODULATION OF THE MESOLIMBIC AND NIGROSTRIATAL DOPAMINE PATHWAYS BY CXCL12 AND CXCR4

Abstract

The role of chemokines in immune function is clearly established. Recent evidence suggests that these molecules also play an important role in the CNS as modulators of neuronal activity. The chemokine CXCL12 has been identified in several regions of the adult rat brain including the substantia nigra, ventral tegmental area and caudate putamen. CXCR4, a receptor activated by CXCL12, is expressed by dopaminergic neurons in the substantia nigra. The research presented herein explored the behavioral modulation of CXCL12, expression of the CXCR4 receptor in the forebrain of the adult rat and the effect of CXCL12 administration on extracellular dopamine and glutamate release in the medial shell of the nucleus accumbens. This research furthered our understanding of how CXCL12 can affect behavior and suggested that the modulation of cocaine-induced behavior by CXCL12 is due to an interaction with CXCR4 receptors in the mesolimbic and nigrostriatal dopamine pathways. The data presented tested the effects of intracranial injections of CXCL12 on cocaineinduced locomotion and stereotypic activity in adult male Sprague Dawley rats. Results demonstrate that intracerebroventricular administration of CXCL12 (25 ng/4 μl) 15 minutes prior to cocaine (20 mg/kg IP) produced a significant potentiation of both ambulatory and stereotypic activity as compared to cocaine alone. The effects of CXCL12 were blocked by administration of the selective CXCR4 antagonist, AMD 3100. Administration of CXCL12 into specific brain regions was performed to further understand the site of action of CXCL12. Bilateral administration of CXCL12 (25 ng/0.5 μl) into the ventral tegmental area 15 minutes prior to cocaine (20 mg/kg IP) significantly potentiated cocaine-induced ambulatory activity, whereas microinjections of CXCL12 into the caudate putamen selectively increased stereotypy. Conversely, administration of CXCL12 into the lateral shell of the nucleus accumbens resulted in an inhibition of cocaine-stimulated ambulatory activity. No alterations in ambulatory or stereotypic activity were observed following CXCL12 administration into the core of the nucleus accumbens. Immunohistochemistry results showed evidence of CXCR4 within the caudate putamen and lateral shell of the nucleus accumbens. Dual labeling immunofluorescence demonstrated that CXCR4 is co-expressed on cholinergic and GABAergic neurons, including co-localization with the D1 dopamine receptor in both the caudate putamen and lateral shell of the nucleus accumbens. Results demonstrated that CXCR4 is co-expressed with choline acetyl transferase, a marker for cholinergic neurons, with GAD C38, a marker for GABAergic neurons, and with the D1 dopamine receptor, also a marker for GABAergic medium spiny neurons. High pressure liquid chromatography studies were conducted using brain dialysate collected from microdialysis probes surgically implanted in the medial shell of the nucleus accumbens. Results demonstrated no significant change in extracellular dopamine or glutamate following an acute administration of CXCL12. The research presented herein sought to determine the behavioral modifications of CXCL12 as well as the localization of CXCR4 in the forebrain of the adult rat. This research also examined changes in extracellular dopamine and glutamate levels following CXCL12 administration. Results demonstrated that CXCL12 does alter the behavioral activity of cocaine. Results also showed that CXCR4 is localized on cholinergic and GABAergic neurons that could be contributing to the behavioral modification. These results have extended our understanding of the complex mechanisms of CXCL12 and CXCR4 in the mesolimbic and nigrostriatal dopamine pathways of the adult rat brain.