Erin Taylor, Eliza White

Much of addiction research in the mesolimbic dopamine (DA) pathway is focused on immune interactions due to high correlation of drug use with infection. Recent work suggests that microglia, native immune cells of the central nervous system, may interact with methamphetamine (METH) to alter its effect on DA release in this pathway. However, the mechanism and effects of microglial function on addictive behavior are unclear. Recent work using lipopolysaccharide (LPS), an antigen that activates microglia, has demonstrated that microglia in the ventral tegmental area contribute to methamphetamine effects on dopamine release through cell body interactions. However, it is unknown whether microglia at terminal regions like the accumbens are involved in psychostimulant effects. Using FSCV in brain slices, the present study attempts to quantify the effect of microglial activation on DA terminal function in the mesolimbic DA pathway, particularly the nucleus accumbens (NAc). The present study also uses two-photon microscopy to examine morphological changes in microglia in response to LPS and METH. Together, FSCV and two-photon microscopy demonstrate the connection between microglia activation and DA terminal function. Bath-application of 1 µg/mL LPS significantly increased the amplitude of DA release after four hours, but had no effect on reuptake. LPS also changed morphology of microglia consistent with an inflammatory immune response. In contrast, acute administration of 10µM METH did not affect the amplitude of DA release at the DA terminal but did significantly decrease the rate of DA reuptake. METH application showed similar morphology changes to LPS. Co-administration of METH after 4 hours of LPS attenuated METH's effect on DA reuptake, showing that inflammation is interacting with DA terminal function. Though further exploration is required to elucidate their exact mechanisms, there is a clear connection between microglial activation and DA terminal function in the NAc.