| 2019 |
Oliver, Chicora F |
K00Activity Code Description:
To support the second phase of a Pre-Doctoral to Post-Doctoral Transition award program that provides 3-4 years of career support. Note: The K00 Post-doctoral Transition Award is anticipated to only be used in conjunction with the F99 Pre-Doctoral Award. |
Ventral Periaqueductal Gray Dopamine Control of Sleep and Arousal
PROJECT ABSTRACT Psychostimulant abuse is a major public health concern, yet no FDA-approved therapies exist. 3,4-methylenedioxypyrovalerone (MDPV) is a type of `bath salt' that is ten times stronger, but mechanistically similar, to cocaine. This psychostimulant has powerful reinforcing effects that manifest as escalating self-administration and relapse following abstinence. Chemokines, chemotactic inflammatory proteins, are dysregulated in cocaine users. The chemokine receptor- ligand pair CXCR4-CXCL12 in particular has been linked to psychostimulant use. Human cocaine users and rodent models have heightened plasma CXCL12 levels, and CXCL12 potentiates the dopaminergic and hyperlocomotive effects of cocaine. Through mastery of rodent self-administration, I have expanded my technical repertoire and revealed that AMD3100, a CXCR4 antagonist, decreases cocaine and MDPV-induced hyperlocomotion, self- administration, and conditioned place preference, reflecting a reduction in the reinforcing effects of MDPV. Moreover, repeated MDPV increases CXCL12 and CXCR4 mRNA in the ventral tegmental area and decreases dendrite morphometrics in the nucleus accumbens (NAC) core. These findings strongly implicate that CXCR4 modulation alters the reinforcing and neuroplastic effects of MDPV. F99 phase research studies will extend these findings by measuring dendrite morphology and neuroelectrical properties of the NAC core following AMD3100 treatment and MDPV self-administration sessions. Structural plasticity will be examined using a Golgi-Cox stain followed by computer-assisted neuron reconstruction. Whole cell patch clamp will be mastered to examine NAC core electrical property dynamics and glutamatergic drive. Learning these electrophysiological techniques will expanding my technical repertoire, elucidate the effects of MDPV self-administration on structural neuroelectrical plasticity in the NAC core, and promote my ultimate career goal of becoming an independent neuroscience researcher. The results of these studies may reveal modulation of the receptor-ligand CXCR4-CXCL12 system as a therapeutic target for treatment of psychostimulant addiction. Finally, the proposed project will provide a foundation upon which a postdoctoral research focus on substance abuse can be built, in preparation for a career as an independent neuroscience researcher.
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0.923 |