Relevance: Many drugs of abuse derive their addiction liability, in part, by activating a specific circuit in the brain called the mesoaccumbens dopamine pathway. The research described in this proposal will determine how opioid receptor activity and calcium channel inhibitors can modulate the dopamine released by various stimulation patterns. This research will advance our understanding of the mesoaccumbens dopamine pathway and may lead to effective treatments for addiction. Project Summary: Dopamine release in the striatum is associated with many brain functions, including motor control, arousal, attention, action selection, energy balance, as well as learning and motivation. The dopaminergic fibers responsible for this release exhibit consistent, tonic firing patterns in quiescent rats. In response to behaviorally relevant stimuli, however, this basal activity is interrupted with brief bursts of high frequency action potentials. The experiments described in this proposal assess how the amount of dopamine actually released by these different firing patterns can be differentially modulated in the dopamine axon terminal. These investigations will make an essential contribution to the field of drug addiction research because many drugs of abuse derive their addiction liability, in part, by raising extracellular dopamine concentrations in a part of the striatum called the nucleus accumbens. For many drugs, including nicotine and heroin, this effect results from an escalation in dopamine neuron burst firing patterns. Fast-scan cyclic voltammetry and amperometry are electrochemical recording techniques that allow the detection of phasic dopamine release in real-time. The experiments in this proposal will utilized these methods in the nucleus accumbens of rat brain slices to assess the impact of both opioid receptor activity and calcium channel blockers on low and high frequency-evoked dopamine release.
The first aim of this proposal will exploit specific kappa and mu opioid receptor agonists and antagonists to determine how opioid receptor activity differentially modulates dopamine release via tonic and burst stimuli.
The second aim of this proposal will explore potential mechanisms for these manipulations and identify the voltage-gated calcium channels that mediate dopamine release in response to tonic and burst stimuli. These studies will further our understanding of dopamine release dynamics, specifically in regards to the tonic and burst firing patterns exhibited by dopamine neurons. This research may lead to effective clinical treatments for drug addiction. ? ? ?
| Ding, Yunmin; Won, Lisa; Britt, Jonathan P et al. (2011) Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc Natl Acad Sci U S A 108:840-5 |
| Kheirbek, Mazen A; Britt, Jon P; Beeler, Jeff A et al. (2009) Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning. J Neurosci 29:12115-24 |
| Britt, Jonathan P; McGehee, Daniel S (2008) Presynaptic opioid and nicotinic receptor modulation of dopamine overflow in the nucleus accumbens. J Neurosci 28:1672-81 |
