Pharmacological and electrophysiological characterizations of dopaminergic modulation of long-term potentiation in the hippocampus CA1 region
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Over the past fifty years, our understanding of dopamine has evolved from a mere acknowledgement of its precursory status in norepinephrine production to the realization that it orchestrates complex modulatory activity in the striatum (reviewed by Onn et al., 2000), the prefrontal cortex (reviewed by Seamans and Yang, 2004), and the hippocampus (reviewed by Lisman and Grace, 2005). Importantly, the hallmark of addictive drugs is their ability to augment dopamine levels in the brain. Because addiction engages the neurophysiological underpinnings of learning and memory, I focused my research on dopaminergic modulation of synaptic plasticity within the hippocampus CA1 region, the brain’s gateway for storage and recall of many types of information. Specifically, I investigated the ability of dopamine to modulate long-term potentiation (LTP), a persisting enhancement of communication between neurons that serves as a cellular model for learning and memory. Using extracellular recording methods, I demonstrated that both D1/5 and D3 agonists enhance LTP via distinct pathways that ultimately converge upon NR2B-NMDARs. I also showed that D4 receptor activation inhibits D1/5-mediated, but not D3-mediated, enhancement of LTP. With whole-cell voltage clamp recording technique, I provided evidence that D3-mediated disinhibition in the stratum radiatum of hippocampus CA1 takes place at extrasynaptic GABAA receptors innvervated by µ-opioid receptor-expressing interneurons. Finally, I addressed the laminar-specificity of cocaine-mediated LTP enhancement in the CA1 region: D3 receptor activation is required for this effect in stratum radiatum; D1/5 receptor activation is required for this effect in stratum oriens. Taken together, my results illustrate the multifaceted nature of dopaminergic modulation of hippocampal LTP and provide numerous pharmacological targets for altering hippocampal output.