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Cocaine Promotes Coincidence Detection and Lowers Induction Threshold during Hebbian Associative Synaptic Potentiation in Prefrontal Cortex.

Journal of Neuroscience 2016 December 17
Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike timing-dependent LTP (t-LTP). Following repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for approximately one week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged following cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/PKA dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated L-type Ca2+ channels (LTCCs) that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction.

SIGNIFICANCE STATEMENT: It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to relapse. We found that repeated cocaine exposure alters a Hebbian associative synaptic learning rule that governs activity-dependent synaptic plasticity in the mouse prefrontal cortex, characterized by a broader temporal window and a lower threshold for spike-timing-dependent long-term potentiation (t-LTP), a cellular form of learning and memory. This rule change is caused by cocaine-exacerbated D1-cAMP/PKA dopamine signaling in pyramidal neurons that in turn pathologically recruits L-type Ca2+ channels to facilitate coincidence detection during t-LTP induction. Our study provides novel insights on how cocaine, even when exposed briefly, may prime neural circuits for subsequent experience-dependent remodeling that may underlie certain addictive behavior.

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