Project Summary/Abstract Over 40 million individuals in the US have a substance use disorder (SUD), and therapies for treating SUD have remained largely inadequate for decades. One of the key challenges in SUD treatment is that many drugs of abuse, including cocaine, negatively impact cognitive flexibility, leaving patients less likely to abstain from drug use. An emerging body of literature shows that agonists of the serotonin 2A receptor (5HT2AR), psychedelic hallucinogens, have remarkable potential for improving long-term cognitive flexibility with implications for treating various psychiatric disorders, including substance use. The highest density of the 5HT2AR expression in the brain is in the claustrum (CLA), an understudied subcortical brain structure with extensive innervation of fronto- cortical areas. The main projection target of the CLA is the anterior cingulate cortex (ACC), and both the CLA and the ACC have been implicated in regulation of drug-seeking behavior and cognitive flexibility. My preliminary behavioral data in rats show that extended access to self-administered cocaine induces cognitive flexibility deficits in a strategy set-shift task, and that 5HT2ARs in the CLA likewise robustly modulate set-shift task performance. Preliminary electrophysiology data show that 5HT induces inhibition of glutamatergic neurotransmission in CLA neurons projecting to the ACC (CLA-ACC neurons) by activating CLA 5HT2ARs. Furthermore, serotonergic signaling via the 5HT2ARs has a profound impact on long-term plasticity of CLA synapses. My preliminary data indicate that application of 5HT2AR agonist, DOI, reverses spike timing- dependent long-term depression (t-LTD) in CLA-ACC neurons and promotes, instead, spike timing-dependent long-term potentiation (t-LTP) of glutamatergic signaling in these cells. The current proposal will test the hypothesis that cocaine changes the timing window for induction of long-term synaptic plasticity in CLA-ACC neurons resulting in cognitive flexibility deficits and increased drug seeking behavior. I speculate that a single activation of 5HT2ARs in the CLA reverses cocaine-induced LTD, with a long-term improvement of cognitive flexibility leading to attenuated reinstatement of cocaine-seeking behavior. I will test this hypothesis by targeted microinjections of DOI into the CLA of rats trained to self-administer cocaine. I will use patch-clamp electrophysiology to establish the timing rules for serotonergic modulation of spike-timing dependent plasticity of excitatory synapses onto CLA-ACC neurons of cocaine exposed rats. Finally, I will combine chemogenetics with Ca2+ imaging in ACC-containing brain slices to establish the extent to which CLA neurons control ACC excitability in control and cocaine experienced rats. The findings of this proposal will reveal the role of CLA serotonin as a novel regional target for substance use research and specifically explore the impact of 5HT2ARs in the CLA on cortically-mediated cognitive flexibility deficits linked to cocaine use.

Project Narrative Drug-seeking and drug relapse behaviors are linked to deficits in cognitive flexibility that are induced by history of substance use. We hypothesize that the anterior cingulate cortex, a key brain structure that regulates cognitive flexibility, is under potent inhibitory control by the serotonin 2A receptors within the claustrum, a little-studied subcortical brain area. Psychedelic serotonin 2A receptor agonists are under active investigation of therapeutic potential for substance use disorder symptoms in humans, and our research proposes a central role for serotonin-dependent plasticity at claustro-cortical synapses in development of drug-induced cognitive deficits in a rat model of cocaine self-administration.