Cocaine Addiction and the Role of Serotonin in Orbitofrontal Cortex Function

National Institute On Drug Abuse

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Abstract

Using whole-cell electrophysiology in brain slices, we find that physiological effects of 5-HT1A and 5-HT2A receptor activation are reduced following withdrawal of either cocaine self-administration (CSA) or yoked cocaine administration (CYA) in pyramidal neurons (PyNs). Moreover, these reduced effects of 5-HT at these receptors persisted for many weeks after cocaine withdrawal, suggesting they may be involved in long-term aspects of cocaine addiction, such as drug craving. As 5-HT in the OFC is implicated in behavioral flexibility, learning and other cognitive abilities, our experiments provide novel information as to the role that 5-HT plays in cocaine addiction, and in the impaired decision-making exhibited during cocaine addiction and withdrawal. In addition, since 5-HT is linked to several neuropsychiatric disorders, such as depression, anxiety, dementia, impulsive-aggression disorder (IAD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD), these experiments provide valuable information as to the clinical utility of targeting the 5-HT system in the OFC as potential therapies. Our previous studies indicate that 5-HT signaling, although present in GABAergic inhibitory neurons known as parvalbumin (PV) cells, is not altered in OFC after withdrawal from cocaine self-administration. Therefore, the changes in 5-HT function related to cocaine exposure appear to be mediated almost entirely by pyramidal neurons in the OFC. Moreover, we also examined changes in OFC PV cells between male and female rats and found that female OFC parvalbumin cells receive weaker glutamatergic synaptic inputs than males and that these synaptic currents are reduced after withdrawal from cocaine self-administration only in males. Additionally, PV cells from male rats were more depolarized after cocaine withdrawal. Pharmacological studies have also shown that the excitation of parvalbumin neurons by 5-HT in the OFC can be blocked by a non-selective antagonist of 5-HT2A/C receptors, known as ketanserin, only in neurons from female rats. To gain additional insight as to whether this indicates a distinct functional expression of 5-HT2A or 5HT2C receptors in parvalbumin neurons between males and females, we have completed studies using more selective antagonists of these receptors, along with a a 5-HT2 receptor-selective agonist known as DOI. Our newest data suggest that PV cells are excited by 5-HT and DOI to a similar degree in males and females, and we have replicated our previous finding that female 5-HT responses are more effectively inhibited by the non-selective 5-HT2A/2C antagonist ketanserin. However, we also find that the effects of 5-HT are completely blocked by the 5-HT2A receptor blocker glemanserin (MDL-11,939) and are unaffected by the selective 5-HT2C blocker SB-242084 in both males and females. Therefore our data suggest that; 1. the effect of 5-HT on OFC PV neurons is mediated by 5-HT2A receptors, and 2. that the greater ability of ketanserin to block 5-HT responses in PV neurons in female rats is is not due to differential expression of 5-HT2A/C receptors between sexes, but rather to some unidentified pharmacological action of this particular drug. It is hoped that these studies of the 5-HT receptor function in the OFC may lead to a greater understanding of their roles in psychiatric illness and addiction, and that this will aid in developing novel therapeutic approaches for treatments in humans.