The role of serotonin in the orbitofrontal cortex in alcohol consumption

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Abstract
Binge alcohol drinking is a public health concern that can dramatically increase the risk for development of alcohol use disorder (AUD). Continued alcohol drinking in the face of negative consequences is another key feature of AUD. A better understanding of the neural circuitry that regulates these behaviors could provide insight as to novel treatments for AUD. Serotonin is a neurotransmitter that has been implicated in alcohol consumption in both human studies and animal models. The orbitofrontal cortex (OFC) is a brain region that both receives serotonergic input from the dorsal raphe and has been implicated in AUD. However, how volitional alcohol consumption impacts serotonin signaling within the OFC and how this contributes to alcohol related behaviors is unknown. Here, we show that a history of alcohol consumption alters the ability of 5-HT to hyperpolarize OFC pyramidal neurons in mice and monkeys. Consistent with this, a history of binge alcohol consumption decreases the expression of the 5-HT 1A but not 5-HT 2A receptor in the OFC from mice. Next, we show that deletion of the 5-HT 1A receptor from the OFC increased alcohol intake and preference in male, but not female mice. Finally, we found that 5-HT 1A receptor deletion led to increased quinine-adulterated alcohol intake, a measure of aversion-resistant drinking, in both male and female mice. Altogether, we identified serotonin signaling in the OFC as key target for modulation of binge and compulsive alcohol consumption. SIGNIFICANCE STATEMENT: Binge alcohol drinking is a public health concern that increases the risk for development of alcohol use disorder (AUD). To develop novel treatments for AUD, there is a need to better understand the neural circuitry that regulates binge alcohol consumption. Serotonin (5-HT) is a neuromodulator implicated in alcohol consumption in human studies and animal models. The orbitofrontal cortex (OFC) is a brain region that both receives 5-HT input and has been implicated in AUD. Here, we show that a history of alcohol consumption alters 5-HT signaling in the OFC of mice and monkeys and that alterations in 5-HT signaling increases alcohol consumption. Altogether, we identified 5-HT signaling in the OFC as a key target for modulating alcohol consumption.
Funding Information
  • Common Fund (K12GM000678)
  • Common Fund (AA028298)
  • Common Fund (AA026485)
  • Common Fund (AA019454)
  • Common Fund (AA01943)
  • Common Fund (OD011092-66)

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