Diurnal rhythms in the nucleus accumbens: Mechanisms and role in substance use disorders

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Abstract Substance use disorders (SUD) are a major public health problem that impact millions of people and their families. The factors that contribute to SUD vulnerability, as well as the transition from drug use to abuse to SUD remain unclear. We know that the reward value for alcohol and drugs of abuse normally varies by time of day. For example, for most individuals, the desire to drink wine or beer is very different at 6:00am compared to 6:00pm. There is a normal, time of day dependent, rhythm in the reward value for these drinks and this rhythm is protective against SUD. In fact one of the key factors that is used to evaluate the transition to addiction is the loss of diurnal rhythmicity in reward value (the desire to drink alcohol in the morning for example). In addition to alcohol, when the reward circuitry has been hijacked by chronic exposure to other drugs of abuse, circadian rhythms in reward circuitry are lost, and these rewards overtime develop equal value at any time of day. Genetic factors (circadian gene variations) also contribute to reduced rhythms in reward at baseline, prior to any drug exposure, and increased SUD-related vulnerability. Indeed mice with circadian gene mutations show greater drug self-administration and a loss in the normal diurnal rhythm in this behavior. By determining the molecular and cellular mechanisms that underlie natural diurnal rhythms in reward, we can potentially help prevent the transition between use to abuse to SUD. Our previous studies have found strong diurnal differences in many aspects of reward circuitry including excitability of neurons in the nucleus accumbens (NAc). We have also found that the circadian protein, NPAS2 plays an important role in the NAc in the regulation of drug reward. In this R01 renewal, we first want to determine if this diurnal difference in excitability is similar in D1R, D2R or cholinergic cells, if it is similar in males and females, if Npas2 mutants have disrupted rhythmicity in MSN excitability, and if this rhythmicity is altered by chronic cocaine self-administration. We then want to identify at a transcriptome level what actively transcribed genes have diurnal rhythms in specific cell types in the NAc. This will help us identify the molecular mechanisms underlying these normal diurnal differences in evoked response. We will then determine how these molecular rhythms are altered with chronic cocaine self-administration. Finally, we will test particular molecular factors to determine their role in regulating diurnal rhythms in excitability. Taken together, the study of the mechanisms that underlie diurnal rhythmicity in reward are important and can help us develop future treatments that help maintain and strengthen these normal rhythms.