Circadian Rhythms and Substance Abuse: Chronobiological Considerations for the Treatment of Addiction.

Reward-related learning, including that associated with drugs of abuse, is largely mediated by the dopaminergic mesolimbic pathway. Mesolimbic neurophysiology and motivated behavior, in turn, are modulated by the circadian timing system which generates ∼24-h rhythms in cellular activity. Both drug taking and seeking and mesolimbic dopaminergic neurotransmission can vary widely over the day. Moreover, circadian clock genes are expressed in ventral tegmental area dopaminergic cells and in mesolimbic target regions where they can directly modulate reward-related neurophysiology and behavior. There also exists a reciprocal influence between drug taking and circadian timing as the administration of drugs of abuse can alter behavioral rhythms and circadian clock gene expression in mesocorticolimbic structures. These interactions suggest that manipulations of the circadian timing system may have some utility in the treatment of substance abuse disorders. Here, the literature on bidirectional interactions between the circadian timing system and drug taking is briefly reviewed, and potential chronotherapeutic considerations for the treatment of addiction are discussed.

Bidirectional interactions between the circadian and reward systems: is restricted food access a unique zeitgeber?

Reward is mediated by a distributed series of midbrain and basal forebrain structures collectively referred to as the brain reward system. Recent evidence indicates that an additional regulatory system, the circadian system, can modulate reward-related learning. Diurnal or circadian changes in drug self-administration, responsiveness to drugs of abuse and reward to natural stimuli have been reported. These variations are associated with daily rhythms in mesolimbic electrical activity, dopamine synthesis and metabolism, and local clock gene oscillations. Conversely, the presentation of rewards appears capable of influencing circadian timing. Rodents can anticipate a daily mealtime by the entrainment of a series of oscillators that are anatomically distinct from the suprachiasmatic nucleus. Other work has indicated that restricted access to non-nutritive reinforcers (e.g. drugs of abuse, sex) or to palatable food in the absence of an energy deficit is capable of inducing relatively weak anticipatory activity, suggesting that reward alone is sufficient to induce anticipation. Recent attempts to elucidate the neural correlates of anticipation have revealed that both restricted feeding and restricted palatable food access can entrain clock gene expression in many reward-related corticolimbic structures. By contrast, restricted feeding alone can induce or entrain clock gene expression in hypothalamic nuclei involved in energy homeostasis. Thus, under ad libitum feeding conditions, the weak anticipatory activity induced by restricted reward presentation may result from the entrainment of reward-associated corticolimbic structures. The additional induction or entrainment of oscillators in hypothalamic regulatory areas may contribute to the more robust anticipatory activity associated with restricted feeding schedules.

Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet.

In Syrian hamsters, some procedures for stimulating behavioural arousal (e.g. running in a novel wheel and sleep deprivation by gentle handling with minimal activity) markedly phase-advance circadian rhythms when applied during the middle of the daily rest period, while other arousal procedures do not (e.g. physical restraint, caffeine and modafinil). The neural basis for this differential effect of arousal procedures on clock resetting is unknown. We used c-fos expression as a marker for neuronal activation to determine whether these arousal procedures differentially activate two nonphotic inputs to the circadian system, the thalamic intergeniculate leaflet (IGL; a proposed nonphotic gateway to the circadian clock) and the hypothalamic hypocretin system (which depolarizes arousal-related cell groups throughout the brain and innervates both the IGL and the peri-suprachiasmatic nucleus region). c-FOS in hypocretin-1-immunoreactive neurons, in hypothalamic nonhypocretin neurons and in the IGL was significantly increased by novel wheel running, gentle handling and physical restraint, but only weakly by systemic injections of modafinil (300 mg/kg) or caffeine (75 mg/kg), at doses that are strongly alerting. Spatial analysis revealed few regional differences in the percentage of cells double-labelled for hypocretin-1 and c-FOS following each treatment. These results suggest that activation of hypocretin neurons (as in the restraint condition) is not sufficient to induce phase shifts, and that gating of arousal effects on circadian clock phase may be downstream from the hypocretin system and from IGL neurons activated by these procedures.