ReviewDiurnal and circadian regulation of reward-related neurophysiology and behavior
Introduction
Addiction is defined as the compulsive seeking and taking of drugs regardless of the known negative consequences. Drugs of abuse act as rewards (i.e., stimuli with intrinsic positive value) and reinforce the behaviors necessary to obtain them. Repeated drug administration can induce neuroplastic changes in the mesocorticolimbic brain regions associated with reward seeking, impulsivity, and emotional regulation, ultimately resulting in the addictive phenotype [1], [2]. Despite recent advances in our understanding of the neurobiology of addiction, individuals undergoing treatment for substance abuse disorders exhibit a high rate of relapse, even after prolonged periods of drug abstinence [3]. Hence, more effective therapies are needed, the development of which hinges on advances in our understanding of the cellular and molecular mechanisms involved in the development and maintenance of addictive behavior.
The circadian system, which produces daily (i.e., ~ 24 h) rhythms in physiology and behavior [4], [5] consists of a hierarchy of tissue- and cell-level oscillators located in both the periphery and brain [6], including brain regions associated with reward processing [7], [8]. Work over the past couple of decades has established a circadian influence on reward-related behavior and neurophysiology [9], [10], [11]. Thus, understanding how the circadian system normally modulates reward processing and how this influence changes with repeated drug administration may provide novel insights into the pathophysiology of addiction and suggest new avenues for treatment. Here, we review the literature on daily rhythms in drug reward and mesocorticolimbic neurophysiology, discuss the potential underlying mechanisms, and summarize the bidirectional interactions between drug intake and circadian clock gene expression.
Section snippets
Circadian rhythms
Circadian rhythms in behavior and physiology, which persist in the absence of environmental timing cues, allow the organism to anticipate and to adapt to the regular daily events that result from the earth's rotation on its axis. These daily rhythms are coordinated by the hypothalamic suprachiasmatic nucleus (SCN), which receives retinal input and synchronizes the internal milieu to the external world [12], [13], [14], [15]. Within the SCN, circadian rhythms in cellular activity are generated
Diurnal rhythms in reward-related behavior
Diurnal rhythms in drug self-administration have been reported across various animal models with peak intake usually observed during the species typical active period, and nadirs during the mid-to-late inactive period [[36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]; Fig. 1A, Table 1, 48]. Rhythms in drug self-administration have been most extensively studied using a discrete trials procedure, where animals are provided with a limited number of opportunities to administer
Diurnal rhythms in mesocorticolimbic neurophysiology
Reward-related behavior is largely mediated by a series of brain structures including, the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), amygdala, and hippocampus, that are interconnected via the dopaminergic mesolimbic pathway that originates in the ventral tegmental area [VTA; [67], [68]]. Hence, daily rhythms in drug reward likely stem from cellular oscillations within in these regions. Using c-Fos as an index of neural activation, we have demonstrated diurnal expression rhythms
Circadian clock genes and mesocorticolimbic neurophysiology
In rodents, rhythmic circadian clock gene expression has been observed in many reward-related brain regions, with the phase of peak expression depending both upon the gene and the structure examined (See Table 3). Various clock genes (clock, npas2, and per1, 2, and 3) are rhythmically expressed at the mRNA level in the NAc, dST, VTA, PFC, and amygdala [8], [77], [83], [85]. At the protein level, rhythmic expression of PER1 or 2 has been observed in the rat NAc, dST, PFC, the bed nucleus of the
Circadian clock genes and reward-related behavior
The effects of circadian clock gene manipulations on mesocorticolimbic neurotransmission are indicative of an influence on reward-related behavior. While accumulating evidence indicates that this is the case, the effects are dependent upon the clock gene manipulated and there exist inconsistencies in the literature. By all measures, clock mutant mice show a hyper hedonic phenotype. These animals exhibit a greater propensity to initiate self-administration of cocaine, have a shorter latency to
Drug administration and mesocorticolimbic circadian clock gene expression
While circadian clock genes can regulate mesocorticolimbic neurophysiology and reward-related behavior, the influence is reciprocal as drug administration can affect circadian clock gene expression in the VTA and in mesolimbic target regions. Acute cocaine or methamphetamine administration induces the expression of per1, per3, cry1, bmal1, npas2 or clock in the NAc, dST, or hippocampus [8], [128], [129], [130]. Similarly, chronic cocaine or alcohol administration has been reported to influence
Rhythmic neural and endocrine inputs to mesocorticolimbic regions
Neural and endocrine inputs are also necessary for cellular rhythmicity in some mesocorticolimbic areas. Certainly, the SCN may modulate mesocorticolimbic cellular rhythmicity as this structure projects indirectly to the VTA via the medial preoptic nucleus [81], and to the mPFC via the paraventricular thalamic nucleus [138]. Indeed, SCN lesions have been reported to eliminate rhythmic DAT and TH expression in the NAc, mPFC or dST [139]. However, it must be cautioned that these latter results
The methamphetamine-sensitive circadian oscillator
Daily responses to drugs of abuse may also be mediated by a non-canonical circadian mechanism. Chronic methamphetamine administered in drinking water can induce behavioral and physiological circadian rhythms in otherwise arrhythmic SCN-lesioned rats [145], [146]. These observations point to the existence of a methamphetamine-sensitive circadian oscillator (MASCO) that is independent from the SCN. While the anatomical locus of the MASCO remains unknown, the induction of rhythmic locomotor
Diurnal and circadian regulation of drug reward in humans
Emerging evidence suggests that a circadian regulation of reward-related behavior also exists in humans. Several inpatient studies have reported a moderate diurnal rhythm in nicotine craving following smoking cessation with a nadir in the early morning and gradual increase across the day [148], [149]. A diurnal variation in cue-induced craving in abstinent heroin users has also been observed across waking hours with a nadir at noon and peaks in the morning and evening [150]. Other work
Conclusions
In sum, the data cited above indicate that diurnal rhythms in drug taking and seeking are associated with rhythmicity in neural activation and neurotransmission in mesocorticolimbic brain regions. The daily rhythms in mesocorticolimbic cellular activity likely result from interactions between local rhythmic circadian clock gene expression, rhythmic neural input, and rhythmic endocrine signaling, with the relative contribution of each of these signals varying across brain regions. While it
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2020, Pharmacology Biochemistry and BehaviorCitation Excerpt :When Per2 expression was compared between light condition groups in each brain region, expression was greater at ZT 4 and ZT 8 and less at ZT 16 and ZT 20 in the LP group versus the other two groups, also reflecting the reversal of Per2 expression in the LP group. Circadian clock genes expressed in DmSTR can modulate dopaminergic neurotransmission, and these daily rhythms in DA release could potentially influence attention and impulsive behavior (Verwey et al., 2016; Webb et al., 2015). While we did not find rhythmic differences in Drd2 or Th, previous studies indicate that Per2-mutant animals had reduced expression of monoamine oxidase (Maoa) resulting in elevated levels of dopamine (Hampp et al., 2008).
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2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :It is worth noting that this relationship ought not apply for threat-related motivation, which operates reactively due to its intense energy requirements (Clark et al., 1989; Wehr, 1990). Circadian modulation of reward function is fairly well characterised in animals (see Webb et al., 2015b for a review), with the strongest evidence being for dopamine-mediated reward motivation. For example, reward-related behaviour varies in a diurnal rhythm, with rats and primates self-administering drugs of abuse at a greater rate during their typical active period (see Logan et al., 2014).