Time of day influences the voluntary intake and behavioral response to methamphetamine and food reward.

The circadian timing system influences a vast array of behavioral responses. Substantial evidence indicates a role for the circadian system in regulating reward processing. Here we explore time of day effects on drug anticipation, locomotor activity, and voluntary methamphetamine (MA) and food intake in animals with ad libitum food access. We compared responses to drug versus a palatable treat during their normal sleep times in early day (zeitgeber time (ZT) 0400) or late day (ZT 1000). In the first study, using a between-subjects design, mice were given daily 1-h access to either peanut butter (PB-Alone) or to a low or high concentration of MA mixed in PB (MA+PB). In study 2, we repeated the experiment using a within-subjects design in which mice could choose between PB-Alone and MA+PB at either ZT 0400 or 1000. In study 3, the effects of MA-alone were investigated by evaluating anticipatory activity preceding exposure to nebulized MA at ZT 0400 vs. ZT 1000. Time of day effects were observed for both drug and palatable treat, such that in the between groups design, animals showed greater intake, anticipatory activity, and post-ingestional activity in the early day. Furthermore, there were differences among mice in the amount of MA ingested but individuals were self-consistent in their daily intake. The results for the within-subjects experiment also revealed robust individual differences in preference for MA+PB or PB-Alone. Interestingly, time of day effects on intake were observed only for the preferred substance. Anticipatory activity preceding administration of MA by nebulization was also greater at ZT 0400 than ZT 1000. Finally, pharmacokinetic response to MA administered intraperitoneally did not vary as a function of time of administration. The results indicate that time of day is an important variable mediating the voluntary intake and behavioral effects of reinforcers.

Phase resetting light pulses induce Per1 and persistent spike activity in a subpopulation of biological clock neurons.

The endogenous circadian clock of the mammalian suprachiasmatic nucleus (SCN) can be reset by light to synchronize the biological clock of the brain with the external environment. This process involves induction of immediate-early genes such as the circadian clock gene Period1 (Per1) and results in a stable shift in the timing of behavioral and physiological rhythms on subsequent days. The mechanisms by which gene activation permanently alters the phase of clock neuron activity are unknown. To study the relationship between acute gene activation and persistent changes in the neurophysiology of SCN neurons, we recorded from SCN neurons marked with a dynamic green fluorescent protein (GFP) reporter of Per1 gene activity. Phase-resetting light pulses resulted in Per1 induction in a distinct subset of SCN neurons that also exhibited a persistent increase in action potential frequency 3-5 hr after a light pulse. By simultaneously quantifying Per1 gene activation and spike frequency in individual neurons, we found that the degree of Per1 induction was highly correlated with neuronal spike frequency on a cell-by-cell basis. Increased neuronal activity was mediated by membrane potential depolarization as a result of a reduction in outward potassium current. Double-label immunocytochemistry revealed that vasoactive intestinal peptide (VIP)-expressing cells, but not arginine vasopressin (AVP)-expressing cells, exhibited significant Per1 induction by light pulses. Rhythmic GFP expression occurred in both VIP and AVP neurons. Our results indicate that the steps that link acute molecular events to permanent changes in clock phase involve persistent suppression of potassium current, downstream of Per1 gene induction, in a specific subset of Per1-expressing neurons enriched for VIP.