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.

We conclude that administration of MA by nebulization is an effective route of self-administration, and our new protocol represents a promising tool for examining the transitions from first intake to long-term use and its behavioral and neural consequences in a non-invasive protocol.

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Previous research shows that participants administered low doses of methamphetamine express more pleasurable effects late in the evening than early in the morning (Hart et al. 2003). By testing the effect of amphetamine aerosol administration on behavior we aimed to determine 1) the brain mechanisms regulating circadian effects of drugs and 2) the brain regions activated in response to anticipation of the drug at different times of day. We measured wheel running activity in response to aerosol administration of amphetamine or water at either 0400h or 1000h in mice maintained in a “skeleton” photoperiod (lights on 0000–0030 and 1130–1200). On the last test day mice were not administered the drug. Brains were collected just prior to the usual time of administration. Administration of amphetamine induced dose dependent wheel running activity. Mice showed anticipatory activity to the drug but not to water. This response was greater at 0400h than at 1000h. This suggests that the circadian system influences brain mechanisms involved in action of drugs of abuse. Brain sections were stained for cFOS, a marker of neuronal activity and regional brain activation, and compared at different times of day.