Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.3 g/L) for 28 consecutive days from postnatal day 28 (P28) to P55. Age-matched control rats consumed water. Behavioral testing for anxiety-related behavior began in adulthood (P62) 7 days after removal of caffeine. Adolescent caffeine consumption enhanced anxiety-related behavior in an open field, social interaction test, and elevated plus maze. Similar caffeine consumption in adult rats did not alter anxiety-related behavior after caffeine removal. Characterization of neuroendocrine measures was next assessed to determine whether the changes in anxiety were associated with modifications in the HPA axis. Blood plasma levels of corticosterone (CORT) were assessed throughout the caffeine consumption procedure in adolescent rats. Adolescent caffeine consumption elevated plasma CORT 24 h after initiation of caffeine consumption that normalized over the course of the 28-day consumption procedure. CORT levels were also elevated 24 h after caffeine removal and remained elevated for 7 days. Despite elevated basal CORT in adult rats that consumed caffeine during adolescence, the adrenocorticotropic hormone (ACTH) and CORT response to placement on an elevated pedestal (a mild stressor) was significantly blunted. Lastly, we assessed changes in basal and stress-induced c-fos and corticotropin-releasing factor (Crf) mRNA expression in brain tissue collected at 7 days withdrawal from adolescent caffeine. Adolescent caffeine consumption increased basal c-fos mRNA in the paraventricular nucleus of the hypothalamus. Adolescent caffeine consumption had no other effects on the basal or stress-induced c-fos mRNA changes. Caffeine consumption during adolescence increased basal Crf mRNA in the central nucleus of the amygdala, but no additional effects of stress or caffeine consumption were observed in other brain regions. Together these findings suggest that adolescent caffeine consumption may increase vulnerability to psychiatric disorders including anxiety-related disorders, and this vulnerability may result from dysregulation of the neuroendocrine stress response system.

Subclinical levels of polysubstance use are a prevalent and understudied phenomenon. Alcohol is a substance commonly co‐used with other substances of other drug classes. These studies sought to determine the consumption effects of combining alcohol drinking and methamphetamine (MA) self‐administration. Male alcohol‐preferring P rats had continuous access to a two‐bottle alcohol drinking procedure in the home cage. Control rats remained alcohol naïve. Rats were also surgically implanted with intra‐jugular catheters and trained to self‐administer saline (control) or MA in daily 2‐hour sessions. We first measured the acquisition and maintenance of MA intake in alcohol‐consuming or control rats. MA intake was initially enhanced by alcohol consumption on a fixed ratio 1 schedule of reinforcement, but this effect did not prevail as the difficulty of the schedule (FR5 and progressive ratio) was increased. We next measured both alcohol consumption and preference before, during and after MA (or saline) self‐administration. MA self‐administration significantly reduced alcohol intake and preference ratios, a robust effect that persisted across several experimental variations. Interestingly, alcohol consumption rebounded following the cessation of MA self‐administration. The effects of MA self‐administration were specific to alcohol intake because it did not alter total fluid consumption or consumption of sucrose. MA self‐administration did not impact blood‐alcohol concentrations or alcohol‐induced loss of righting reflex suggesting no effect of MA intake on the alcohol metabolism or sensitivity. Together, the results suggest that MA intake disrupts alcohol consumption and preferences but not the reverse in alcohol‐preferring P rats.

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Rationale and objective: Previous work has demonstrated that dopamine and adenosine receptors are involved in drug seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D 2 -like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation.Methods: Adult male Sprague-Dawley rats were trained to lever press for MA in daily 2-hour self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days. After 1 day of abstinence, lever pressing was extinguished in 6 daily extinction sessions. Treatments were administered systemically prior to a 2-hour reinstatement test session.Results: An increase in MA seeking was observed following the administration of the dopamine D 2 -like agonist, quinpirole, or the D 3 receptor agonist, 7-OH-DPAT. Stimulation of D 2 or D 4 receptors was ineffective at inducing MA seeking. Quinpirole-induced MA seeking was inhibited by D 3 receptor antagonism (SB-77011A or PG01037), an adenosine A 1 agonist, CPA, and an adenosine A 2A agonist, CGS 21680. MA seeking induced by a MA priming injection or D 3 receptor stimulation was inhibited by a pretreatment with the adenosine A 1 agonist, CPA, but not the adenosine A 2A agonist, CGS 21680. Conclusions:These results demonstrate the sufficiency of dopamine D 3 receptors to reinstate MA seeking that is inhibited when combined with adenosine A 1 receptor stimulation.

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