Effects of Caffeine on Reinforcement Learning in Healthy Adults Using PET/MRI

Adenosine 2A receptors (A2AR) colocalize with and exerts allosteric antagonism to dopamine D2 receptors (D2R) by co-forming functional heterodimers in the striatum. Preliminary studies using positron emission tomography (PET) with [11C]Raclopride have shown increased D2/D3R availability by A2AR antagonism with caffeine and decreased D2/D3R availability by enhanced adenosine signaling during sleep deprivation, supporting the notion of A2AR-D2R interactions in vivo. However, how A2AR-D2R interactions contribute to D2R-mediated neurocognitive functions is scarcely investigated.

Reinforcement learning, a dopamine-mediated cognitive process crucially involved in various human behaviors including habit, preference, belief, and resistance to change, is often found altered in dopamine-associated disorders. For instance, hyper-dopaminergic function in the striatum, as observed in psychosis, leads to a reduction in reward learning and a blunted task-related neural activity. Through the antagonistic effect of A2AR on D2R signaling, blocking A2AR can potentially enhance D2R-mediated negative reinforcement, a.k.a. a "no-go" response. In rodents, A2AR agonists diminish reinforcement of psychostimulants, while an A2AR antagonist can facilitate reward-seeking effects of reinforcers. Hence, in this double-blind randomized crossover study, the investigators aim to use caffeine, an adenosine antagonist as well as a commonly used psychostimulant by nearly 80% of the worldwide population, to examine whether blocking A2AR will enhance D2R-modulated reinforcement learning/no-go responses through modulating D2R signaling pharmacologically.

The long-term goal of this study is to further the understanding of molecular mechanisms related to A2AR-D2R heterodimers and the clinical potential of modulating A2AR-D2R interactions. Twelve young healthy non-smokers will enroll in this study. Each participant will undergo a caffeine and a placebo condition. In each condition, participants will first go through a 6-day ambulatory washout period where participants will be asked to abstain from caffeinated dietary, alcohol, and drugs, and stay in regular bed- and wakeup time. On day 7, a PET/fMRI scan will take place at noon, and a caffeine or placebo tablet will be administered orally 20 mins prior to the scan.

Simultaneous PET/fMRI will be used to examine the association between the neurochemical changes (i.e., D2/D3R availability as quantified by [11C]Raclopride) and the hemodynamic responses (i.e., task-related blood oxygen level-dependent fMRI activity) during reinforcement learning in the caffeine condition compared to placebo. It is hypothesized that enhanced D2/D3R availability mediates the facilitating effect of caffeine on reinforcement learning. Specifically, the investigators expect that caffeine will enhance fMRI responses in reward-related brain regions, and that the increased fMRI response will positively correlate with a change in D2/D3R availability.

Inclusion criteria

• Age ≥ 18 and ≤ 45.
• Habitual caffeine intake ≥ 100 mg and ≤ 450 mg daily.
• Non-smokers.
• Clinically healthy.
• Have normal vision or corrected to normal vision.

Exclusion criteria

• Pregnant or lactating women.
• Women using hormonal contraceptives.
• BMI < 18.5 or > 29.9
• Sleep disturbance or extreme chronotype.
• Urine test positive on one of the following substances: benzoylecgonine, morphine, d-Methamphetamine, d-Amphetamine, Benzodiazepines, Secobarbital, Methadone, Buprenorphine Glucuronide, Nortriptyline, MDMA, Oxycodone, PCP, Propoxyphene, and Cannabis/THC
• Diagnosis of depression, anxiety, psychosis, or neurologic disorders in the last 5 years.
• Heart or cardiovascular diseases.
• Diabetes or other metabolic diseases.
• Under chronic medications, for instance, painkiller and steroid.
• Allergy to lactose (main ingredient of blank control dose)
• Incapable to operate the tasks or comprehend the study information in English.

General MRI and PET safety exclusion criteria for all subjects:

• Metallic foreign bodies such as cardiac pacemakers, perfusion pumps, aneurysm clips, metallic tattoos anywhere on the body, tattoos near the eye.
• Pre-existing medical conditions including a likelihood of developing seizures or claustrophobic reactions
• Inability to lie flat on scanner bed for about 90 min as assessed by physical examination and medical history (e.g. arthritis)
• Recent exposure to radiation (i.e., PET from other research studies) that, when combined with this study, would be above the allowable limits
• Pregnancy or breastfeeding: A negative serum or urine pregnancy test is required on the day of the PET procedure
• Body weight of > 300 lbs (weight limit of the MRI scanner table)