A major new article reviews the recently discovered properties of adenosine A2A receptor-dopamine D2 receptor (A2AR-D2R) and adenosine A1 receptor-dopamine D1 receptor (A1R-D1R) isoforms, both of which are major targets of caffeine, and discusses the therapeutic implications of these findings. Preclinical evidence suggests that caffeine and selective A2AR antagonists could be used to treat motivational symptoms of depression and cognitive and affective impairments of attention-deficit/hyperactivity disorder.

In addition, new research suggests that A1R-D1R heteromers, which regulate the excitability of spinal motor neurons, could be targeted by A1R antagonists for the treatment of spinal cord injury. The study, published in the Journal of Caffeine and Adenosine Research, discusses caffeine and selective adenosine receptor antagonists as potential new therapeutic tools.

Caffeine and selective A2AR antagonists as new therapeutic tools for motivational symptoms of depression

Although depression is often thought of as involving mood symptoms, such as sadness and negative affect, it is important to note that depression is also characterized by motivational dysfunction, such as apathy or inactivity, psychomotor retardation, fatigue, and a general lack of behavioral activation. These motivational symptoms of depression can be very debilitating and difficult to treat. Although selective serotonin reuptake inhibitors (SSRIs) are the most commonly used treatment for depression and are very useful for treating anxiety and mood-related symptoms, they are relatively poor at treating motivational dysfunction. Furthermore, motivational dysfunction in human psychopathology is not limited to depression; patients with schizophrenia and Parkinson's disease also display negative symptoms, inactivity, and fatigue. For all of these reasons, it is important to develop animal models of activation-related psychiatric symptoms.

A large body of research in this area has also focused on drugs that act on adenosine. Direct administration of the adenosine A2AR agonist CGS2168 into the nucleus accumbens of mice produces a low-effort bias and reduced effort on a lever-pressing task. In addition, A2AR antagonists such as isotetraphenylamine, MSX-3, MSX-4, and preladenant are able to reverse the low-effort bias induced by the D2R antagonists, haloperidol and eticlopride, and the vesicular monoamine transporter inhibitor tetrabenazine. In contrast to A2AR antagonism, blockade of the A1R does not reverse the effects of D1 antagonism on either the D1R or D2R. The reversal effect is greatest when the effects of the D2R antagonist are reversed using an A2AR antagonist, which is also consistent with the anatomical data.

Nonselective adenosine antagonists, caffeine and theophylline, have also been shown to exert effects in tests of effort-based choice. Caffeine and theophylline reversed the effects of D2R antagonism on effort-related choices, and caffeine (5 or 10 mg/kg) increased lever-pressing output in rats without food restriction. Taken together, these studies suggest that drugs acting at A2A receptors, as well as nonselective adenosine antagonists, may be useful in treating motivational impairments in patients with depression.

Caffeine and selective A2AR antagonists as therapeutic tools for cognitive and mood impairment in ADHD

ADHD is one of the most common chronic psychiatric disorders in children, with a global prevalence estimated at 5.9-7.1% in children/adolescents and 1.2-7.3% in adults. ADHD persists into adulthood in many cases and its onset is associated with attention deficits, hyperactivity, and/or cognitive impulsivity. In ADHD, the primary role of disturbed dopaminergic neurotransmission in the frontal cortex is the basis for current pharmacological treatment with psychostimulants, more commonly methylphenidate. However, in recent years, there has been an increase in the understanding of the regulatory role of adenosine receptors on dopamine neurotransmission. There is sufficient evidence to suggest that adenosine receptors are targets for drug development in a variety of disorders with dysregulated dopamine neurotransmission, including ADHD.

Many studies have shown that caffeine treatment improves memory and attention deficits and normalizes dopaminergic function in adolescent and adult SHR (a validated animal model of ADHD). Acute treatment with caffeine improves social memory, object recognition memory, spatial learning deficits, etc., exhibited in adult SHR under different behavioral paradigms. Acute administration of selective A2AR antagonists also improves short-term social memory, but selective A1R antagonists do not.

Importantly, chronic caffeine treatment provides long-term cognitive benefits in SHR. Long-term caffeine administration during adolescence improves short-term recognition performance, memory and attention deficits in adult SHR, and normalizes dopaminergic function by reducing dopamine reuptake in the striatum and frontal cortex of SHR. These results are consistent with the well-documented interaction between A2AR-mediated adenosine and TrkB-mediated BDNF signaling cascades.

The study also investigated the effects of chronic caffeine intake and physical exercise on mood disorders in SHR. The results showed that chronic caffeine intake and physical exercise had significant independent antidepressant effects in SHR without changing anhedonia-like behaviors. These findings provide the first evidence that long-term caffeine intake has beneficial effects on mood disorders as observed in animal models of ADHD. A review of clinical and preclinical studies on caffeine and ADHD strongly suggests that we may need to reconsider the possible therapeutic role of caffeine in ADHD and that better controlled studies (also including control for A2AR gene polymorphisms) are needed.