The endogenous agonist for these receptors is adenosine, which is a purine nucleoside that is important for processes such as energy transfer in the form of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) and signal transduction in the form of cyclic adenosine monophosphate (cAMP). A2B and A3 receptors require concentrations of caffeine that do not occur at normal physiological levels or with normal levels of caffeine consumption in order to be antagonized, and will therefore not be considered as a possible mechanism for caffeine-induced anxiety.Caffeine acts as an antagonist of adenosine A1 and A2A receptors. Adenosine is a normal neuromodulator that activates adenosine g-protein coupled receptors. The actions of A1 and A2A receptors oppose each other but are both inhibited by caffeine due to its function as an antagonist.A2A receptors are coupled to Gs proteins which activate adenylate cyclase and some voltage gated Ca2+ channels. A2A receptors are located in dopamine rich brain regions. A2A receptor mRNA was found in the same neurons as the dopamine receptor D2 within the dorsal striatum, nucleus accumbens and tuberculum olfactorium. A2A receptors are not found in neurons that express the dopamine receptor D1 receptors and Substance P. Within the striatum, part of the basal ganglia, activation of A2A receptors by adenosine increases GABA release, an inhibitory neurotransmitter. When caffeine binds to the receptor, less inhibitory neurotransmitter is released, supporting caffeines role as a central nervous system stimulant.A1 receptors are paired with the G-proteins of Gi-1, Gi-2, Gi-3, Go1, and Go2.
This establishes the relationship between the abused chemical agent and the observed clinical effects. Caffeine has been proven to act as an antagonist on adenosine receptors, which acts as a stimulant and therefore fulfills this criteria. Symptoms must also not have a more likely clinical cause, such as another type of anxiety disorder, come before the ingestion of the intoxicating substance, or last for an extended amount of time after stopping the use of the substance. Diagnosis also requires that the panic attacks or anxiety due to the use of the intoxicating substance cause a certain amount of disturbance in the patient or lead to deficiency of varying types of daily performance. Diagnostic features
In addition to the criteria above, it is important to recognize that the diagnostic criteria for substance/medication-induced anxiety disorder are not met if the symptoms of panic come before the intoxication by the substance. In caffeine-induced anxiety disorder, a diagnosis will not be made if symptoms of anxiety or panic precede the ingestion of caffeine. Also, if symptoms persist for more than one month after substance intoxication, the diagnosis cannot be made. Persistence and continuation of symptoms beyond the initial consumption of caffeine suggest an alternate diagnosis that would better explain the long-lasting symptoms. Anxiety symptoms caused by caffeine are often mistaken for serious mental disorders including bipolar disorder and schizophrenia, leaving patients medicated for the wrong issue. A caffeine-induced anxiety disorder diagnosis should be made, rather than a substance abuse or intoxication diagnosis, when symptoms of panic attacks or anxiety predominate.