Genetic And Neurophysiological Substrates

The behavioral effects of caffeine are strongly influenced by genetic mechanisms and their neuro-physiological expressions. Both the extent of habitual caffeine consumption and the magnitude of responses to single doses appear to be subject to a hereditary predisposition (Carrillo et al., 1998). The effect likely occurs through cytochrome P450 CYP1A2, which is involved in caffeine metabolism. It is governed principally by genetic mechanisms, with a heritability estimate of 0.725 (Rasmussen et al., 2002). The genetic predisposition is expressed, at least in part, as the bimodally distributed ability to acetylate molecules possessing an amino functional group. The principal direct genetic effect is likely on the adenosine A2A receptors, which are inhibited by caffeine (Lindskog et al., 2002). These receptors are found in the kidneys, digestive system, bronchial tree, heart and peripheral vasculature, and in the brain.

In the brain, adenosine acts as a neurotransmitter. It is synthesized in glial cells and neurons, and its release into extracellular space is enhanced during states of fatigue and sleep (Adrien, 2001). The adenosine A2A receptors act, in part, by inhibiting the N-methyl-D-aspartate (NMDA) component of excitatory synaptic currents (Gerevich et al., 2002), and the neural distribution of these receptors suggests some probable sites of action of caffeine in the brain. Included are the striatum and medulla, as well as portions of the basal forebrain, the mesopontine area, and the sleep-regulating preoptic nucleus of the hypthothalamus (Boros et al., 2002). The nucleus acubens (Solinas et al., 2002) and the lateral amygdala (Svenningsson et al., 1999) may also be involved. Caffeine probably produces its stimulatory effect, in part, by blocking the A2A receptors that activate the GABAergic neurons populating the inhibitory tracts to the striatal dopaminergic reward system (Daly and Fredholm, 1998). The neural distribution of adenosine receptors is also consistent with the apparent neuroprotective effects of caffeine in Parkinson's disease (Chen et al., 2001), where it may act to prevent dopamine deficits, and in Alzheimer's disease (Maia and de Mendonca, 2002).

0 0

Post a comment