Research in the Early 1990s
Ferré said that it is well known that the mechanism underlying the motor and reinforcing effects of cocaine and amphetamine are caused by the drugs’ stimulation of central dopaminergic transmission, particularly in the striatum. The striatum, the input structure of the basal ganglia, is an area of the brain involved in the elicitation and learning of reward-related behaviors, and it contains the highest concentration of dopamine and dopamine receptors. Cocaine and amphetamine are able to produce psychostimulant effects by binding to what is known as a dopamine transporter and either blocking (e.g., cocaine) or reversing (e.g., amphetamine) its effects. In both cases, the end result is a significant increase of dopamine in the extracellular space, which in turn activates the postsynaptic dopamine D1 and D2 receptors.
In contrast to cocaine and amphetamine, in the early 1990s scientists already knew that the main mechanism underlying caffeine psychostimulation was adenosine receptor antagonism. It was known then that caffeine at brain concentrations obtained after drinking coffee was enough to block the effects of the A1 and A2A receptors, with A2B being involved only in pathological situations and A3 having little affinity for caffeine. (There are four adenosine receptors: A1, A2A, A2B, and A3.) The question then was, How does adenosine modulate the dopaminergic system?
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Also in the 1990s, scientists were aware that caffeine does not produce a clear or strong presynaptic dopamine-releasing effect. That is, it does not really increase dopamine in the extracellular space in the brain. Knowing that, Ferré and collaborators investigated the possibility of a postsynaptic interaction between adenosine and dopamine receptor signaling (Ferré et al., 1991a). They used the reserpinized mouse model to test their hypothesis. (Reserpine depletes dopamine and other catecholamines in the brain, resulting in an animal becoming immobile, or cataleptic. The only way to counteract the catatelptic effect is to administer a dopamine receptor agonist, that is, something that stimulates the postsynaptic dopaminergic receptors.) They used bromocriptine (a D2 agonist) to produce locomotor activity in reserpinized mice. They found that the locomotor effect of bromocriptine was counteracted by the adenosine receptor agonists NECA (an A1/A2A agonist) and L-PIA (an A1 agonist) with a potency that suggested predominant involvement of A2A receptors.
Ferré and collaborators (1991a) also found that caffeine (an A1/A2A agonist) and caffeine metabolites theophylline (an A1/A2A agonist) and paraxanthine, but not theobromine, had the opposite effect; that is, they potentiated locomotor activity of bromocriptine. That finding suggested the existence of an antagonistic interaction between the postsynaptic adenosine A2A and dopamine D2 receptors, through which A2A receptor agonists would behave as D2 receptor antagonists, and A2A receptor antagonists would behave as dopamine as D2 receptor agonists. Indeed, in a separate study, Ferré et al. (1991b) demonstrated for the first time that central administration of an A2A receptor agonist would produce catalepsy, as a dopamine D2 receptor antagonist would do. Later, when selective adenosine A2A receptor antagonists became available, others demonstrated the opposite effect: that A2A receptor antagonists elicit motor activation (Karcz-Kubicha et al., 2003).
The findings reported in Ferré et al. (1991a,b) strongly suggested that caffeine produces motor activation by blocking adenosine A2A receptor-mediated inhibition of dopamine D2 receptor activation. Later, through radioligand-binding experimentation, Ferré and his team found evidence for a more direct interaction between the two receptors (Ferré et al., 1991c), with the dopamine D2 receptor antagonist being displaced by dopamine in a dose-dependent manner and with the ability of dopamine to displace the antagonist being modified by the addition of an adenosine A2A receptor agonist (CGS21680). That is, the agonist CGS21680 decreased the affinity of dopamine D2 receptors for dopamine. That experiment also demonstrated that the A2A and D2 receptors should be localized in the same neuron. But which neuron was it?
Subsequent study pointed to the efferent striatal gamma-aminobutyric acid (GABA)-ergic medium spiny neuron, also known as MSN. MSNs are efferent neurons that constitute more than 95 percent of the striatal neuronal population. They receive two main inputs: glutamatergic inputs from the cortical-limbic-thalamic area and mesencephalic dopaminergic inputs from the substantia nigra and ventral tegmental area. There are two subtypes of MSNs, each of which gives rise to a separate efferent pathway connecting the striatum with the output structures of the basal ganglia (i.e., the medial segment of the globus pallidus and the substantia nigra pars reticulate). One of the pathways is direct, the other indirect. Using freely moving rats, Ferré et al. (1993) inserted one probe into the striatum, where cell bodies of the indirect MSN are localized, and another probe into the ipsilateral global pallidus, where the nerve terminals of the indirect MSN are localized and where GABA is released. They found that perfusion of a D2 receptor agonist, pergolide, through the striatal probe resulted in a significant reduction of extracellular levels of GABA in the ipsilateral globus pallidus. The effect was significantly counteracted by the striatal coperfusion of an A2A receptor agonist, CGS21680, and significantly potentiated by the xanthine theophylline.
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