Naturally rewarding stimuli (i.e. food, sex, etc) increase the activity of dopamine cells in the mesocorticolimbic dopamine system causing increased dopamine release in brain areas such as the nucleus accumbens. Drugs of abuse mimic these effects, and hence, overexcite our brain’s natural reward system. Therefore, tempering drug-induced amplification of dopamine signaling is one approach to reduce the powerful effects of drugs on the brain. We have been exploring the potential of the neuromodulator, adenosine, to reduce excessive dopamine signaling that contributes to the development and persistence of psychostimulant abuse.
Dopamine’s effects in the brain are mediated by postsynaptic D1 and D2 receptors. Adenosine A1 and A2A receptors are uniquely positioned to counteract the excessive stimulation of dopamine receptors produced by drugs of abuse. Thus, adenosine receptor stimulation provides a “brake” on excessive dopamine receptor activity that ultimately influences drug-induced changes in neuronal function and behavior. My laboratory has been exploring three aspects of the role of adenosine-dopamine receptor interactions in psychostimulant abuse. First, we are interested in how psychostimulants such as cocaine and methamphetamine alter the expression of adenosine and dopamine receptors in the mesocorticolimbic dopamine system that may reduce adenosine receptor activity and favor excessive dopamine stimulation. Second, we are investigating how adenosine receptor stimulation impacts psychostimulant-induced behaviors (i.e. drug taking and relapse). Third, we are analyzing the mechanisms by which adenosine and dopamine receptors interact to influence psychostimulant-induced behaviors.
Dopamine-Adenosine Interactions in Direct Pathway Neurons
Adenosine also plays important roles in regulating neuronal signaling in the direct pathway neurons. Adenosine A1 receptors are expressed presynaptically where they compete with A2A receptors through receptor-receptor interactions to inhibit glutamate release. Postsynaptically, A1 receptors are co-expressed with dopamine D1 receptors on dynorphin-containing neurons of the direct pathway. Postsynaptic A1 and D1 receptors exert opposing influences one another including allosteric receptor-receptor interactions and opposing intracellular signaling cascades. It remains unclear how these complementary roles of pre- and postsynaptic A1 and D1 receptors in the striatum may contribute to addictive-like behaviors.
We are interested in determining how manipulating pre- and post-synaptic adenosine A1 receptors alter reward and relapse behavior and what mechanisms are involved in this process.
Dopamine-Adenosine Interactions in Indirect Pathway Neurons
In the striatum, adenosine A2A receptors are co-expressed with dopamine D2 receptors on enkephalin-containing neurons of the indirect pathway. A2A and D2 receptors exert a number of effects that oppose one another through both allosteric receptor-receptor interactions and opposing intracellular signaling cascades that ultimately influence cellular functioning and behavioral responses. The complementary roles of A2A and D2 receptors in the striatum may provide a mechanism whereby inhibitory regulation of D2 receptors via A2A receptor stimulation is lost following repeated psychostimulant treatment allowing pronounced D2 receptor signaling and an increase in addictive-like behaviors.
We are interested in determining how stimulation of adenosine A2A receptors alter reward and relapse behavior and what mechanisms are involved in this process.