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Our research has demonstrated that pharmacologically stimulating adenosine A₁ or A_2A receptors successfully reduces drug-seeking and relapse behaviors for both cocaine and methamphetamine. We have shown that stimulating adenosine A₁ receptors during extinction training before a relapse event, or directly during a relapse event, significantly dampens cocaine seeking. This potent protective effect is mediated primarily by presynaptic A₁ receptors localized within the nucleus accumbens. Furthermore, our behavioral assays have demonstrated that target activation of adenosine A₁ receptors effectively reduces cue-induced drug craving and subsequent relapse behaviors for methamphetamine. 

Chronic exposure to drugs of abuse fundamentally alters how neuromodulatory systems communicate. A central line of our research investigates exactly how psychostimulants like cocaine and methamphetamine modify the expression of adenosine and dopamine receptors across the mesocorticolimbic dopamine system. Repeated psychostimulant exposure suppresses natural adenosine receptor activity, stripping the brain of its endogenous "brake" and creating an environment that favors unchecked, excessive dopamine stimulation. We utilize precise behavioral testing alongside molecular assays to evaluate how these receptor expression shifts drive the development, transition, and long-term persistence of psychostimulant abuse.

Adenosine plays an essential role in regulating neuronal signaling within the striatal direct pathway. Presynaptic adenosine A₁ receptors are expressed where they compete directly with A_2A receptors through receptor-receptor interactions to inhibit glutamate release. Postsynaptic A₁ receptors are highly co-expressed with dopamine D₁ receptors on dynorphin-containing neurons of the direct pathway. These postsynaptic A₁ and D₁ receptors exert opposing influences on one another via both allosteric receptor-receptor interactions and competing intracellular signaling cascades. Our lab is actively working to determine exactly how manipulating these complementary pre- and postsynaptic adenosine A₁ receptor pools alters reward and relapse phenotypes, shedding light on how these direct pathway dynamics contribute to compulsive addictive behaviors.

Within the striatal indirect pathway, adenosine A_2A receptors are co-expressed alongside dopamine D₂ receptors on enkephalin-containing neurons. These receptor networks oppose each other through intricate allosteric receptor-receptor interactions and opposing intracellular signaling cascades that directly dictate cellular functioning and animal behavior. Following repeated psychostimulant treatment, the inhibitory regulation of D₂ receptors via A_2A stimulation is often lost, resulting in unbraked D₂ receptor signaling that facilitates an increase in addictive-like behaviors. Mechanistically, we discovered that A₁ receptor stimulation specifically blocks downstream dopamine D₃-driven relapse pathways while leaving D₂ and D₄ receptor signaling entirely intact. Our ongoing studies seek to resolve how selective stimulation of these adenosine A_2A receptor networks can be harnessed to normalize indirect pathway output and suppress relapse.