Receptor heteromer is defined as a macromolecular complex composed of at least two (functional) receptor units with biochemical properties that are demonstrably different from those of its individual components. We have two main lines of research: First (A), the discovery of receptor heteromers with functional or pathological significance in the CNS, particularly those localized in brain circuits involved in drug addiction;second (B), preclinical and clinical pharmacological targeting of those receptor heteromers. 

 A). The identification of functionally significant receptor heteromers implies, first, the study of heteromerization of transfected receptors in mammalian cell lines using Bioluminescence Resonance Energy Transfer and the identification of their unique biochemical properties. Once a biochemical property of the heteromer is determined, it can be used as a biochemical fingerprint of the receptor heteromer in native tissues. By using this approach we have previously discovered a number of dopamine and adenosine receptor heteromers. Last year we discovered that the dopamine D4 receptor, which has been very elusive in showing its functional significance, forms receptor heteromers with D2 receptors that modulate striatal glutamate release and we described its potential relevance for Attention Deficit Hyperactivity Disorder (ADHD). We therefore hypothesized that the functional role of D4 receptors could be better understood by its ability to modulate other more abundant receptors with already characterized neuronal functions. We then used this rational to discover the enigmatic role of D4 receptors in the pineal gland. D4 receptors are highly expressed in the pineal gland during the dark cycle, and they follow a circadian rhythm, disappearing during the light period. We demonstrated that the production of melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D4 receptors (1). Through α1B-D4 and β1-D4 receptor heteromerization dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. These data provide a new perspective on dopamine function mediated by D4 receptors and constitute the first example of a circadian-controlled receptor heteromerization (1). We have previously described and pharmacologically characterized the existence of functionally significant heteromers between adenosine A2A and D2 receptors in the rodent and human striatum (2,3). We are now studying the possible impact of sleep-dependent variations of endogenous adenosine on the function of A2A-D2 receptor heteromers. In a previous PET study we found that sleep deprivation, which increases adenosine concentration in the brain, decreases the binding of 11Craclopride to D2 receptors in the human brain. In our more recent human PET study (4), we found that the dopamine increases induced by methylphenidate in the ventral striatum (measured as decreases in the binding of 11Craclopride to D2 receptors compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation (4). These findings are consistent with an adenosine-dependent down-regulation or decreased ligand affinity of D2 receptors in ventral striatum with sleep deprivation, upon co-activation of the A2A receptor in the A2A-D2 receptor heteromer. B). Receptor heteromer-selective drugs could in principle be ligands that bind with more affinity to any of the two protomers of the heteromer than to the same receptor units when not forming heteromers. The proof of concept came from a previous study we published the previous year, where we found that some adenosine A2A receptor antagonists would have a different striatal pre-/postsynaptic pharmacological profile depending on their preferential ability to bind A1-A2A or A2A-D2 receptor heteromers (localized pre- or postsynaptically, respectively) (reviewed in ref. 2). In a more recent study we were able to dissect two subpopulations of postsynaptic A2A receptors, which would depend on their ability to form or not heteromers with D2 receptors (5). The main pharmacological tool was the A2A receptor antagonist SCH-442416, which binds with very low affinity to A2A-D2 receptor heteromers) (2). SCH-442416 selectively counteracted locomotor depression in rats induced by the D2 receptor antagonist raclopride (by acting at the postsynaptic A2A receptor not forming heteromers with the D2 receptor) at doses that modulate striatal glutamate release (by acting at the presynaptic A2A receptor forming heteromers with the A1 receptor), but do not produce motor activation (which depends on A2A receptor forming heteromers with D2 receptor) (2,5). On the other hand, another A2A receptor antagonist, KW-6002, seems to preferentially postsynaptic (2), which, by its ability to potentiate D2 receptor function, and therefore reducing the inhibitory output of the basal ganglia indirect pathway, makes it a good candidate for the treatment of Parkinsons disease (3). Next question is which A2A receptor antagonists could be of clinical use in drug addiction. Presynaptic A2A receptor antagonists could be useful to counteract relapse, since preclinical data indicate that cortico-striatal glutamatergic is very much involved in reinstatement of drug self-administration. But postsynaptic A2A receptor antagonists are also potentially useful. It has been postulated that the reported reduction in the number of striatal D2 receptors combined with a reduction in dopamine cell activity in cocaine abusers leads to a reduced sensitivity to natural rewards, predisposing cocaine dependent individuals to drug seeking as a means of temporarily providing stimulation of this system. PET studies have indicated a significant correlation between reduction in D2 receptor binding and reduced metabolism in the orbitofrontal cortex, cingulate cortex, and dorsolateral prefrontal cortex. This reduction in prefrontal cortical activity may also be important for cocaine addiction, as these brain regions are involved in working memory, decision making, and inhibitory control, which are impaired in cocaine-dependent subjects. It is unknown whether enhancing dopamine function (directly or indirectly) in the striatum in cocaine dependent subjects would affect prefrontal cortical brain function and the processes subserved by the prefrontal cortex, including working memory and inhibitory control. We sought to determine the effects administration of an A2A receptor antagonist SYN115 with strong postsynaptic activity (strong motor activation in dopamine-denervated rodents) on brain function in cocaine dependent subjects (6). fMRI results showed that for 7-digit working memory activation there was significantly greater activation from SYN115 compared to placebo in portions of left (L) lateral orbitofrontal cortex, L insula, and L superior and middle temporal pole (6). These findings are consistent with enhanced dopamine function in the striatum in cocaine dependent subjects via blockade of A2A receptors producing increased brain activation in the orbitofrontal cortex and other cortical regions. This suggests that at least some of the changes in brain activation in prefrontal cortical regions in cocaine dependent subjects may be related to altered striatal dopamine function, and that enhancement of dopamine function via adenosine A2A receptor blockade could be explored further for amelioration of neurobehavioral deficits associated with chronic cocaine use.

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Project End
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Budget End
Support Year
7
Fiscal Year
2012
Total Cost
$1,932,282
Indirect Cost
Name
National Institute on Drug Abuse
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Type
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Ferré, Sergi (2016) Mechanisms of the psychostimulant effects of caffeine: implications for substance use disorders. Psychopharmacology (Berl) 233:1963-79
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