Role of D2-like Heteroreceptor Complexes in the Effects of Cocaine, Morphine, and Hallucinogens

One emerging concept is that direct physical receptor-receptor interactions in heteroreceptor complexes or altered balance with their homoreceptor complexes population can contribute to disease progression. Antagonistic A2AR-D2R-like receptor-receptor interactions in heteroreceptor complexes in the ventral striatum play a role in cocaine addictive behaviors. A2AR-D2R heteroreceptor complexes are hypothesized to be critically involved in cocaine reward and reinstatement of seeking, and more specifically that the activation of the A2AR protomer of this heteroreceptor complex inhibits the development and maintenance of cocaine addictive behavior. D2R-5-HT2AR heteroreceptor complexes in the brain represent a new target for hallucinogenic drugs. The psychotic-like actions of the 5-HT2AR hallucinogens can involve an enhancement of D2R protomer signaling via an abnormal facilitatory allosteric receptor-receptor interaction in the D2R-5-HT2AR heteroreceptor complex in the striatum. This gives novel insights into the molecular mechanism for the therapeutic actions of atypical antipsychotic drugs with a high affinity for the 5-HT2AR receptors. D4R-MOR heteroreceptor complexes appear to exist in the GABA striosome-nigral pathway, which plays a role in habit learning and the transition from impulsive to compulsive drug use. Antagonistic allosteric D4R-MOR interactions in these complexes block the effect of morphine on MOR protomer recognition and Gi/o coupling. D4R agonists targeting the D4R protomer of this receptor complex can be a novel strategy for counteracting morphine addiction development.