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Arrestins and GRKs in Drug Addiction

Drug addiction is a chronic and devastating disease. The addiction to drugs of abuse is believed to arise from long-term molecular and cellular adaptations analogous to those mediating learning and memory but “hijacked” by addictive drugs. Psychostimulants (PS), such as cocaine or amphetamine, enhance the dopamine concentration by blocking DA transporter and/or inducing non-vesicular DA release. The enhanced DA concentration in the brain increases the activity of DA receptors, altering the intracellular signaling mechanisms. Some of the downstream signaling effects of PS are well documented. Among the most robust signaling adaptations seen after repeated cocaine administration is the up-regulation of the cAMP-PKA pathway in the nucleus accumbens. Thus, overactive dopaminergic signaling likely plays a role in the molecular adaptations induced by chronic intake of PS. The intake of PS creates powerful bursts of DA-mediated signaling in the DA-receptive brain areas, such as Acb (define), placing a great burden on the regulatory mechanisms. Addicts often “binge” on PS, consuming a large amount of drugs in a short time, which places additional stress on the system. The main regulatory mechanism initiated in response to persistent activation of G protein-coupled receptors, such as DA receptors, and aimed at reducing excessive signaling, is homologous desensitization. Arrestins and GRKs are the key players in this process. GRKs phosphorylate agonist-activated GPCRs, thus enabling high-affinity arrestin binding, which terminates G-protein-dependent signal transduction. The increased availability of arrestins and/or GRKs facilitates receptor desensitization and suppresses signaling, whereas reduced availability of arrestins/GRKs has the opposite effect.

It is likely that chronic consumption of PS drugs compromises the ability of the receptor desensitization machinery to control signaling in the brain. This may be due to the drug-induced down-regulation of GRKs and/or arrestins or simply due to enhanced demand for both proteins that the system is unable to meet. In this case, increased availability of GRK6/arrestin would facilitate desensitization, thus relieving the pressure of excessive signaling, reducing drug-induced long-term plasticity, and alleviating addictive behavior. Conversely, suppression of receptor desensitization by reducing the availability of GRKs should be expected to enhance the addictive effects of PS. We are currently examining the role of GRKs and arrestins in PS addiction using lentivirus-mediated overexpression or knockdown of GRK6 in the brain and determining the changes in drug-induced behaviors, such as conditioned place preference and locomotor sensitization. If we find that GRKs do play a role in drug-induced signaling changes, they could be targeted to combat addiction.