Interference Peptides to Probe Addiction

Anthony George phillips

Abstract


   Drug addiction is a complex neuropsychiatric disorder in which repeated self-administration of psychoactive drugs including amphetamines, cocaine, nicotine, heroin and alcohol induces long-lasting changes in neural function and behaviour. There is growing support for the hypothesis that addiction may involve mechanisms of neural plasticity (Long-Term Potentiation/ Depression; LTP/LTD) implicated in learning and memory, and in particular with associative mechanisms which serve to link environmental stimuli with drug reward; as well as strengthening instrumental responses required for drug self-administration. Craving is a key feature of relapse that results from repeated exposure to drugs of abuse and is modeled in preclinical studies as a drug-induced increased in motor activity following intermittent injections of psychostimulants and other drugs of abuse (i.e. behavioural sensitization). Thomas and colleagues report enhancement of LTD of glutamatergic transmission in the NAc in sensitized rats following repeated cocaine, providing the first correlation between acquired LTD and drug addiction. LTD expression is absolutely dependent on clathrin-mediated AMPAR removal (endocytosis) from the synapses and Y.T. Wang and colleagues identified a novel tyrosine phosphorylation-dependent endocytic motif (869YKEGYNVYG877) in GluR2 CT that is absolutely required for AMPAR endocytosis.  Based on this sequence, a GluR23Y interference peptide was developed and fused to human immunodeficiency virus-type 1 (HIV-1) Tat protein to allow for intracellular delivery. Tat- peptide can reach sites of action in brain at effective concentrations within 30 min of IV administration. Based on these findings, we confirm that intracerebral injections of Tat- GluR23Y peptide  into 1) the ventral tegmental area (VTA) can block induction and maintenance of behavioural sensitization; whereas similar injections into the nucleus accumbens (NAc) but not VTA, blocks the expression of sensitized locomotor activity. Remarkably, combined treatment with amphetamine and Tat-GluR23Y infusions into the VTA blocked subsequent attempts to induce sensitized behaviour for several weeks. Accordingly, these data provide strong support for a causative relationship between LTD and sensitization. Van den Oever et al., report that microinjection of Tat- GluR23Y  interference peptide into the medial prefrontal cortex blocked cue-induced relapse to heroin-seeking behavior, thus providing independent confirmation of the validity of  our interference peptide strategy to selectively target aspects of synaptic plasticity related to drug addiction.


Keywords


addiction;synaptic plasticity;AMPA receptor endocytosis



ISSN 1903-7236