Interference with AMPA receptor endocytosis : effects on behavioral and neurochemical correlates of amphetamine sensitization

A hallmark of drug addiction is the compulsive drug taking behaviour that persists despite detrimental and adverse consequences. The gradual sensitization to the effects of drugs has been proposed to be an underlying mechanism for increased drug use and it serves as an animal model of craving and enduring neural plasticity. Evidence from studies conducted in rodents, non-human primates and humans have supported a role for sensitization in the development of states that promote drug taking. Rodent studies have also demonstrated that repeated exposure to drugs producing behavioural sensitization increases dopamine (DA) levels in the nucleus accumbens (NAc) and contributes to the acquisition of drug self-administration behaviour as well as the effort level to actively acquire a drug. The changes in neural functioning following repeated drug exposure is attributed to alterations in synaptic connections that underlie and are crucial for normal brain function as well as mechanisms of learning and memory. There is recent evidence supporting the development of a new class of interference peptides aimed at repairing functional and structural alterations in brain regions implicated in a number of psychiatric disorders. One such interference peptide, Tat-GluA2₃Y, blocks long-term depression (LTD) at glutamatergic synapses and has also been demonstrated to block the expression of behavioural sensitization and significantly reduce cue-induced reinstatement of heroin self-administration. This peptide interferes with the interaction between α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor and Brag2, a clathrin-adaptor protein which initiates the process of AMPA receptor endocytosis, leading to LTD. Results from the studies contained in this dissertation suggest that modulating protein-protein interactions with Tat-GluA2₃Y can influence the synaptic modifications following repeated amphetamine exposure, to effectively block the development and long-term maintenance of behavioral sensitization in a context-dependent manner. Effects of this peptide can be applied to understanding the circuitry and mechanisms involved in the development of psychostimulant sensitization, possibly serving as a platform from which to develop a novel pharmacotherapeutic approach for treating drug addiction.Medicine, Faculty ofGraduat