Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats

Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats

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J Psychiatry Neurosci 2014; 39(3): 189-199

Fiona Y. Choi, MA; Soyon Ahn, PhD; Yu Tian Wang, PhD; Anthony G. Phillips, PhD

Department of Psychiatry, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colo., USA


Background: Behavioural sensitization has been linked to drug craving in both clinical and preclinical studies of addiction. Increased motor activity is accompanied by enhanced dopamine (DA) release, particularly in the nucleus accumbens (NAcc). The neural bases of sensitization are linked to alterations in synaptic connections that also underlie learning and memory. The present study uses an “interference” peptide, Tat-GluA23Y, that blocks long-term depression (LTD) at glutamatergic synapses by disrupting the endocytosis of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), to explore the role of this form of synaptic plasticity in the induction and maintenance of sensitization.

Methods: Rats were given 5 injections of d-amphetamine (d-AMPH, 1.0 mg/kg, intraperitoneal) every second day. Tat-GluA23Y , was administered by 2 different routes (intravenously and intracerebrally to the ventral tegmental area [VTA] or to the NAcc) before each injection of d-AMPH. After a 14-day drug-free period, expression of behavioural sensitization was evoked by a challenge injection of d-AMPH (0.5 mg/kg, intraperitoneal). Dopamine efflux in the NAcc was measured by high-pressure liquid chromatography with electrochemical detection analyses of brain dialysates on days 1, 9 and 24 of the intravenous peptide experiment.

Results: Systemic administration of Tat-GluA23Y during the induction phase blocked maintenance of behavioural sensitization and attenuated the maintenance of neurochemical sensitization. Intra-VTA infusion of Tat-GluA23Y before each administration of d-AMPH did not affect induction, but inhibited maintenance and subsequent expression of sensitization, whereas intra-NAcc infusion of the peptide did not affect induction or maintenance of sensitization

Limitations: The relevance of behavioural sensitization in rodents is related to the development of craving and does not provide direct measures of drug reinforcement.

Conclusions: These findings confirm that drug-induced neuroplasticity is labile and may be subject to disruption at a time when long-lasting associations between drug reward and contextual stimuli are formed. Furthermore, the unique ability of Tat-GluA23Y to block maintenance of behavioural sensitization implicates LTD in the consolidation of essential associative memories. Tat-GluA23Y has the unique ability to disrupt functional neuroadaptations triggered by repeated psychostimulant exposure and therefore may protect against the development of craving and drug seeking behaviours.

Submitted Jan. 3, 2013; Revised Mar. 29, July 8, July 25, 2013; Accepted July 26, 2013.

Acknowledgements: This project was supported by operating grants from the Canadian Institutes of Health Research (CIHR) to A.G. Phillips (MOP 38069) and to Y.T. Wang (MOP 38090). F.Y. Choi was supported by a doctoral fellowship from the CIHR-funded Integrated Mentor Program in Addictions Research Training program and subsequently by a research assistantship from CIHR (MOP 38069). We thank Ms. Kitty So for her invaluable technical assistance with the microdialysis studies. Portions of these data were included in the Eli Lilly Canada Heinz Lehmann Award Lecture presented by A.G. Phillips during the Joint Meeting of the CCNP/SSNP in Copenhagen, Denmark, in April 2009.

Competing interests: None declared by F.Y. Choi and S. Ahn. Y.T. Wang and A.G. Phillips declare a pending patent (PCT/CA2004/ 001813) for an IV formulation of the interference peptide Tat-GluA23Y. A.G. Phillips also declares a grant, unrelated to the present study, from Panora Pharmaceuticals. He served until July 2013 on the board of directors of Allon Therapeutics.

Contributors: All authors designed the study and reviewed and approved it for publication. F.Y. Choi and S. Ahn acquired and analyzed the data, which A.G. Phillips also analyzed. F.Y. Choi, S. Ahn and A.G. Phillips wrote the article.

DOI: 10.1503/jpn.120257

Correspondence to: A.G. Phillips, 2255 Wesbrook Mall, Department of Psychiatry, University of British Columbia, Vancouver BC V6T 2A1;