title: Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of amphetamine sensitization in male rats.
abstract: 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-GluA2(3Y), 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-GluA2(3Y), 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-GluA2(3Y) during the induction phase blocked maintenance of behavioural sensitization and attenuated the maintenance of neurochemical sensitization. Intra-VTA infusion of Tat-GluA2(3Y) 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.
  
  
  CONCLUSIONS
  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-GluA2(3Y) to block maintenance of behavioural sensitization implicates LTD in the consolidation of essential associative memories. Tat-GluA2(3Y) 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.
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC.
authors.forename: Fiona Y
authors.initials: FY
authors.lastname: Choi
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC.
authors.forename: Soyon
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC.
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of British Columbia, Vancouver, BC.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002408:Catheters, Indwelling; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D002491:Central Nervous System Agents / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid; D015259:Dopamine Agents / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000503:physiopathology
chemical_list: D057846:Cell-Penetrating Peptides; D002491:Central Nervous System Agents; D015259:Dopamine Agents; D018091:Receptors, AMPA; C000595429:Tat-GluA2(3Y) peptide; D000661:Amphetamine