A Proposed Mechanism for Stimulant-Induced Behavioral Sensitization Involving the Transporter VMAT
Elucidating mechanisms that drive drug craving is crucial to develop pharmacological interventions for addiction. Repeated exposure to psychostimulants produces an enhanced behavioral and neurochemical sensitivity to both the drug and drug-related cues, known as sensitization. We hypothesize that VMAT, the protein responsible for storage of dopamine (DA) into the vesicles, may be functionally altered to redistribute DA between the cytoplasmic pool and the vesicular pool based on demands for drug-mediated release versus neurotransmission in the context of conditioned environmental cues. To examine the role of VMAT, we pretreated rats with a VMAT blocker, tetrabenazine (TBZ), before each daily treatment of a regimen of seven amphetamine (AMPH) injections and subsequently tested for the blockade of psychomotor sensitization. Two behavioral approaches were implemented to examine the role of VMAT in mediating behavioral sensitization, Aim 1) AMPH evoked behavior and Aim 2) electrically evoked behavior, because these behaviors reflect different mechanisms that are known to become sensitized. In Aim 1), rats were previously prepared with unilateral striatal DA-depletions using 6-OHDA infused into the medial forebrain bundle. After the 7-day Induction Phase, rats were tested for expression of sensitization or its blockade by TBZ by measuring AMPH-evoked rotational behavior. In Aim 2), rats with electrode implants into the MFB that produced electrically stimulated rotational behavior (ESRB), underwent an induction phase and an expression phase as in Aim 1, except that ESRB was tested for sensitization or blockade by TBZ. Within Subjects comparisons from the Induction Phase corroborate expression phase of sensitization and acute effects of TBZ. Between Subjects comparisons from the Expression Phase also demonstrated sensitization of both AMPH-evoked rotational behavior and ESRB. Additionally, these data show that sensitization was blocked in both pharmacokinetic driven and exocytotic-like driven behaviors by TBZ pretreatment. VMAT may sensitize AMPH-evoked responses and behavior evoked by environmental stimuli that activate endogenous neural communication. Future research must evaluate the effects of VMAT blockade during AMPH exposure upon DA overflow/exocytosis and investigate potential pharmacotherapeutic interventions that target VMAT function.
Neurosciences|Biochemistry|Pharmaceutical sciences|Molecular chemistry
Garcia, Valeria, "A Proposed Mechanism for Stimulant-Induced Behavioral Sensitization Involving the Transporter VMAT" (2021). ETD Collection for University of Texas, El Paso. AAI28540876.