Targeting the trace amine-associated receptor 1 in psychomotor stimulant addiction.
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Psychomotor stimulant drugs, such as cocaine and amphetamine-type substances, including amphetamine and methamphetamine (METH), are potent central nervous system (CNS) stimulants with highly addictive potential. They are widely used and abused around the world, generating a staggering burden on society and the individual’s family, yet no specific medications have been found to safely facilitate detoxification and promote quicker recovery from chronic stimulant abuse. The mainstay pharmacological approach for stimulant addiction has largely relied on directly altering neurotransmission of the classic monoamines, especially dopamine (DA), which is a key mediator of psychostimulant’s effects. However, progress has been hindered by the limited efficaciousness and potential non-specific side effects associated with direct manipulation of the DA system. The newly discovered trace amine-associated receptor 1 (TAAR1) has gained increasing attention as a novel target for the pharmacological development of new addiction treatments. TAAR1 belongs to a family of G protein-coupled receptors (GPCRs) and is activated by trace amines (TAs), a group of endogenous amines that are intimately related to the classic monoamines. TAAR1 shares overlapping CNS distribution with the major monoaminergic pathways and is directly activated by some psychostimulants including METH. Early evidence from in vitro preparations and in vivo transgenic studies indicated an important role of TAAR1 in the regulation of DA transmission and psychostimulant action, leading to the hypothesis that pharmacological targeting of TAAR1 may present a promising avenue for addiction treatment. However, due to the unavailability of highly selective TAAR1 agonists until very recently, a direct assessment of this hypothesis has been difficult. The goal of the present thesis is to investigate systematically the potential therapeutic effectiveness of TAAR1-based agents in clinically-relevant animal models of addiction. Specifically, we will examine the ability of newly generated TAAR1 selective partial and full agonists to modulate key abuse-related behavioural and neurochemical effects of cocaine and METH. This is accomplished across three major sets of experiments, with 10 experiments in total. The findings obtained from the current work provide evidence of highly favourable properties of TAAR1 agonists, consistent with an efficacious anti-addiction medication, and support the candidacy of TAAR1 as a pharmacological target for the treatment of stimulant addiction.