UC San Diego

The classical monoamine neurotransmitters — dopamine, norepinephrine, and serotonin — are critically involved in a range of brain functions and their transporters (DAT, NET, and SERT) are targets for many psychoactive drugs. Some of the oldest and most widely prescribed psychotherapeutics (e.g., antidepressants, psychostimulants) are monoaminergic drugs, but their mechanisms remain poorly understood and many pose serious safety or efficacy challenges to patients. Still, there have been few meaningful advances in neuropsychiatric drug development over the last three decades. Growing evidence suggests that MDMA and other psychedelics may transform care for an array of poorly treated conditions. The purpose of my dissertation is to elucidate the mechanisms underlying the behavioral effects of monoaminergic drugs to inform the development of novel, optimized drugs that retain or lack specific therapeutic or adverse effects. We have taken a systematic approach to examining monoamine transporter inhibitors and reversers at both low and high doses on various behavioral outcomes in mice. In Chapter 2, we explore whether existing drugs may mimic the therapeutic, memory-enhancing effects of low-dose psychostimulants but lack the adverse, reinforcing effects of high-dose psychostimulants. Bupropion (a low affinity DAT inhibitor) and atomoxetine (a high affinity NET inhibitor) produced these desired effects in combination but not alone. In Chapter 3, we systematically analyze all preclinical findings on the cognitive effects of MDMA with a critical focus on dose. We found no evidence that low, clinically relevant doses (< 3 mg/kg MDMA) produce cognitive impairments. In Chapter 4, we further analyze the potential adverse effects of MDMA across a wide range of doses. High doses (≥ 3 mg/kg MDMA) produced memory impairments and some evidence of an addictive potential while low, clinically relevant doses (≤ 1 mg/kg MDMA) did not. In Chapter 5, we present a novel method for assessing prepulse inhibition of acoustic startle in rodents, which may be especially useful for antipsychotic drug screening. In Chapter 6, we discuss our findings in the context of the current “psychedelic renaissance” and provide a roadmap for systematically analyzing classical and novel monoaminergic compounds to advance drug development for the most critical unmet medical needs in neuropsychiatry.