John A. Schetz
University of North Texas Health Science Center, USA
Title: Unraveling the complex psychopharmacology associated with the adverse neuropsychiatric side effects and recreational use of HIV-1 antiretroviral drugs
Biography
Biography: John A. Schetz
Abstract
Efavirenz has been a mainstay of HAART since its introduction in 1998. Though recently downgraded by DHHS from a first-line to an alternative treatment due to risk of neuropsychiatric adverse events (NPAE), both WHO and South African guidelines continue to recommend efavirenz as the preferred NNRTI for HAART in adults, and generic forms are becoming available. Yet, only recently has significant progress been made towards a molecular mechanistic appreciation of efavirenz-mediated NPAEs and its attractiveness as a recreational drug. Contributing factors are rapid brain accumulation and a narrow therapeutic window. Receptor pharmacology studies indicate that within a concentration range relevant to its brain exposure, efavirenz disrupts dopaminergic, serotoninergic, cholinergic, and GABAergic systems. Hence, the combined effects on these neurotransmitter systems is likely to be responsible for some of efavirenz’s NPAEs, such as sleep disturbances, depression, anxiety, hallucinations, dizziness, headaches and memory impairments. Specifically, a number of CNS off-target interactions for efavirenz have been identified, including with the 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, M1, M3 and GABA-A receptors, DAT, SERT, and VMAT2 transporters, and MAO-A. In rats trained to discriminate LSD from saline, efavirenz partially substitutes for LSD and this substitution is blocked by pre-treatment with a 5-HT2A receptor selective antagonist. Efavirenz also apparently competes for the same binding site at the 5-HT2A receptor as LSD, and prolonged chronic treatment with efavirenz drastically reduces 5-HT2A receptor levels. Findings from our receptor pharmacology studies and those in animals and humans correlate primarily with behavioral effects related to depressive, anxiogenic, hallucinogenic, and sleep disturbances.