Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada; Department of Molecular Genetics, the Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
2 papers in the library · 23 citations · publishing 2017-2024
A single dose of a 5-HT2A receptor agonist, given systemically or directly into the ventral tegmental area (VTA), blocks the aversive conditioned response to drug withdrawal in rats and mice. The treatment also prevents the neural switch from a drug-naive to a drug-dependent motivational system, which is linked to BDNF-mediated adaptations in the VTA. The findings suggest that 5-HT2A agonists may reverse a drug-dependent state and reduce withdrawal-induced aversion, offering a potential therapeutic approach for substance use disorders.
A classic theory of addiction, opponent-process theory, holds that a drug's immediate rewarding effects are followed by an aversive aftereffect that drives continued use. This study tested whether a 5-HT2A agonist (4-AcO-DMT, a psychedelic) follows that pattern in male rats. In a standard place-preference test 24 hours after dosing—when the drug had cleared—the rats showed no preference for the drug-paired location, suggesting no rewarding aftereffect. However, when the test was modified to capture only the acute drug effect, the rats did show a place preference, indicating the drug itself was rewarding. In a separate test measuring only the 24-hour aftereffect, that aftereffect also produced a strong place preference.