A single administration of the hallucinogen, 4-acetoxy-dimethyltryptamine, prevents the shift to a drug-dependent state and the expression of withdrawal aversions in rodents.

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.

Study at a glance

Abstract

Despite several studies suggesting the therapeutic use of 5-hydroxytryptamine receptors type 2A (5-HT2A ) agonists in the treatment of substance use disorders, the neurobiological basis accounting for such effects are still unknown. It has been observed that chronic exposure to drugs of abuse produces molecular and cellular adaptations in ventral tegmental area (VTA) neurons, mediated by brain-derived neurotrophic factor (BDNF). These BDNF-induced adaptations in the VTA are associated with the establishment of aversive withdrawal motivation that leads to a drug-dependent state. Growing evidence suggests that 5-HT2A receptor signaling can regulate the expression of BDNF in the brain. In this study, we observed that a single systemic or intra-VTA administration of a 5-HT2A agonist in rats and mice blocks both the aversive conditioned response to drug withdrawal and the mechanism responsible for switching from a drug-naive to a drug-dependent motivational system. Our results suggest that 5-HT2A agonists could be used as therapeutic agents to reverse a drug dependent state, as well as inhibiting the aversive effects produced by drug withdrawal.