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

Abstract

Despite several studies suggesting the therapeutic use of 5-hydroxytryptamine receptors type 2A (5-HT ) 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-HT 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-HT 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-HT agonists could be used as therapeutic agents to reverse a drug dependent state, as well as inhibiting the aversive effects produced by drug withdrawal.

5-HT 2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area

“…While the mechanisms underlying the therapeutic outcomes associated with 5-HT 2A R agonist treatment have remained unclear, evidence suggests that circuitry adaptations in the ventral midbrain are important. For example, the transition to escalating drug intake in rodents has been associated with inhibition-resistant VTA GABA neuron firing (38,44), and intra-VTA infusion of a 5-HT 2A R agonist can prevent such dependence-related transitions (45). We observed similar irregular VTA GABA neuron firing in response to GABAergic stimulation or ethanol application following acute stress exposure, which was ameliorated by TCB-2.…”

Persisting Reductions in Cannabis, Opioid, and Stimulant Misuse After Naturalistic Psychedelic Use: An Online Survey

“…Ayahuasca has been shown to reduce amphetamine self-administration in adolescent rats and normalize amphetamine related locomotor behavior (102). Vargas-Perez and colleagues found a single administration of the serotonin 2A agonist psychedelic 4-AcO-DMT (103) prevented development of opioid and nicotine dependence and blunted withdrawal response in rats and mice (104). Together, these data suggest serotonin 2A psychedelics may hold considerable potential as novel therapeutics in treating various SUDs.…”

Cessation and reduction in alcohol consumption and misuse after psychedelic use

“…These results highlight an important and potentially transdiagnostic therapeutic mechanism of psychedelic-assisted addiction treatment, which is also currently being studied in people who use cocaine (ClinicalTrials.gov Identifier: NCT02037126, 2014b). Based on current and previous findings including preclinical data (Cata-Preta et al, 2018; Godinho et al, 2017; Oliveira-Lima et al, 2015; Vargas-Perez et al, 2017), it seems plausible that serotonin 2A agonist psychedelics may possess some inherently anti-addictive properties, and that in humans, these may be mediated by overall intensity and/or mystical-type effects of the drug experience (Bogenschutz et al, 2015; Garcia-Romeu et al, 2015).…”