British Journal of Pharmacology
May 5, 2009
Daniela Braida, Valeria Capurro, Alessia Zani et al.
145 citations
Salvinorin A, the active ingredient in Salvia divinorum, produced both anxiety-reducing and antidepressant-like effects in rats and mice. These effects were prevented by blocking either kappa-opioid or CB1 cannabinoid receptors. Salvinorin A reduced fatty acid amide hydrolase activity in the amygdala but showed very weak binding to CB1 receptors. The findings suggest that both kappa-opioid and endocannabinoid systems mediate these mood-altering effects, which may help explain subjective experiences reported by recreational users.
Biological psychiatry
February 1, 2008
Daniela Braida, Valeria Limonta, Valeria Capurro et al.
107 citations
Salvinorin A, a drug from the plant Salvia divinorum, produces rewarding effects in rats at low to moderate doses but becomes aversive at the highest doses tested. In conditioned place preference tests, doses between 0.1 and 40 micrograms per kilogram given subcutaneously were rewarding, while 160 micrograms per kilogram was aversive. In self-administration tests, doses of 0.1 to 0.5 micrograms per infusion given intracerebroventricularly were rewarding, but 1 microgram per infusion was aversive. The rewarding effect was blocked by pretreatment with either a cannabinoid CB1 receptor antagonist or a kappa-opioid receptor antagonist. Salvinorin A also increased dopamine levels in the shell of the nucleus accumbens by about 150 percent. These findings indicate that the rewarding effects involve interaction between kappa-opioid and endocannabinoid systems.
Translational Psychiatry
September 4, 2024
Antonio Inserra, Antonella Campanale, Tamim Rezai et al.
24 citations
Rapid-acting antidepressants, such as dissociative anesthetics, psychedelics, and empathogens, may improve psychiatric disorders by modulating neuroplasticity, neurotransmission, and immunity. Preliminary evidence suggests these drugs are accompanied by epigenetic changes—including alterations in DNA methylation, histone modifications, and non-coding RNA regulation—in stress-responsive brain regions, similar to those seen with conventional antidepressants. Whether these epigenetic changes causally contribute to therapeutic effects, are a consequence, or are unrelated remains unknown. Candidate mechanisms involve neuronal activity, serotonin and TRKB signaling, and direct interaction with chromatin. Causation, cell type-specificity, and mechanisms are largely unconfirmed.
Cannabis and Cannabinoid Research
January 8, 2024
Timothy G. Freels, S. Westbrook, E. Zamberletti et al.
Adolescent female rats self-administered more vaporized THC-dominant cannabis extract than adolescent males. In adulthood, only females exposed to cannabis during adolescence showed impairments in behavioral flexibility, requiring more trials and making more regressive errors on an attentional set-shifting task, compared to vehicle-exposed rats. These sex differences were not observed when rats received a noncontingent dosing regimen that matched the amount females self-administered. No differences were found in effort-based decision making. In the medial prefrontal cortex, only female cannabis-exposed rats had more reactive microglia, with no changes in myelin basic protein or dendritic spine density. The findings indicate sex-specific long-term effects of adolescent cannabis use on brain structure and behavior.
International Journal of Molecular Sciences
August 18, 2021
Marina Gabaglio, Erica Zamberletti, Cristina Manenti et al.
Cannabis is widely used by adolescents, and animal studies have shown long-term harm from its main psychoactive component, THC, but often ignore other cannabinoids like CBD. In female rats, giving THC and CBD together in a 3:1 ratio—based on illegal cannabis samples—reduced some behavioral changes and alterations in CB1 receptors and microglia in the prefrontal cortex caused by THC alone. However, a combination resembling 'light cannabis' (CBD:THC at 33:1, total THC 0.3%) caused lasting cognitive problems and anhedonia, along with increased GAD67 levels in the prefrontal cortex, indicating possible long-term effects on GABA signaling.
Neurobiology of disease
March 1, 2014
Erica Zamberletti, Sarah Beggiato, Luca Steardo et al.
Adolescent exposure to THC in female rats leads to long-lasting behavioral changes in adulthood, including memory deficits, social withdrawal, altered emotional reactivity, and heightened sensitivity to the effects of PCP. These changes are accompanied by reduced levels of the enzyme GAD67 and the neurotransmitter GABA in the prefrontal cortex, as well as increased glutamate and cFos activity in the prefrontal cortex and dorsal striatum. The findings suggest that adolescent THC exposure may contribute to the development of psychotic-like behaviors later in life.