Science
November 21, 2003
Per Svenningsson, Eleni T. Tzavara, Robert Carruthers et al.
312 citations
Three drug classes—dopaminergic agonists (e.g., D-amphetamine), serotonergic agonists (e.g., LSD), and glutamatergic antagonists (e.g., PCP)—produce schizophrenia-like effects in animals. A common signaling pathway involving the protein DARPP-32 mediates these effects. DARPP-32 is phosphorylated or dephosphorylated at three sites, leading to synergistic inhibition of protein phosphatase-1 and regulation of downstream effectors GSK-3, CREB, and c-Fos. In mice lacking DARPP-32 or with point mutations at its phosphorylation sites, the drugs' effects on sensorimotor gating and repetitive movements were strongly reduced, indicating DARPP-32's essential role in these psychotomimetic actions.
Journal of Neuroscience
November 23, 2011
Benjamin Di Cara, Roberto Maggio, Gabriella Aloisi et al.
97 citations
MDMA (ecstasy) activates trace amine-1 receptors (TA1Rs), which normally inhibit dopamine and serotonin release. In mice lacking TA1Rs, MDMA caused only hyperthermia (not the biphasic temperature response seen in normal mice), produced larger increases in dopamine levels in the striatum, frontal cortex, and nucleus accumbens, and led to greater locomotion that was blocked by haloperidol. Serotonin release was also amplified in TA1R-deficient mice. A TA1R agonist reduced the dopamine- and serotonin-releasing effects of another drug in normal mice but not in knockout mice. TA1Rs thus limit MDMA's neurochemical and behavioral effects, suggesting they play a regulatory role in the drug's actions.
Molecular psychiatry
June 1, 2025
Anderson Camargo, Anna Nilsson, Reza Shariatgorji et al.
5 citations
Prophylactic ketamine administration buffers passive stress-induced maladaptive behaviors caused by chronic stress exposure. It also prevents stress-induced disturbances of tryptophan metabolism in the dorsal raphe nuclei (DRN) and blocks the reduction of the protein p11 in that region. p11 deficiency increases susceptibility to stress-related depression-like behaviors, and these effects depend partly on p11 function in serotonergic neurons. Viral-mediated reduction of p11 in the DRN produces a stress-susceptible phenotype. The pro-resilience effect of ketamine is lost when p11 is selectively deleted in serotonergic neurons, revealing a previously unexplored role of the DRN circuit in regulating stress susceptibility and ketamine's resilience-enhancing actions.
Neuropsychopharmacology
July 7, 2026
Wojciech Pasławski, D Doyon, Carl Johan Ekman et al.
Psilocybin, a rapid-acting antidepressant, reduces levels of the neuropeptide galanin and noradrenaline in cerebrospinal fluid, suggesting that normalization of these co-transmitters is a key pharmacodynamic effect. This finding comes from a secondary analysis of a randomized, placebo-controlled trial with multimodal biomarker measurements. The results indicate a selective effect of psilocybin on these specific neurotransmitters, offering insight into its mechanism of action in major depressive disorder.