Journal of Psychopharmacology
December 8, 2010
Liselore Koedood, Adam L. Halberstadt, Susan B Powell et al.
212 citations
Psilocin, the active metabolite of psilocybin, acts as an agonist at 5-HT1A, 5-HT2A, and 5-HT2C receptors. In mice, psilocin induced head twitch response (HTR) via 5-HT2A receptors, as effects were absent in mice lacking that gene. In the behavioral pattern monitor (BPM), psilocin decreased locomotor activity, holepoking, and time in the chamber center; these effects were blocked by the 5-HT1A antagonist WAY-100635 but not by 5-HT2C antagonism or 5-HT2A gene deletion. 5-MeO-DMT produced similar BPM effects attenuated by WAY-100635. Psilocin and 5-MeO-DMT decreased path linearity via 5-HT2C and 5-HT1A receptors, respectively. 1-methylpsilocin induced HTR via 5-HT2A but was inactive in the BPM, suggesting greater pharmacological selectivity and potential as a therapeutic alternative to psilocybin.
Psychopharmacology
December 9, 2010
Adam L. Halberstadt, Virginia Lehmann-Masten, Mark A. Geyer et al.
35 citations
Loss of metabotropic glutamate 5 (mGlu5) receptor activity, either through gene deletion or pharmacological blockade, causes locomotor hyperactivity and reduced habituation in mice. The serotonergic hallucinogen and 5-HT2A agonist DOM (0.5 mg/kg) increased this hyperactivity, while the 5-HT2A antagonist M100907 (1.0 mg/kg) reduced it. M100907 (0.1 mg/kg) also blocked hyperactivity induced by the mGlu5-negative allosteric modulator MPEP. These findings indicate a functional interaction between mGlu5 and 5-HT2A receptors, suggesting mGlu5 receptors may mitigate the behavioral effects of 5-HT2A hallucinogens or that mGlu5 knockout mice have increased sensitivity to such agonists.
Behavioural Brain Research
October 1, 2020
Dionisio A Amodeo, Omron Hassan, Landon M. Klein et al.
25 citations
Activating serotonin 2A (5-HT2A) receptors impairs behavioral flexibility in male mice, as measured by a probabilistic reversal learning task. The selective 5-HT2A agonist 25CN-NBOH increased the number of trials needed to reach criterion during reversal learning, while the broader agonist DOI alone did not. However, combining DOI with a 5-HT2C receptor antagonist (SER-082) also impaired reversal learning, suggesting that 5-HT2A and 5-HT2C receptors have opposing effects on this aspect of executive function. All groups performed similarly on the initial spatial discrimination, indicating that the impairment was specific to adapting to changing contingencies.
Psychopharmacology
February 14, 2019
Adam L. Halberstadt, Jochem V. F. Zee, Muhammad Chatha et al.
21 citations
Chronic treatment with an mGlu2/3 receptor agonist, LY379268, attenuated the head-twitch response (HTR) induced by the selective 5-HT2A agonist 25CN-NBOH in mice, even when tested 48 hours after the last dose. Acute LY379268 also reduced the HTR by about 50%. The HTR was completely blocked by a 5-HT2A antagonist but not by a 5-HT2C antagonist. In locomotor tests, acute LY379268 reduced PCP-induced hyperactivity in mice that had received chronic vehicle treatment, but only a trend for an interaction was seen in the chronic LY379268 group. These results support a functional interaction between mGlu2/3 and 5-HT2A receptors in modulating behavioral responses to 5-HT2A activation.
Journal of Psychiatric Research
July 1, 2025
Joris Kamp, Megan E Sikkink, Mahalah R Buell et al.
In mice with reduced Sp4 expression, a gene linked to schizophrenia in humans, restoring Sp4 in young adults partially corrected two schizophrenia-related behavioral deficits—prepulse inhibition and hypersensitivity to ketamine—but did not improve context memory. The SP4 gene is strongly associated with schizophrenia risk; human studies show that loss of one copy increases odds of schizophrenia by about 9-fold. These results suggest that Sp4 restoration in adulthood may reverse some but not all behavioral abnormalities, supporting further investigation of SP4 as a potential drug target.
Pharmacology, biochemistry, and behavior
September 1, 2016
Adam L. Halberstadt, James Hyun, Michael A Ruderman et al.
N-allylnormetazocine (NANM) disrupts prepulse inhibition (PPI) of acoustic startle in mice, a measure of sensorimotor gating. Racemic NANM and its (+)-isomer produced dose-dependent PPI disruption (3-30 mg/kg), while the (-)-isomer had no effect. Blocking kappa opioid or sigma-1 receptors did not prevent this disruption, and a selective kappa agonist also had no effect on PPI. The findings indicate that NANM's effects on sensorimotor gating are mediated through the PCP site of the NMDA receptor, not through kappa or sigma-1 receptors, consistent with evidence that sigma-1 receptors are not linked to hallucinogenic or psychotomimetic effects.
Psychopharmacology
April 1, 2016
Adam L. Halberstadt, Natalia Slepak, James Hyun et al.
Methoxetamine (MXE), a ketamine analog sold online, produces behavioral effects in rats that closely resemble those of other dissociative anesthetics like phencyclidine (PCP) and ketamine. In Sprague-Dawley rats, MXE disrupted prepulse inhibition (PPI) of acoustic startle at doses of 3 and 10 mg/kg, with a potency ranking (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) that matches their affinities for the PCP binding site on NMDA receptors. In the behavioral pattern monitor, 10 mg/kg MXE caused locomotor hyperactivity, reduced rearing, increased path roughness, and perseverative locomotion—effects similar to those of PCP. These findings indicate MXE acts as a dissociative drug with abuse potential comparable to PCP and ketamine.