Examination of the mechanisms underlying the discriminative stimulus properties of the atypical antipsychotic amisulpride

Behav Pharmacol. 2024 Feb 1;35(1):47-54. doi: 10.1097/FBP.0000000000000760. Epub 2023 Nov 15.

Abstract

Amisulpride is an atypical benzamide antipsychotic/antidepressant, whose mechanism of action is thought to depend mainly on dopamine D2/3 receptor activity, but also with some serotonin 5-HT2B/7 effects. The present study examined the role of D2/3 receptors and 5-HT2B/7 receptors in amisulpride's discriminative stimulus. Selective agonists and antagonists of the above receptors were tested in adult, male C57BL/6 mice trained to discriminate 10 mg/kg amisulpride from vehicle in a two-lever drug discrimination assay. After acquisition of the two-lever discrimination, the amisulpride generalization curve yielded an ED50 = 0.56 mg/kg (95% CI = 0.42-0.76 mg/kg). Substitution tests found that the D2/3 antagonist raclopride (62.7% Drug Lever Responding), D2/3 agonist quinpirole (56.6% DLR), 5-HT7 agonist LP-44 (50.1% DLR) and 5-HT7 antagonist SB-269970 (36.7% DLR) produced various degrees of partial substitution for the amisulpride stimulus, whereas the 5-HT2B agonist BW 723C86 (17.9% DLR) and 5-HT2B antagonist SB-204741 (21.1% DLR) yielded negligible amisulpride-like effects. In combination tests with amisulpride, quinpirole decreased percent responding from 98.3% to 57.0% DLR, LP-44 decreased percent responding from 97.6% to 76.7% DLR, and BW 723C86 reduced percent responding from 95.66% to 74.11% DLR. Taken together, the results from stimulus generalization and antagonism studies suggest that amisulpride has a complex discriminative cue that involves mainly mixed D2/3 receptor antagonist/agonist effects and, to a lesser degree, mixed 5-HT7 receptor agonist/antagonist and perhaps 5-HT2B receptor antagonist effects.

MeSH terms

  • Amisulpride / pharmacology
  • Animals
  • Antipsychotic Agents* / pharmacology
  • Discrimination Learning
  • Dose-Response Relationship, Drug
  • Indoles*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Piperazines*
  • Quinpirole / pharmacology
  • Tetrahydronaphthalenes*
  • Thiophenes*

Substances

  • Antipsychotic Agents
  • Amisulpride
  • 4-(2-methylthiophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide
  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • Quinpirole
  • Indoles
  • Piperazines
  • Tetrahydronaphthalenes
  • Thiophenes