Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice

Abstract

Muscarinic and dopamine brain systems interact intimately, and muscarinic receptor ligands, like dopamine ligands, can modulate the reinforcing and discriminative stimulus (SD) effects of cocaine. To enlighten the dopamine/muscarinic interactions as they pertain to the SD effects of cocaine, we evaluated whether muscarinic M1, M2 or M4 receptors are necessary for dopamine D1 and/or D2 antagonist mediated modulation of the SD effects of cocaine. Knockout mice lacking M1, M2, or M4 receptors, as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. Effects of pretreatments with the dopamine D1 antagonist SCH 23390 and the dopamine D2 antagonist eticlopride were evaluated. In intact mice, both SCH 23390 and eticlopride attenuated the cocaine discriminative stimulus effect, as expected. SCH 23390 similarly attenuated the cocaine discriminative stimulus effect in M1 knockout mice, but not in mice lacking M2 or M4 receptors. The effects of eticlopride were comparable in each knockout strain. These findings demonstrate differences in the way that D1 and D2 antagonists modulate the SD effects of cocaine, D1 modulation being at least partially dependent upon activity at the inhibitory M2/M4 muscarinic subtypes, while D2 modulation appeared independent of these systems.

Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals

“…Therefore, we focus on the M 4 receptor here. M 4 -KO mice display an increase in cocaine self-administration compared to controls (Schmidt et al, 2011;Thomsen and Caine, 2016), similar to that observed in D 3 -KO mice described above. Increased cocaine selfadministration in M 4 -KO mice was observed at intermediate doses of cocaine under both a FR and a PR schedule of reinforcement, manifested as an upward shift of cocaine selfadministration dose-response curves (Schmidt et al, 2011).…”

Muscarinic receptor M 4 positive allosteric modulators attenuate central effects of cocaine

“…The experimental procedure was as previously described (Thomsen et al, 2012, 2010; Thomsen and Caine, 2016). In brief, mice were trained to discriminate 10 mg/kg cocaine from saline, under an FR 10 schedule of food reinforcement.…”

The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice

“…The active and ineffective doses of drugs were selected by the literature studies. 9,[19][20][21][22][23] The effective and sub-effective doses of SCE have been selected on the basis of the results in the forced swim test as shown in Fig. 1, and confirmed in the tail suspension test (data not shown).…”