Effects of Acute and Chronic Treatments with Dopamine D₂ and D₃ Receptor Ligands on Cocaine versus Food Choice in Rats

Abstract

Dopamine D receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D- and D-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D agonist -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1-indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D agonist PF-592,379 [5-[(2,5)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D antagonist PG01037 [-[()-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D-and D-preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment.

Effects of muscarinic M1 receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

“…The M 1 /M 4 receptor-preferring agonist xanomeline reduced cocaine taking in rats given access to choose between cocaine or a palatable food reinforcer [23]. Unlike effects of dopamine receptor ligands in the same assay [24,25], the effects of M 1 /M 4 stimulation grew larger during subchronic dosing, and subsisted briefly after ended treatment [23]. In mice, M 1 /M 4 stimulation facilitated extinction of cocaine seeking and prevented reinstatement of cocaine seeking when administered during extinction or between cocaine exposure and extinction [26].…”

Early Life Stress and the Onset of Obesity: Proof of MicroRNAs’ Involvement Through Modulation of Serotonin and Dopamine Systems’ Homeostasis

“…In addition, overexpression of let-7d is negatively correlated with the expression of DRD3 in the hippocampus of mice (Bahi and Dreyer, 2018). The activity of the DRD3 is controversy in the context of food intake, but some evidences associate it with eating disorders and decreased food intake (Thomsen et al, 2017;González et al, 2019). The expression of DAT, the major controller of dopamine levels in the synaptic clefts, is post-transcriptionally regulated on cell culture of dopaminergic neurons by miR-137 and miR-491 (Jia et al, 2016).…”

The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

“…As thoroughly reviewed by Sokoloff and Le Foll [9], D3R drugs reduce cocaine-motivated behaviors on high-but not low-effort schedules of reinforcement. Dopamine D3R partial agonists and antagonists are generally ineffective in altering cocaine intake on low fixed ratio schedules requiring 5 or fewer responses [10][11][12][13][14]. Similarly, we have found that cocaine intake on a low-effort variable interval (VI) 60 s schedule of reinforcement is only affected at doses of D3R partial agonists and antagonists that also affect sucrose reinforcement and cocaine-induced locomotor activity [11].…”