Effects of acute and chronic treatments with dopamine D 2 and D 3 receptor ligands on cocaine vs. food choice in rats Running title: Effects D 2 and D 3 ligands on cocaine choice in rats

ABSTRACT Dopamine D 3 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, non-drug reinforcer. This study compared acute and chronic effects of dopamine D 2 -and D 3 -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 2 agonist NPA and antagonist L-741,626 produced leftward and rightward shifts in cocaine dose-effect curves, respectively, while the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, NPA and L-741,626 effects on cocaine self-administration showed marked tolerance, while suppression of food-reinforced behavior persisted. Acute effects of the D 3 ligands were less systematic and most consistent with nonselective decreases in cocaine-and food-maintained responding. Chronically, the D 3 agonist PF-592,379 increased cocaine choice, whereas an intermediate dose of the D 3 antagonist PG01037 produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance developed to this effect, and lower and higher doses were ineffective. D 3 ligands failed to significantly modify total cocaine intake, but caused persistent decreases in food intake. Thus, D 2 -and D 3 -preferring ligands showed distinct profiles, consistent with different pharmacological actions

Effects of muscarinic M₁receptor stimulation on reinforcing and neurochemical effects of cocaine in rats

Cocaine addiction is a chronic illness characterized by maladaptive drug-induced neuroplastic changes that confer lasting vulnerability to relapse. Over several weeks we observed the effects of the M(1) receptor-selective agonist VU0364572 in adult male rats that self-administer cocaine in a cocaine vs. food choice procedure. The drug showed unusual long-lasting effects, as rats gradually stopped self-administering cocaine, reallocating behavior towards the food reinforcer. The effect lasted as long as tested and at least 4 weeks. To begin to elucidate how VU0364572 modulates cocaine self-administration, we then examined its long-term effects using dual-probe in vivo dopamine and glutamate microdialysis in nucleus accumbens and medial prefrontal cortex, and ex vivo striatal dopamine reuptake. Microdialysis revealed marked decreases in cocaine-induced dopamine and glutamate outflow 4 weeks after VU0364572 treatment, without significant changes in dopamine uptake function. These lasting and marked effects of M(1) receptor stimulation reinforce our interest in this target as potential treatment of cocaine addiction. M(1) receptors are known to modulate medium spiny neuron responses to corticostriatal glutamatergic signaling acutely, and we hypothesize that VU0364572 may oppose the addiction-related effects of cocaine by causing lasting changes in this system