Cholinergic muscarinic systems have been shown to influence dopaminergic function in the central nervous system. In addition, previous studies of benztropine analogs that inhibit dopamine uptake and show antagonism at muscarinic receptors show these drugs to be less effective than cocaine in producing its various prototypic effects such as locomotor stimulation. Because previous pharmacological studies on these topics have used nonselective M 1 antagonists, we examined the interactions of preferential M 1 muscarinic antagonists and cocaine. Dose-dependent increases in extracellular levels of dopamine in selected brain areas, the nucleus accumbens (NAc) shell and core, and the prefrontal cortex, were produced by cocaine but not by the preferential M 1 antagonists telenzepine and trihexyphenidyl. When administered with cocaine, however, both M 1 antagonists dose-dependently increased the effects of cocaine on dopamine in the NAc shell, and these effects were selective in that they were not obtained in the NAc core or in the prefrontal cortex. Telenzepine also increased locomotor activity, although the effect was small compared with that of cocaine. The locomotor stimulant effects of trihexyphenidyl, in contrast, approached those of cocaine. Telenzepine attenuated, whereas trihexyphenidyl enhanced the locomotor stimulant effects of cocaine, with neither drug facilitating cocaine-induced stereotypy. The present results indicate that preferential antagonist effects at muscarinic M 1 receptors do not uniformly alter all of the effects of cocaine, nor do they explain the differences in effects of cocaine and benztropine analogs, and that the alterations in dopamine levels in the NAc shell do not predict the behavioral effects of the interactions with cocaine.Both clinical and preclinical data support the existence of extensive interactions between the dopaminergic and cholinergic muscarinic systems in various central nervous system functions and disease, including Parkinson's disease, schizophrenia, and cocaine dependence. Preclinical studies have shown that the administration of muscarinic M 1 receptor agonists and antagonists increase or decrease, respectively, levels of extracellular DA in striatal and cortical areas (Xu et al., 1989;De Klippel et al., 1993;Gronier et al., 2000). Cocaine self-administration by rats increases concentrations of acetylcholine in the NAc shell (Mark et al., 1999) and increases acetylcholine turnover rates in several brain regions (Smith et al., 2004a,b) compared with passively administered cocaine. Changes in acetylcholine resulting from cocaine administration seem to be due to activation of cholinergic interneurons in the NAc and dorsal striatum (Berlanga et al., 2003), and cocaine treatment can produce an up-regulation of muscarinic binding at 1 day, but not 30 min after treatment (Macêdo et al., 2001). Finally, cholinergic lesions of posterior nucleus accumbens and ventral pallidal regions produced a leftward shift of the cocaine dose-effect curve in rats trained to self-adm...