Midbrain dopamine neurons are activated directly by cholinergic agonists or by stimulation of the cholinergic neurons in the laterodorsal tegmental nucleus (LDT) of the pons in rats. In urethane-anesthetized mice, electrical stimulation of the LDT resulted in a rapid, stimulus-time-locked increase in dopamine release in the nucleus accumbens (NAc), followed several minutes later by a prolonged increase in dopamine release. In mutant mice with truncated M5 receptors, the prolonged phase of dopamine release was absent, but the initial, rapid phase of dopamine release was fully observed. We conclude that M5 muscarinic receptors on midbrain dopamine neurons mediate a prolonged facilitation of dopamine release in the NAc. These results imply that M5 muscarinic receptors play an important role in motivational behaviors driven by dopamine activity in the accumbens.

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.Key words: M5; muscarinic; cholinergic; dopamine; self-stimulation; reward; oligodeoxynucleotide Dopamine-containing neurons of the ventral tegmental area (VTA) and substantia nigra (SN) are important for brain-stimulation and drug rewards (Phillips and Fibiger, 1978;Gallistel and Karras, 1984;Wise, 1978;Stellar and Corbett, 1989). Because rewarding stimulation of the medial forebrain bundle directly activates mainly nondopaminergic myelinated axons, dopamine neurons are believed to be indirectly activated in brain-stimulation reward (Yeomans et al., 1985b;Bielajew and Shizgal, 1986).One important input to dopamine neurons is from cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei, which monosynaptically activate dopamine neurons via nicotinic and muscarinic receptors (Clarke and Pert, 1985;Fujimoto et al., 1990;Bolam et al., 1991;Lacey et al., 1990;Futami et al., 1995). Cholinergic agonists nicotine and carbachol injected near dopamine cells increase dopamine release in the dorsal striatum or nucleus accumbens (Imperato et al., 1986;Blaha and Winn, 1993;Blaha et al., 1996).Cholinergic receptors in the VTA are important for brainstimulation reward. Hypothalamic brain-stimulation reward induces acetylcholine release in the VTA (Rada et al., 2000). Acetylcholine in the VTA increases bar-pressing rates for brainstimulation reward (Redgrave and Horrell, 1976). Muscarinic blockers in the VTA approximately double thresholds for brainstimulation reward, whereas nicotinic blockers increase thresholds by ϳ20% (Yeomans et al., 1985a;Kofman et al., 1990;Yeomans and Baptista, 1997). Nicotinic receptors in the VTA are believed important for the mediation of nicotine self-administration (Corrigall and Coen, 1989;Corrigall et al., 1992Corrigall et al., , 1994, nicotineinduced locomotion (Museo and Wise, 1990;Reavill and Stolerman, 1990), and nicotine-induced dopamine release in rats (Nissell et al., 1994).Five muscarinic receptor genes have been cloned (Kubo et al., 1986;Bonner et al., 1987Bonner et al., , 1988Peralta et al....

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