No abstract

Little is known about the physiological roles of the M5 muscarinic receptor, the last member of the muscarinic receptor family (M1-M5) to be cloned. In the brain, the M5 receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area. Dopaminergic neurons located in the ventral tegmental area are known to play important roles in mediating both the rewarding effects of opiates and other drugs of abuse and the manifestations of opiate͞drug withdrawal symptoms. We therefore speculated that acetylcholine-dependent activation of M 5 receptors might modulate the manifestations of opiate reward and withdrawal. This hypothesis was tested in a series of behavioral, biochemical, and neurochemical studies using M 5 receptor-deficient mice (M5 ؊/؊ mice) as novel experimental tools. We found that the rewarding effects of morphine, as measured in the conditioned place preference paradigm, were substantially reduced in M 5 ؊/؊ mice. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M 5 ؊/؊ mice. In contrast, the analgesic efficacy of morphine and the development of tolerance to the analgesic effects of morphine remained unaltered by the lack of M 5 receptors. The finding that M 5 receptor activity modulates both morphine reward and withdrawal processes suggests that M 5 receptors may represent a novel target for the treatment of opiate addiction.T he M 5 muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M 1 -M 5 ) to be cloned (1, 2). Owing to the lack of ligands that can selectively stimulate or inhibit the M 5 receptor (3, 4), the physiological roles of this receptor subtype have remained obscure (5, 6). To address this issue, we recently used a gene-targeting approach to gen-Immunoprecipitation studies have shown that M 5 receptors are expressed at very low levels in the brain, representing less than 2% of the total muscarinic receptor population (M 1 -M 5 ) (8). Interestingly, M 5 receptor mRNA has been identified as the only muscarinic receptor mRNA in dopamine-containing neurons of the substantia nigra and the ventral tegmental area (VTA) (9, 10). It has therefore been proposed that M 5 receptors may play a role in modulating dopamine release from midbrain dopaminergic neurons (9, 10). Consistent with this hypothesis, we recently demonstrated that muscarinic agonist-induced increases in striatal dopamine release were reduced in M 5 Ϫ/Ϫ mice (7). Moreover, Forster et al. (11) recently reported that the sustained increase in dopamine levels in the nucleus accumbens (Acb) observed after electrical stimulation of the laterodorsal tegmental nucleus (12) is absent in M 5 Ϫ/Ϫ mice. Laterodorsal tegmental nucleus neurons represent the major source of cholinergic input to the dopamine-containing neurons of the VTA (13, 14) that project to the Acb and other limbic areas (15-17). It is therefore likely that activation of M 5 receptors express...