M5 Muscarinic Receptors Are Required for Prolonged Accumbal Dopamine Release after Electrical Stimulation of the Pons in Mice

Abstract

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.

The Role of Acetylcholine in Cocaine Addiction

“…ACh infusions into the VTA potentiate ICSS (Redgrave and Horrell, 1976) and the ACh agonist carbachol and the AChE inhibitor neostigmine (which increases ACh concentrations) are both self-administered into the VTA (Ikemoto and Wise, 2002). M 5 receptor-deficient (M 5 À/À ) rats lack sustained NAc DA release following electrical stimulation of VTA cholinergic input (Forster et al, 2002), and striatal DA release induced by oxotremorine is significantly reduced in these M 5 receptor-knockout mice (Zhang et al, 2002). The absence of M 5 receptors on the VTA likely accounts for the lower rate of cocaine self-administration in M 5 À/À rodents (Fink-Jensen et al, 2003; Thomsen et al, 2005).…”

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

“…Antisense 14,15 and gene targeting technologies have emerged as powerful new tools in identifying the receptor subtypes involved in various muscarinic cholinergic functions. [16][17][18][19][20][21] Although pharmacological, neuroanatomical and clinical studies have suggested an important role of muscarinic receptors in synaptic plasticity and memory, the functions of the individual muscarinic receptor subtypes remain unclear. In this study, we have used M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice to investigate the functional importance of M2 and M4 receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes.…”

Deletion of the M 5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia

“…Moreover, previous studies have shown that activation of muscarinic receptors stimulates the activity of dopaminergic VTA neurons (18)(19)(20)(21). Given the known facilitatory effects of M 5 receptor activation on dopamine release from midbrain dopaminergic neurons (7,11), we hypothesized that M 5 receptor activation might modulate the behavioral and neurochemical correlates of drug reward and withdrawal. To test this hypothesis, we initially examined whether inactivation of the M 5 receptor gene affected the rewarding properties of morphine, the prototypical opiate analgesic, and the severity of morphine withdrawal symptoms.…”

“…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)(16)(17).…”

“…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)(16)(17). It is therefore likely that activation of M 5 receptors expressed by VTA neurons (9,10) is responsible for the prolonged efflux of dopamine in the mouse Acb following laterodorsal tegmental nucleus stimulation (11).…”