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. 2012;3(2):80-89.
doi: 10.1021/cn200110q.

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

Ditte Dencker  1 , Morgane Thomsen, Gitta Wörtwein, Pia Weikop, Yinghong Cui, Jongrye Jeon, Jürgen Wess, Anders Fink-Jensen
Affiliations

Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease

Ditte Dencker et al. ACS Chem Neurosci. 2012.

Abstract

The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson's disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as "dopamine based". There are five known muscarinic receptor subtypes (M(1) to M(5)). Due to their overlapping expression patterns and the lack of receptor subtype-specific ligands, the roles of the individual muscarinic receptors have long remained elusive. During the past decade, studies with knock-out mice lacking specific muscarinic receptor subtypes have greatly advanced our knowledge of the physiological roles of the M(1)-M(5) receptors. Recently, new ligands have been developed that can interact with allosteric sites on different muscarinic receptor subtypes, rather than the conventional (orthosteric) acetylcholine binding site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse and Parkinson's disease. The present review highlights recent studies carried out using muscarinic receptor knock-out mice and new subtype-selective allosteric ligands to assess the roles of M(1), M(4), and M(5) receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the CNS.

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Figures

Figure 1
Figure 1
Exaggerated cocaine-induced increases in dopamine in the nucleus accumbens of M4–/– mice. Cocaine-induced increases in extracellular dopamine in M4–/– (white symbols/bars) and M4+/+ (black symbols/bars) mice were measured by in vivo microdialysis in freely moving animals in the nucleus accumbens after s.c. administration of cocaine 10 mg/kg (squares), 30 mg/kg (circles), or vehicle (triangles) Cocaine (30 mg/kg) caused a greater increase in extracellular dopamine in M4–/– mice (open circles) compared to WT mice (filled circles). Inset shows dopamine as % baseline, area under the curve (AUC) from 20 to 80 min (***p < 0.001, **p < 0.01, *p < 0.05). [Reprinted with permission from Psychopharmacology.]
Figure 2
Figure 2
Increased amphetamine-induced hyperlocomotion in D1-M4–/– mice. To induce behavioral sensitization repeated injections of amphetamine (amph; 2 mg/kg, s.c.) were paired with exposure of the mice to activity test cages for 1 h per day. After an initial saline injection at day 0, D1-M4–/– mice (black) and control floxed littermates (white) were divided into two groups that received either saline (triangles) or amphetamine (circles) for 6 days. In D1-M4–/– mice, amphetamine-induced hyperlocomotion was significantly greater on days 4 and 5 as compared to day 1 (#p < 0.05, ###p < 0.001). In control mice, amphetamine injections resulted in a clear trend toward enhanced locomotor responses on days 2–5; however, this effect did not reach statistical significance. The repeated amphetamine injections generally induced higher levels of hyperlocomotion in D1-M4–/– mice, reaching significance on days 4 and 5 (*p < 0.05, p < 0.01). After a 13-day drug- and test-free period, all mice were injected with amphetamine on day 20 and retested. Amphetamine pretreated D1-M4–/– mice showed a significantly increased locomotor response (###p < 0.001 versus amphetamine-pretreated control mice). The observed hyperlocomotion could not be ascribed to context conditioning (day 21). [Reprinted with permission Journal of Neuroscience.]
Figure 3
Figure 3
Lack of attenuation of amphetamine-induced hyperlocomotion by xanomeline in D1-M4–/– mice. The effect of xanomeline (xan) on amphetamine (amph)-induced hyperlocomotion was measured after coadministration of xanomeline, vehicle (veh), and/or amphetamine (2 mg/kg, s.c.) for 2 h in an open field arena. Amphetamine induced a significant increase in locomotor activity (measured as total distance moved) in both genotypes (*p < 0.05, **p < 0.01 vs vehicle). In floxed control mice, 2 mg/kg xanomeline reversed the amphetamine-induced hyperlocomotion, but had no effect in D1-M4–/– mice (###p < 0.001 vs WT). [Reprinted with permission from Journal of Neuroscience.]
Figure 4
Figure 4
Reduced attenuation of the discriminative stimulus of cocaine by xanomeline in both M1–/– and M4–/– mice. WT mice, M1–/– mice and M4–/– mice were trained to discriminate 10 mg/kg (i.p.) cocaine from saline in a standard drug discrimination procedure. Pretreatment with 1.8 mg/kg xanomeline (s.c.) produced a significant (8-fold) rightward shift in the cocaine dose–effect function in the WT mice. This effect was still significant, but blunted or more variable, in both M1–/– mice and M4–/– mice. Ordinates: % responses emitted on the cocaine-paired side (top panels); rate of responding (maintained by food), in responses per second (bottom panels). [Reprinted with permission from Psychopharmacology.]
Figure 5
Figure 5
Increased intravenous cocaine self-administration in M4–/– mice. Intravenous cocaine self-administration was measured under an FR 1 (A) and a PR (B) schedule of reinforcement in M4–/– mice (open symbols) and WT littermates (filled symbols). M4–/– mice exhibited higher response rates than WT mice at cocaine doses of 0.3 and 1.0 mg/kg/infusion under the FR 1 schedule. Under the PR schedule of reinforcement, M4–/– mice reached higher breaking points than WT mice at the 1.0 mg/kg per infusion dose (*p < 0.05, **p < 0.01, and ***p < 0.001 vs WT). [Reprinted with permission from Psychopharmacology.]
Figure 6
Figure 6
Reduced cocaine-conditioned place preference (CPP) in M5–/– mice. Mice were initially habituated to the two-compartment CPP apparatus to determine the side-preference of each individual mouse. Mice were then administered either cocaine (2.5 mg/kg, i.p.) or saline and placed in either the preferred (saline) or nonpreferred (cocaine) compartment for 30 min for 7 days. On the test day, when side-preference was reassessed, cocaine induced significantly less CPP in M5–/– compared to WT mice (‡ p<0.05 vs pretest; ** p < 0.01 vs M5–/– mice). [Reprinted with permission from Journal of Neuroscience Research.]
Figure 7
Figure 7
Reduced intravenous cocaine self-administration in M5–/– mice. Intravenous cocaine (0.03, 0.3, 3.2 mg/kg per infusion) self-administration was measured under a progressive ratio schedule of reinforcement in M5–/– (open) and M5± (gray) mutant mice and their WT littermates (black). M5–/– mice reached lower breaking points than WT mice at doses of 0.03 and 0.32 mg/kg per infusion (†p < 0.05, ††p < 0.01 vs WT). [Reprinted with permission from Journal of Neuroscience.]
Figure 8
Figure 8
Increased amphetamine-induced hyperlocomotion in M5–/– mice. To induce behavioral sensitization repeated injections of amphetamine (amph; 2 mg/kg, s.c.) were paired with exposure of the mice to an open field arena for 45 min per day. After an initial saline injection at day 0, M5–/– mice and WT controls were divided into two groups that received either saline or amphetamine for 6 days. The repeated amphetamine administration significantly increased locomotor activity in both genotypes, however this effect was significantly greater in M5–/– compared to WT mice (*p < 0.05). After a 6-day, followed by an 8-day drug- and test-free period, all mice were injected with amphetamine on days 12 and 20 and retested. Amphetamine pretreated M5–/– mice showed a significantly increased sensitized locomotor response (*p < 0.05 vs amphetamine-pretreated WT mice). [Reprinted with permission from Psychopharmacology.]
Figure 9
Figure 9
Increased amphetamine-potentiated nucleus accumbens dopamine release in M5–/– mice. The effect of amphetamine (2 mg/kg, i.p.) on medial forebrain bundle-stimulated dopamine release in the nucleus accumbens of M5–/– and M5+/+ mice was measured by fixed potential amperometry. Amphetamine increased dopamine efflux in both genotypes. This effect was significantly enhanced in M5–/– compared to WT mice (*p < 0.05, **p < 0.01, ***p < 0.001). [reprinted with permission from Psychopharmacology.]
Figure 10
Figure 10
Reduced cataleptic effect of antipsychotic drugs in M4–/– mice. Cataleptic responses were measured as the time spent in the placed position (cutoff time: 60 s), at 30, 60, and 90 min after i.p. drug injection. Catalepsy induced by haloperidol (A, B) or risperidone (C, D) was attenuated in M4–/– mice compared to WT mice. (*p < 0.05, ***<0.001). The effect of scopolamine (Scop, 5.0 mg/kg, i.p. after 90 min) was examined 120 min after the initial drug administration. Scopolamine significantly reduced the cataleptic responses in both genotypes (††p < 0.01, †††p < 0.001) [Reprinted with permission from European Journal of Pharmacology.]
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