Central Dopaminergic Neurotransmission Research Articles

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Drug Induced Neuroleptic Malignant Syndrome: A Case Report

Neuroleptic malignant syndrome (NMS) causes fever, muscle rigidity, and impaired mental status. Drugs that influence central dopaminergic neurotransmission and almost all neuroleptics, including newer atypical antipsychotics, are also associated with it. While uncommon, NMS remains a critical differential diagnosis for patients with fever and mental status changes due to the requirement for prompt resuscitation to prevent morbidity and mortality. We present a case of a 21-year-old man with schizophrenia who attended the emergency room with generalized muscle rigidity, high-grade fever, and disturbed mental status for 12 days. His serum creatine phosphokinase was elevated (CPK). The computed tomography (CT) of the brain was normal, and the CSF was clear and cell-free. The patient was given muscle relaxants, dopamine agonists, and biperiden. After three days, rigidity, fever, and consciousness improved. A few cases of antipsychotic-induced NMS have been reported. Healthcare professionals should be aware of this fatal side effect.

Parkinson's Disease Medication Prescribing and Administration During Unplanned Hospital Admissions.

Parkinson's disease (PD) is the second most common neurodegenerative disease with a lifetime risk of 1% to 3%. Treatment includes supplementation of central dopaminergic neurotransmission with levodopa preparations and dopamine agonists. Misprescribing and delayed administration of these medications on admission to hospital can result in increased morbidity and mortality. We aimed to assess the accuracy of time-critical PD medication prescribing and administration during unplanned hospital admissions. Patients admitted during a 15-month period with PD on time-critical PD medications were included. Their electronic patient records were compared with the pharmacist medication reconciliation to assess accuracy of admission prescribing. Accuracy of administration was assessed by comparing the time medications were administered to the time they were due. Statistical Package for Social Sciences software was used to perform statistical analysis in this study. A total of 102 admissions of 70 patients (67% men) were included for analysis. These patients were on 1.6 ± 0.8 time-critical PD medications before admission, accounting for 4.1 ± 1.8 administrations per day. Time-critical medications were prescribed correctly on admission in 50% of admissions, with errors in medication timing most common (31.6%). Of all doses, 51.7% were administered >30minutes late, and 29.7% of doses were administered >1 hour late. Female sex, a higher number of medications, and more frequent administrations were significantly associated with the rate of medication error. This study demonstrates high rates of inaccurate prescribing and inaccurate administration of time-sensitive medication in a cohort of patients with PD admitted acutely to hospitals.

Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease

Parkinson disease (PD) is a neurodegenerative disease mainly characterized by the loss of nigral dopaminergic neurons in the substantia nigra pars compacta. Patients suffering from PD develop severe motor dysfunctions and a myriad of non-motor symptoms. The treatment mainly consists of increasing central dopaminergic neurotransmission and alleviating motor symptoms, thus promoting severe side effects without modifying the disease’s progress. A growing body of evidence suggests a close relationship between neuropeptide S (NPS) and its receptor (NPSR) system in PD: (i) double immunofluorescence labeling studies showed that NPSR is expressed in the nigral tyrosine hydroxylase (TH)-positive neurons; (ii) central administration of NPS increases spontaneous locomotion in naïve rodents; (iii) central administration of NPS ameliorates motor and nonmotor dysfunctions in animal models of PD; (iv) microdialysis studies showed that NPS stimulates dopamine release in naïve and parkinsonian rodents; (v) central injection of NPS decreases oxidative damage to proteins and lipids in the rodent brain; and, (vi) 7 days of central administration of NPS protects from the progressive loss of nigral TH-positive cells in parkinsonian rats. Taken together, the NPS/NPSR system seems to be an emerging therapeutic strategy for alleviating motor and non-motor dysfunctions of PD and, possibly, for slowing disease progress.

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology.

Background:Binge-eating disorder (BED) is a common psychiatric condition with adverse psychological and metabolic consequences. Lisdexamfetamine (LDX) is the only approved BED drug treatment. New drugs to treat BED are urgently needed.Methods:A comprehensive review of published psychopathological, pharmacological and clinical findings.Results:The evidence supports the hypothesis that BED is an impulse control disorder with similarities to ADHD, including responsiveness to catecholaminergic drugs, for example LDX and dasotraline. The target product profile (TPP) of the ideal BED drug combines treating the psychopathological drivers of the disorder with an independent weight-loss effect. Drugs with proven efficacy in BED have a common pharmacology; they potentiate central noradrenergic and dopaminergic neurotransmission. Because of the overlap between pharmacotherapy in attention deficit hyperactivity disorder (ADHD) and BED, drug-candidates from diverse pharmacological classes, which have already failed in ADHD would also be predicted to fail if tested in BED. The failure in BED trials of drugs with diverse pharmacological mechanisms indicates many possible avenues for drug discovery can probably be discounted.Conclusions:(1) The efficacy of drugs for BED is dependent on reducing its core psychopathologies of impulsivity, compulsivity and perseveration and by increasing cognitive control of eating. (2) The analysis revealed a large number of pharmacological mechanisms are unlikely to be productive in the search for effective new BED drugs. (3) The most promising areas for new treatments for BED are drugs, which augment noradrenergic and dopaminergic neurotransmission and/or those which are effective in ADHD.

An Obituary to Jacques Glowinski (1936–2020)

This is an obituary of Dr. Jacques Glowinski (1936-2020), one of the last «giants» of Neuropharmacology trained in the sixties in the laboratory of Julius Axelrod (Nobel Prize in 1970). He was a founding father of this discipline in France and his famous laboratory (INSERM Unit 114) at the Collège de France in Paris has trained for 40 years (1966-2006) generations of fellows who became leader neuroscientists in France and abroad. His most important scientific contributions completely revisited the regulatory mechanisms of central dopaminergic neurotransmission and its implications in neuropsychiatric disorders.

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson’s disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

Induction of immediate early genes expression in the mouse striatum following acute administration of synthetic cathinones

Synthetic cathinones (SCs) form one of the most prominent group of the New Psychoactive Substances. SCs enhance central dopaminergic and noradrenergic neurotransmission, and are used as substitutes for illicit psychostimulants, namely cocaine, amphetamine, and methamphetamine. Changes in the expression of immediate early genes (IEGs) in the striatum underlie the addictive potential of drugs of abuse belonging to distinct pharmacologic groups. This work was aimed to assess the impact of acute administration of the prominent SCs on the mRNA levels of IEGs in the mouse striatum. Effects of 3,4-MDPV, 2,3-MDPV, α-PVP, PV8, PV9, methcathinone (MC) and 3-fluoromethca-thinone (3-FMC) on the mRNA levels often IEGs, one and two hours after exposure, were measured in the mouse striatum using the quantitative RT-PCR technique. All SCs used in the study produced increased mRNA levels of the following IEGs: Areg, c-fos, Csrnp1, Dusp1, Dusp14, Egr2, Egr4 and FosB. Additionally, the majority of SCs increased the expression of Homer! and c-jun. The magnitude of observed changes varied by the drug, analyzed gene and, in many cases, by time after administration. This study demonstrates that SCs increase the expression of IEGs in the mouse striatum, which may lead to a plethora of effects, as proteins encoded by the analyzed genes are involved in diverse actions, including an acute response to the drug and the neuroplasticity underlying the development of addiction.

Differences in the dopaminergic reward system in rats that passively and actively behave in the Porsolt test

The aim of the study was to assess appetitive responses and central dopaminergic neurotransmission in passive and active rats divided according to their immobility time in the Porsolt swim test and exposed to restraint stress. Passive rats had more episodes of appetitive 50-kHz ultrasonic vocalization (USV) during rat encounter after social isolation and spent significantly more time in the amphetamine-associated context in conditioned place preference test, compared to active rats. Restraint stress decreased sucrose preference, but increased appetitive vocalization and reinforced the conditioned place preference only in passive animals that was associated with increased dopamine concentration in the amygdala. Restraint stress increased also the level of Cocaine- and Amphetamine Regulated Transcript (CART) peptide, a neuromodulator linked to dopamine neurotransmission, in the central nucleus of amygdala, while decreasing it the nucleus accumbens shell in passive rats. In the parvocellular region of paraventricular nucleus of the hypothalamus passive animals had a higher expression of CART compared to passive restraint rats and active control rats.The obtained results show that active and passive rats in the Porsolt test differ significantly in response to appetitive stimuli, which can be additionally changed under stress conditions. The underlying mechanisms are probably associated with differences in dopaminergic activity and CART signaling in reward system.

Brief exposure to obesogenic diet disrupts brain dopamine networks.

ObjectiveWe have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).MethodsWe examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET).ResultsWe found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens–anterior cingulate) and sensorimotor circuits (caudate/putamen–thalamus–sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.ConclusionThese studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.

Neuroleptic malignant syndrome: the diagnostic dilemma

Neuroleptic malignant syndrome (NMS) is a life-threatening, often fatal idiosyncratic reaction to neuroleptic or other drug therapies that antagonise the central dopaminergic neurotransmission. The clinical presentation of NMS is very heterogeneous. The lack of specific levels of symptom severity in currently used diagnostic criteria dims the diagnosis of NMS. Therefore differential diagnosis is of priority, because NMS is a diagnosis of exclusion. The aim of this paper is to present a complex clinical picture in a patient that after a differential diagnostic exclusion of other medical conditions and intoxications is diagnosed as NMS. Case reports such as these help raise awareness of this clinical issue.

Effect of COMT Val108/158Met Genotype on Risk for Polydipsia in Chronic Patients with Schizophrenia

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.

Caffeine and Substance Use Disorders

Caffeine and Substance Use Disorders

Prevalence and profile of Restless Legs Syndrome in Parkinson's disease and other neurodegenerative disorders: A case-control study

BackgroundRestless Legs Syndrome (RLS) is associated with impaired central dopaminergic neurotransmission. Though a link between RLS and parkinsonism has been proposed, the prevalence of RLS in parkinsonian disorders is poorly documented. ObjectiveTo determine the prevalence of RLS in patients with Parkinson's Disease (PD), Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). MethodsWe evaluated 187 consecutive patients with parkinsonian disorders (PD = 134, PSP = 27, MSA = 21, DLB = 5) and 172 healthy controls. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria and the severity of RLS was assessed in patients with definite RLS. Quality of sleep was evaluated with established scales. ResultsThe prevalence of RLS was higher in patients compared to controls (9.6% vs. 2.9%; p = 0.009) and was highest in PD (11.9%). RLS was present in only one patient each with MSA and PSP and none with DLB. The mean IRLSSG severity score of patients was 16.2 ± 6.5. The global Pittsburgh Sleep Quality Index score and Epworth Sleepiness Scale score were significantly higher in patients compared to controls (p < 0.001). PD patients with RLS had lower Parkinson's Disease Sleep Scale (PDSS) score compared to patients without RLS (p = 0.023). There was no significant difference in gender, age, duration and severity of PD between the two groups. ConclusionsOur study found a higher prevalence of RLS in PD compared to healthy controls or other parkinsonian disorders. Apart from PDSS score, there was no significant difference in the clinical characteristics of PD patients with and without RLS.

1026 – Electroconvulsive therapy as an effective treatment in neuroleptic malignant syndrome: purposely a case

NMS is an infrequent, life-threatening neurologic emergency usually associated with the use of neuroleptics and some other agents that affect central dopaminergic neurotransmission. Because of its low frequency, heterogeneous nature and clinical variability it might be difficult to diagnose. To identify risk factors to develop a NMS and to set effective treatments. Literature search was performed in PubMed and UpToDate. Report of a case at our center: 69 year old man with psychotic depression which do not improve with optimal doses of SSRIs, Mirtazapine and Benzodiazepines. Olanzapine (10mg) was added and symptoms compatible with a neuroleptic malignant syndrome were appeared. Supportive care was needed because of medical complications. A treatment with bromocriptine, sertraline, lorazepam and dantrolene was begun with little improvement. It was decided to begin ECT. It was applied a ECT therapy (12 bifrontotemporal sessions, 380mCu) with a high and effective response. Pshycosis and pshycomotor symptoms disappeared and depression decreased significantly. Hence a high index of suspicion is needed in the diagnosis of NMS in order to reduce mortality and secuelae. Differential diagnosis must be performed with confusional states due to medical cause, catatonia, serotoninergic syndrome and other neurologic states. As for the treatment, general support meassures and several farmacologic options have been used, though none of them have proved to decrease mortality. ECT remains a good option for improvement of the syndrome as well as the pychiatric condition. No systematic clinical trials evaluating the efficacy of different treatments have been done so far.

Clavulanic acid induces penile erection and yawning in male rats: Comparison with apomorphine

The beta-lactamase inhibitor clavulanic acid induced penile erection and yawning in a dose dependent manner when given intraperitoneally (IP, 0.05–5mg/kg), perorally (OS, 0.1–5mg/kg) and intracereboventricularly (ICV, 0.01–5μg/rat) to male rats. The effect resembles that of the dopamine receptor agonist apomorphine given subcutaneously (SC) (0.02–0.25mg/kg), although the responses of the latter followed a U inverted dose–response curve, disappearing at doses higher than 0.1mg/kg. Clavulanic acid responses were reduced by about 55% by haloperidol, a dopamine D2 receptor antagonist (0.1mg/kg IP), and by d(CH2)5Tyr(Me)2-Orn8-vasotocin, an oxytocin receptor antagonist (2μg/rat ICV), both given 15min before clavulanic acid. A higher reduction of clavulanic acid responses (more than 80%) was also found with morphine, an opioid receptor agonist (5mg/kg IP), and with mianserin, a serotonin 5HT2c receptor antagonist (0.2mg/kg SC). In contrast, no reduction was found with naloxone, an opioid receptor antagonist (1mg/kg IP). The ability of haloperidol, d(CH2)5Tyr(Me)2-Orn8-vasotocin and morphine to reduce clavulanic acid induced penile erection and yawning suggests that clavulanic acid induces these responses, at least in part, by increasing central dopaminergic neurotransmission. Dopamine in turn activates oxytocinergic neurotransmission and centrally released oxytocin induces penile erection and yawning. However, since both penile erection and yawning episodes were reduced not only by the blockade of central dopamine and oxytocin receptors and by the stimulation of opioid receptors, which inhibits oxytocinergic neurotransmission, but also by mianserin, an increase of central serotonin neurotransmission is also likely to participate in these clavulanic acid responses.

Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients

Dopamine dysregulation in restless legs syndrome (RLS) may be varied by the severity of RLS, which could contribute to the conflicting results from previous functional neuroimaging studies on the central dopaminergic neurotransmission of RLS. The aim of this study was to observe whether reduced striatal dopaminergic neurotransmission is associated with moderate to moderately severe RLS. Thirteen elderly patients with RLS and 12 normal elderly controls were enrolled in the study. All the subjects were dopaminergic-drug naïve and twelve patients with RLS had the severity of moderate to moderately severe degree based on the International Restless Legs Syndrome Study Group (IRLSSG) Severity Scale. We compared dopamine transporter density (DAT) availability and D2 receptor density in the striatum between patients with RLS and controls using [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane single-photon emission computed tomography (SPECT) and [(123)I]iodobenzamide SPECT. Dopamine transporter density of patients with RLS was increased in the caudate (P = 0.037), posterior putamen (P = 0.041), and entire striatum (P = 0.046) compared with that of normal controls. DAT density was higher in the anterior putamen of patients with RLS than controls, although statistically not significant (P = 0.079). There was no difference in the D2 receptor density between patients with RLS and normal controls in the whole striatum or any of subregions. Dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission may underlie the pathogenesis of RLS, and decreased dopaminergic neurotransmission may cause moderate to moderately severe RLS in the elderly.

Association of prolactin serum levels and severity of alcohol dependence and withdrawal symptoms

Previous studies have shown that prolactin serum levels are elevated during alcohol withdrawal, normalizing during abstinence. Prolactin secretion ist regulated by dopamine (prolactin inhibiting factor) and so prolactin may possibly reflect alterations of central dopaminergic neurotransmission. We studied prolactin serum levels in 99 male patients during the first two weeks of alcohol withdrawal and early abstinence, compared to 43 healthy controls. Psychological measurements were used to assess the severity of alcohol dependence, the extent of withdrawal symptoms, craving, depressive symptoms and anxiety. Alcohol dependent patients showed elevated prolactin serum levels during the whole study period. Furthermore, prolactin serum levels at admission for detoxification treatment were associated with the severity of alcohol withdrawal (CIWA-Ar) and of alcohol dependence (SESA) but not with the other assessed psychological parameters. Our study confirms previous findings showing an elevation of prolactin serum levels in alcohol dependent patients and early abstinence. The described association with withdrawal symptoms and the severity of alcohol dependence may partially be explained by a pathophysiological connection between prolactin and dopaminergic as well as glutamatergic neurotransmission.

Involvement of a Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4Preferring Muscarinic Receptor Agonist Xanomeline

Disturbances in central dopaminergic neurotransmission are believed to be centrally involved in the pathogenesis of schizophrenia. Central dopaminergic and cholinergic systems interact and the cholinergic muscarinic agonist xanomeline has shown antipsychotic effects in clinical studies. Preclinical studies indicate that the M(4) muscarinic cholinergic receptor subtype (mAChR) modulates the activity of the dopaminergic system and that this specific mAChR subtype is involved in mediating the antipsychotic-like effects of xanomeline. A specific neuronal subpopulation that expresses M(4) mAChRs together with D(1) dopamine receptors seems to be especially important in modulating dopamine-dependent behaviors. Using mutant mice that lack the M(4) mAChR only in D(1) dopamine receptor-expressing cells (D1-M4-KO), we investigated the role of this neuronal population in the antipsychotic-like effects of xanomeline in amphetamine-induced hyperactivity and apomorphine-induced climbing. Interestingly, the antipsychotic-like effects of xanomeline in the two models were almost completely abolished in D1-M4-KO mice, suggesting that M(4) mAChRs colocalized with D(1) dopamine receptors are centrally involved in mediating the antipsychotic-like effects of xanomeline. This is consistent with the hypothesis that activation of the M(4) mAChR represents a potential target for the future medical treatment of psychosis.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a life-threatening idiosyncratic reaction to antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. It has been associated with virtually all neuroleptics, including newer atypical antipsychotics, as well as a variety of other medications that affect central dopaminergic neurotransmission. Although uncommon, NMS remains a critical consideration in the differential diagnosis of patients presenting with fever and mental status changes because it requires prompt recognition to prevent significant morbidity and death. Treatment includes immediately stopping the offending agent and implementing supportive measures, as well as pharmacological interventions in more severe cases. Maintaining vigilant awareness of the clinical features of NMS to diagnose and treat the disorder early, however, remains the most important strategy by which physicians can keep mortality rates low and improve patient outcomes.