Muscarinic Cholinergic System Research Articles

Muscarinic receptors in the ocular surface

A wide distribution of the eye's muscarinic receptor system has been found and several roles for the muscarinic system in the eye proposed, although functional consequences of muscarinic receptor activation are not always fully characterized. The present paper reviews current knowledge about the presence of muscarinic receptors in the ocular surface and the implication of alterations on their expression and/or functioning in eye diseases. Several authors have described alterations in muscarinic receptor subtype expression in the eye under pathological conditions. In conjunctiva of vernal keratoconjunctivitis patients, the expression of muscarinic receptor subtypes is altered in both the epithelium and stroma. Under proinflammatory conditions, M2-muscarinic receptor expression is upregulated in conjunctival epithelial cells in vitro. M3-muscarinic receptor altered distribution has been found in the lacrimal gland of NOD mice. The cholinergic muscarinic system plays diverse roles. Alteration in the expression and/or functioning of muscarinic receptors may be implicated in the etiopathogenesis of some ocular diseases. Their pharmacological regulation may therefore have therapeutic value. Knowledge of the specific receptor subtypes expressed in each tissue may help to avoid some undesired secondary side effects in some cases when muscarinic agonists or antagonists are used.

Feature binding and affect: Emotional modulation of visuo-motor integration

The primate cortex represents the external world in a distributed fashion, which calls for a mechanism that integrates and binds the features of a perceived or processed event. Animal and patients studies provide evidence that feature binding in the visual cortex is driven by the muscarinic–cholinergic system, whereas visuo-motor integration may be under dopaminergic control. Consistent with this scenario, we present indication that the binding of visual and action features is modulated by emotions through the probable stimulation of the dopaminergic system. Interestingly, the impact of emotions on binding was restricted to tasks in which shape was task-relevant, suggesting that extracting affective information is not automatic but requires attention to shape.

Cholinergic mechanisms in schizophrenia: Current concepts

Although the neurotransmitter dopamine plays a prominent role in the treatment of schizophrenia, the dopamine hypothesis fails to explain several aspects of the disorder. It is evident that the pathophysiology of schizophrenia involves other neurotransmitter systems as well. In this review, we discuss the increasing data implicating the cholinergic system in its pathogenesis. Cholinergic neurotransmission plays a crucial role in various central nervous system functions. The cholinergic system consists of two families of receptors, the muscarinic cholinergic and the nicotinic cholinergic, that use acetylcholine as a neurotransmitter. Data from clinical pharmacology, neuroimaging, and postmortem studies suggest an alteration of the muscarinic cholinergic system in schizophrenia. Muscarinic agonists are being evaluated as new treatment options with putative antipsychotic and cognition enhancing properties. Smoking is highly prevalent among schizophrenic subjects. Nicotine improves attention in schizophrenia. Nicotinic receptors, in particular the α7 nicotinic receptor, are candidates for the development of new medications to treat cognitive and perceptual deficits in schizophrenia. This review summarizes the evidence in support of a role for the muscarinic cholinergic system and the nicotinic cholinergic system in the pathophysiology of schizophrenia. As current treatments fail to sufficiently address all aspects of schizophrenia, promising new pharmacologic approaches that focus on the cholinergic system are currently under development.

Expression of carotid body muscarinic receptors in developing cats

Cholinergic muscarinic system is involved in chemoreceptor activity, however the developmental pattern of M1 and M2 muscarinic receptors (R) in the carotid body (CB) has not been assessed. Using real time RT-PCR, northern and western blots analyses, M1 and M2 receptors as well as tyrosine hydroxylase (TH, rate limiting enzyme for dopamine synthesis) mRNA and protein levels were evaluated in the CB of 1 and 15 day-old, 2 month-old and adult cats. M1R mRNA significant increased by 100% and 300% in 2 month-old and adult cats vs. 1 and 15 day-old, but protein decreased 50% at these ages vs. 1 and 15 day-old. Expression level of M2R mRNA or protein did not changed. TH mRNA and protein levels decreased gradually with age. TH protein levels were 35%, 45% and 53% lower at 15 days, 2 months and in adult cats vs. 1-day-old, respectively. Hence, since M1 is involved in the chemosensory activity while the M2 in the regulation of acetylcholine and dopamine release from chemosensitive cells, this pattern of age dependent expression levels of M1 and M2 R in cat CB suggests that the physiological role of these receptors on CB function changes with age. Founded by Fondation de la recherche des maladies infantiles

Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in rats

Objective The leaves of sage ( Salvia officinalis L., Lamiaceae) are reported to have a wide range of biological activities, such as anti-bacterial, fungistatic, virustatic, astringent, eupeptic and anti-hydrotic effects. To determine the mnemogenic effect of sage leaves, we investigated the effects of ethanolic extract of sage leaves and its interaction with cholinergic system on memory retention of passive avoidance learning in rats. Methods Post-training intracerebroventricular (i.c.v) injections were carried out in all the experiments except ethanolic extract (i.p. intraperitoneally). Results Administration of ethanolic extract (50 mg/kg), pilocarpine (0.5 and 1 mg/rat), the muscarinic cholinoceptor agonist, and nicotine (0.1 and 1 μg/rat) increased, while mecamylamine (1, 5 μg/rat), the muscarinic cholinoceptor antagonist, and mecamylamine (0.01 and 0.1 μg/rat), the nicotine cholinoceptor antagonist decreased memory retention in rats. Activation of muscarinic cholinoceptors by pilocarpine potentiated the response of ethanolic extract. Also, pharmacological blockade of scopolamine attenuated potentiating effect of ethanolic extract. Activation of nicotinic cholinoceptor by nicotine potentiated the response of ethanolic extract. Blockade of nicotinic cholinoceptor by mecamylamine attenuated the response of ethanolic extract. Conclusion It is concluded that the ethanolic extract of salvia officinalis potentiated memory retention and also it has an interaction with muscarinic and nicotinic cholinergic systems that is involved in the memory retention process.

P.3.e.009 Cognitive enhancement in schizophrenia: the role of dopamine and noradrenaline in the prefrontal cortex

The present experiments were designed to examine the effects of alpha-1 adrenergic stimulation and inhibition on memory encoding and to investigate whether the alpha-1 adrenergic and muscarinic cholinergic systems interact in the regulation of spatial navigation behavior in the Morris water maze test and we also studied the effects of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d-aspartate (NMDA) receptor complex, on the performance of scopolamine-treated rats in this task. Pre-training subcutaneous administration of St-587 (a putative alpha-1 agonist) at 1000 μg kg−1 or 1500 μg kg−1 improved water maze navigation to a hidden platform. Prazosin (an alpha-1 antagonist), 300–2000 μg kg−1, did not significantly impair the spatial navigation performance. Pre-training administration of prazosin 1000 μg kg−1, but not 300 μg kg−1, slightly potentiated the deficit in water maze navigation seen after scopolamine (200 μg kg−1, pre-training intraperitoneal injection). Pre-training administration of St-587 at a dose 1500 μg kg−1, but not 500 μg kg−1, slightly ameliorated the scopolamine-induced (200 μg kg−1) impairment in performance of rats. Pre-training administration of prazosin at doses 300 or 1000 μg kg−1 or St-587 at doses 500 μg kg−1 or 1500 μg kg−1 did not have any significant influence on the scopolamine-induced (200 μg kg−1) increase of swimming speed. Furthermore, d-cycloserine at the dose of 300 μg kg−1 but not 1000 or 3000 μg kg−1 reversed the scopolamine (200 μg kg−1)-induced deficit in acquisition of the water maze task but not the increase in motor output (increased swimming speed). These results indicate that the stimulation of alpha-1 adrenoceptors may facilitate the encoding of new information. These findings suggest that alpha-1 adrenergic mechanisms do not participate or at least are not the most critical part of the noradrenergic system in the interaction between noradrenaline and muscarinic receptors in the modulation of learning and memory. In addition, these results suggest that d-cycloserine may be effective in alleviating states of central cholinergic hypofunction.

Central Muscarinic Receptor Subtypes Regulating Voiding in Rats

Muscarinic receptors are distributed widely in the brain. A recent study revealed that central muscarinic receptors are involved in voiding regulation. However, to our knowledge the role of each muscarinic receptor subtype has not been resolved. Therefore, we evaluated the effect of intracerebroventricular administration of selective muscarinic M1 to M4 receptor antagonists on voiding function in rats. Female Sprague-Dawley rats were cannulated for intracerebroventricular infusion under halothane anesthesia. In experiment 1 cystometry was performed in conscious rats, and BC and maximal voiding pressure were measured. In experiment 2 a catheter was inserted via the bladder dome to the bladder neck and UPP was measured by saline infusion. Repeat cystostomy was performed, and saline infusion and discharge saline, BC, maximal IVP and minimal UPP were measured in conscious rats. Pirenzepine, methoctramine, pFHHSiD and MT-3 were used as selective M1, M2, M3 and M4 muscarinic receptor antagonists, respectively, which were injected intracerebroventricularly. In experiment 1 pirenzepine and pFHHSiD increased BC and decreased maximal voiding pressure. Methoctramine and MT-3 decreased BC. In experiment 2 pirenzepine and pFHHSiD increased BC and minimal UPP, and decreased maximal IVP. Methoctramine and MT-3 decreased BC and maximal IVP. Minimal UPP remained unchanged. Intracerebroventricular administration of muscarinic M1 and M3 receptor antagonists inhibited urination in conscious rats, while M2 and M4 receptor antagonists induced excitatory changes.

Neuropharmacology of cognition and memory: A unifying theory of neuromodulator imbalance in psychiatry and amnesia

The case of HM, a man with intractable epilepsy who became amnesic following bilateral medial temporal lobe surgery nearly half a century ago has instigated ongoing research and theoretical speculation on the nature of memory and the role of the hippocampus. Neuropsychological testing showed that although HM had extensive anterograde memory loss he could still acquire motor and cognitive skills implicitly, but could not remember the context of this learning. This has lead to declarative and procedural descriptions of the memory process. Cholinergic and monoaminergic neurotransmitter systems have also been implicated in the memory process and anticholinergic drugs traditionally have been associated with impairment of declarative memory. The cholinergic hypothesis of Alzheimer's disease is a classic example of an application of these neuropharmacological findings. In schizophrenia, preattentive deficits have been amply demonstrated by unconscious priming studies. Memory processes are also impaired in these patients. Dopamine, glutamate and even cholinergic dysfunction has been implicated in the clinical picture of schizophrenia. The present paper will attempt to bring together both the anatomical and pharmacological data from these disparate fields of research under a cohesive theory of cognition and memory. A hypothesis is presented for an inverse relationship between monoaminergic and cholinergic systems in the modulation of implicit (unconscious) and explicit (conscious) cognitive processes. It is postulated that muscarinic cholinergic receptors and monoaminergic systems facilitate unconscious and conscious processes, respectively, and they disfacilitate conscious and unconscious processes, respectively (the purported inverse relationship). In fact, the muscarinic and monoaminergic modulations of a neural network are proposed to be finely balanced such that, if, the activity of one receptor system is modified then this by necessity has effects on the other system. It takes into account receptor subtypes and their effects mediated through excitatory and inhibitory G-protein complexes. For example, m1/D2 and D1/m4 paired receptor subtypes, colocalized on separate neurons would have opposing functional effects. A theory is then presented that the critical underlying pathophysiology of schizophrenia involves a hypofunctional muscarinic cholinergic system, which induces abnormal facilitation of monoaminergic subsystems such as dopamine (e.g., a decrease in m1R function would potentiate D2R function). This extends the idea of an inverted U function for optimal monoaminergic concentrations. Not only would this impair unconscious preattentive processes, but according to the hypothesis, explicit cognition as well including memory deficits and would underlie the mechanism of psychosis. Contrary to current thinking a different view is also presented for the role of the hippocampus in the memory process. It is postulated that long-term explicit memory traces in the neocortex are laid down by phasic coactivation of forebrain projecting monoaminergic systems above some basal firing rate, such as the rostral serotonergic raphe, which projects diffusely to the cortex and according to a modified Hebbian principle. This is the proposed principal function of the hippocampal theta rhythm. The phasic activation of the cholinergic basal forebrain is mediated by projections from a separate cortical structure, possibly the lateral prefrontal cortex. Phasic muscarinic receptor activation is proposed to strengthen implicit memory traces (at a synaptic level) in the neocortex. Thus, the latter are spared by medial temporal surgery explaining the dissociation of explicit from implicit memory.

Cholinergic modulation of status epilepticus in the rat barrel field region of primary somatosensory cortex

Status epilepticus (SE) represents a serious medical emergency that can produce long-lasting brain damage as well as cognitive and memory deficits. However, the mechanisms that determine the emergence of SE from a single seizure and the prolonged duration of SE are unknown. Therefore, we used pharmacological tools to investigate the cellular mechanisms that underlie this prolonged epileptic activity in the rat barrel field region of somatosensory cortex (S1BF). Electrocortical and unitary extracellular field recording in the rat S1BF region was used to assess abnormal epileptiform activity induced by intracerebral application of 4-aminopyridine (4-AP). Simultaneously, electromyographic (EMG) activity was recorded from mystacial pad musculature. Intracerebral injection of 4-AP induced an SE that was paralleled by an increase of whisker activity that was not synchronized with the electrocortical recording. The seizures were originated ipsilaterally in the cortex of the injected hemisphere and propagated to the contralateral cortex with lower amplitude. The application of the glutamatergic NMDA receptor antagonist d (−)-2-amino-5-phosphonopentanoic acid (AP5) strongly increased the seizure-onset latency. The muscarinic receptor antagonist atropine changed the continuous rapid spiking pattern of SE to periodic discharges, while glutamatergic or GABAergic antagonist did not modify the electrographic features of SE. Our data suggest that the muscarinic cholinergic system plays an important role in the seizure modulation during SE in the somatosensory cortex, while their emergence is controlled, in part, by glutamatergic NMDA receptors.

Evaluation of levetiracetam effects on pilocarpine-induced seizures: Cholinergic muscarinic system involvement

Levetiracetam (LEV) is a new antiepileptic drug effective as adjunctive therapy for partial seizures. It displays a unique pharmacological profile against experimental models of seizures, including pilocarpine-induced seizures in rodents. Aiming to clarify if anticonvulsant activity of LEV occurs due to cholinergic alterations, adult male mice received LEV injections before cholinergic agonists’ administration. Pretreatment with LEV (30–200 mg/kg, i.p.) increased the latencies of seizures, but decreased status epilepticus and death on the seizure model induced by pilocarpine, 400 mg/kg, s.c. (P400). LEV (LEV200, 200 mg/kg, i.p.) pretreatment also reduced the intensity of tremors induced by oxotremorine (0.5 mg/kg, i.p). [ 3H]- N-methylscopolamine-binding assays in mice hippocampus showed that LEV200 pretreatment reverts the downregulation on muscarinic acetylcholine receptors (mAChR), induced by P400 administration, bringing back these density values to control ones (0.9% NaCl, i.p.). However, subtype-specific-binding assays revealed that P400- and LEV-alone treatments result in M 1 and M 2 subtypes decrease, respectively. The agonist-like behavior of LEV on the inhibitory M 2 mAChR subtype, observed in this work, could contribute to explain the reduction on oxotremorine-induced tremors and the delay on pilocarpine-induced seizures, by an increase in the attenuation of neuronal activity mediated by the M 1 receptors.

Effects of mercury on neurochemical receptor‐binding characteristics in wild mink

Piscivorous wildlife, such as mink (Mustela vison), routinely are exposed to mercury (Hg) in their natural environment at levels that may cause adverse behavioral outcomes. The purpose of this study was to determine if a correlation exists between neurochemical receptors and concentrations of Hg in the brains of wild mink. Specifically, receptor-binding assays were conducted to characterize the muscarinic cholinergic (mACh) and dopaminergic-2 (D2) systems in brain tissues collected from mink trapped in the Yukon Territory, Ontario, and Nova Scotia (Canada), and values were correlated with total Hg and methyl Hg (MeHg) concentrations in the brains. A significant correlation was found between Hg (total Hg and MeHg) and mACh receptor density (r = 0.546; r = 0.596, respectively) or ligand affinity (r = 0.413; r = 0.474, respectively). A significant negative correlation was found between total Hg and D2 receptor density (r = -0.340) or ligand affinity (r = -0.346). These correlations suggest that environmentally relevant concentrations of Hg may alter neurochemical function in wild mink, and that neurochemical receptor-binding characteristics can be used as a novel biomarker to assess Hg's effects on wildlife. Given the importance of the muscarinic cholinergic and dopaminergic pathways in animal behavior, further studies are required to explore the physiological and ecological significance of these findings.

Letter Regarding Article by Okoshi et al, “Neuregulins Regulate Cardiac Parasympathetic Activity: Muscarinic Modulation of β-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion”

To the Editor: Okoshi and colleagues1 studied the modulatory role of neuregulin-1 on parasympathetic activity in the heart. This interesting study on isolated cardiomyocytes showed that heterozygous gene deletion of neuregulin-1 abrogated the inhibitory activity of the muscarinic cholinergic system on β-adrenergic signaling. Because protein levels of M2 muscarinic receptors and G protein subunits were unchanged in neuregulin-1–deficient cardiomyocytes, the authors proposed that neuregulins support normal parasympathetic modulation of excess β-adrenergic stimulation of the heart. In a recent article in Circulation ,2 we reported that exogenously administrated neuregulin-1 attenuated β-adrenergic responses of isolated papillary muscles in the absence …

Habituation of exploratory activity in aged rats: effects of pyritinol

Acetylcholine (Ach) is a neurotransmitter considered to play a critical role in processes underlying behavior, learning, and memory. Pyritinol (pyrithioxine, Encephabolâ, PRT) is a nootropic drug that increases cholinergic transmission in the central nervous system. Behavioral habituation following multiple exposures to an open field is an experimental paradigm frequently used to assess the cognitive actions of drugs. In this paradigm the decrease of exploratory activity as a function of repeated exposure to the same environment is taken as an index memory. In the present study, effects PRT administrated to aged rats in powder form added to the diet (200 mg /kg / day, p.o., for 14 days) were evaluated in the habituation to an open field. A total of 18 aged rats were randomly assigned to one of two groups control (vehicle-treated rats, n = 8) and experimental group (PRT-treated rats, n = 10) and were used in the following procedure. In the exploratory task, the post-training treatment with PRT significantly decreased the number of total area crossings and rears when compared to the control group, indicating habituation. PRT treatment enhanced retention in the total number of area crossings and rears when compared with control animals. Taken together, the data of present study suggest that muscarinic cholinergic systems could be involved in the effect of PRT in habituation of exploratory activity to an open field in aged rats.

Immunocytochemical localization of choline acetyltransferase and muscarinic ACh receptors in the antenna during development of the sphinx moth Manduca sexta

Immunocytochemistry with monoclonal antibodies was used to investigate the locations of muscarinic acetylcholine receptors (mAChR) and choline acetyltransferase (ChAT) in sections of the developing antennae of the moth Manduca sexta. The results were correlated with a previous morphological investigation in the developing antennae which allowed us to locate different cell types at various stages of development. Our findings indicated that the muscarinic cholinergic system was not restricted to the sensory neurons but was also present in glial and epidermal cells. By day 4-5 of adult development, immunoreactivity against both antibodies was present in the axons of the antennal nerve, and more intense labeling was present in sections from older pupae. At days 4-9, the cell bodies of the sensory neurons in the basal part of the epidermis were also intensely immunolabeled by the anti-mAChR antibody. In mature flagella, large numbers of cells, some with processes into hairs, were strongly labeled by both antibodies. Antennal glial cells were intensely immunolabeled with both antibodies by days 4-5, but in later stages, it was not possible to discriminate between glial and neural staining. At days 4-9, we observed a distinctly labeled layer of epidermal cells close to the developing cuticle. The expression of both ChAT and mAChRs by neurons in moth antennae may allow the regulation of excitability by endogenous ACh. Cholinergic communication between neurons and glia may be part of the system that guides axon elongation during development. The cholinergic system in the apical part of the developing epidermis could be involved in cuticle formation.

Antinociceptive properties of acetylenic thiophene and furan derivatives: Evidence for the mechanism of action

The aim of the present study was to evaluate the antinociceptive potential of the acetylenic thiophene and furan derivatives: 3-(furan-2-il) prop-2-yn-1-ol 1, 1-(thiofen-2-il) pent-1yn-3-ol 2 and 4-(thiofen-2-il)-2-metilbut-3-yn-2-ol 3 on three different pain models in mice. The pain models evaluated were the acetic acid-induced writhing, capsaicin-induced pain and the tail immersion test. The possible mechanisms involved in the antinociceptive effect of these compounds were also investigated. Thus, the acetylenic thiophene and furan derivatives presented antinociceptive effect in the pain tests caused by chemical agents. Statistical analysis showed that compounds 1 and 3 increased the latency for tail withdrawal in the tail immersion test (phasic pain). Besides, the role of the opioidergic, muscarinic cholinergic and dopaminergic systems in the acetic acid-induced writhing was examined. The antinociceptive effect of compounds 2 and 3 was prevented by pretreatment with naloxone (1 mg/kg, s.c), but not by atropine (5 mg/kg, s.c) or metoclopramide (1 mg/kg, s.c). Neither naloxone nor metoclopramide prevented the antinociceptive effect caused by compound 1, while the pretreatment with atropine antagonized the antinociceptive action of this compound. The compounds 1– 3 used in this study did not reveal any motor impairment to mice in the open field. The results suggest that compounds 2 and 3 induced antinociception in the abdominal writhing test and that their effects are mediated by opiodergic receptors, while the antinociceptive effect of compound 1 may involve muscarinic cholinergic receptors.

Caffeine, but not nicotine, enhances visual feature binding

The distributed organization of the human visual cortex calls for a mechanism that integrates and binds the features of a perceived event, and neural synchronization is a prime candidate to serve that purpose. Animal studies suggest that synchronization in the visual cortex is enhanced by the muscarinic cholinergic system. Here we show that in healthy humans the binding of shape and colour, and of shape and location, of visual objects is increased by stimulating the muscarinic cholinergic system (caffeine consumption) but not by stimulating the nicotinic cholinergic system (nicotine consumption). Binding across perception and action is unaffected by either manipulation, suggesting a specific link between the visual system and the muscarinic cholinergic system.

Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium

Given the progressive and constant increase of average life expectancy, an increasing number of elderly patients undergo surgery. After surgery, elderly patients often exhibit a transient reversible state of cerebral cognitive alterations. Among these cognitive dysfunctions, a state of delirium may develop. Delirium is an aetiologically non-specific syndrome characterised by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behaviour and the sleep-wake cycle. Delirium appears to occur in 10-26% of general medical patients over 65, and is frequently associated with a significant increase in morbidity and mortality. During hospitalization, mortality rates have been estimated to be 10-26% of patients who developed post-operative delirium, and 22-76% during the following months. Over the last few decades, post-operative delirium has been associated with several pre-operative predictor factors, as well as age (50 years and older), alcohol abuse, poor cognitive and functional status, electrolyses or glucose abnormalities, and type of surgery. The uncertain pathogenesis of post-operative cognitive dysfunctions and delirium has not permitted a causal approach to developing an effective treatment. General anesthesia affects brain function at all levels, including neuronal membranes, receptors, ion channels, neurotransmitters, cerebral blood flow and metabolism. The functional equivalents of these impairments involve mood, memory, and motor function behavioural changes. These dysfunctions are much more evident in the occurrence of stress-regulating transmission and in the alteration of intra-cellular signal transduction systems. In addition, more essential cellular processes, that play an important role in neurotransmitter synthesis and release, such as intra-neuronal signal transduction and second messenger system, may be altered. Keeping in mind the functions of the central muscarinic cholinergic system and its multiple interactions with drugs of anesthesia, it seems possible to hypothesize that the inhibition of muscarinic cholinergic receptors could have a pivotal role in the pathogenesis not only of post-operative delirium but also the more complex phenomena of post-operative cognitive dysfunction.

Pharmacologic Interactions between the Muscarinic Cholinergic and Dopaminergic Systems in the Modulation of Prepulse Inhibition in Rats

Prepulse inhibition (PPI) of the acoustic startle reflex is a sensorimotor gating process known to be deficient in a number of neurologic and psychiatric conditions, including schizophrenia. Multiple lines of evidence have indicated that the dopaminergic and muscarinic cholinergic systems play an important role in modulating PPI. Moreover, interactions between the dopaminergic and muscarinic cholinergic systems are well known; however, little is known about potential interactions between the two systems in modulating PPI. Therefore, the purpose of the present studies was to determine whether interactions occur between the muscarinic cholinergic and dopaminergic systems in modulating PPI. The efficacy of muscarinic cholinergic receptor agonists in reversing the disruption of PPI induced by apomorphine, a D1/D2 dopamine receptor agonist, was evaluated in male Sprague-Dawley rats. The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonist BuTAC [([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl-]-1-azabyciclo-[3.2.1])octane oxalate] reversed the apomorphine-induced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine. The muscarinic agonists oxotremorine, RS86 [[2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride], pilocarpine, milameline, and sabcomeline also reversed the apomorphine-induced disruption of PPI. Moreover, the muscarinic antagonist scopolamine also disrupted PPI, and the D2-like receptor antagonist haloperidol, but not the D1-like receptor antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], reversed the scopolamine-induced disruption. In addition, xanomeline produced a significant reversal of the disruption in PPI produced by scopolamine. Collectively, the present findings demonstrate that a functional interaction occurs between the muscarinic cholinergic and dopaminergic systems in modulating PPI and that muscarinic cholinergic agonists may be effective in the treatment of the PPI and other cognitive impairments observed in schizophrenia.

Neuronal nicotinic receptor subtypes: defining therapeutic targets.

Humans have appreciated the beneficial properties of the tobacco plant for thousands of years. These effects include alertness, reduced anxiety, muscle relaxation, and analgesia. Yet it has been less than two decades since the central actions of nicotine have been examined in earnest for potential therapeutic applications. In fact, the cholinergic systems, in comparison to other neurotransmitter systems of the body, have been relatively poorly exploited in terms of therapeutic agents, and the muscarinic cholinergic systems have been relegated mainly to the treatment of gastrointestinal disorders and glaucoma; for the nicotinic system, antagonists are used to induce muscle paralysis during certain surgical procedures. For both families of cholinergic receptors, widespread exploitation in terms of therapeutics has been limited by significant side effect profiles associated with available cholinergic drugs.

Involvement of the peripheral cholinergic muscarinic system in the compensatory ovarian hypertrophy in the rat.

In the present experiments, unilateral ovariectomy (ULO) induced compensatory hypertrophy (COH) of the remaining rat ovary (60%-85% increase in ovarian weight, total proteins, and total RNA and DNA). An increased thymidine uptake preceded the organ enlargement. COH was inhibited by i.p.-administered muscarinic antagonist propantheline (dose-dependently) or botulinum toxin delivered locally to the ovary. The effects were reversed by bethanecol i.p. (a muscarinic agonist). In sham ULO animals, [3H]-scopolamine binding to ovarian membranes indicated the existence of muscarinic receptors (Kd 2.5 nM, Bmax 12 fmol/mg proteins, Hill 1.0). The ovarian 1,2-diacylglycerol (DAG) was 120-150 pmol/mg tissue and did not react to carbachol in vitro (50 microM). At 15 minutes after ULO, the [3H]-scopolamine binding was unchanged (Kd 2.6 nM, Bmax 12.6 fmol/mg tissue, Hill 1.0), but the ovarian DAG was increased (280-350 pmol/mg tissue) and increased further in response to carbachol (460-550 pmol/mg tissue). After ULO, ovarian DAG remained continuously responsive to carbachol. The ULO-induced DAG increase and enhanced susceptibility to carbachol were inhibited by the botulinum toxin or atropine pretreatments. Abdominal vagotomy done immediately before ULO also inhibited the ULO-induced DAG increase and DAG responsiveness to carbachol. However, when the vagotomy was performed 10 mins after ULO, the ovarian DAG remained responsive to carbachol in vitro. The data suggest that the peripheral cholinergic system, including the ovarian muscarinic receptors, stimulates COH. This is apparently associated with the ULO-induced coupling of the ovarian muscarinic receptors to phosphoinositide (PI) breakdown. Vagus plays a role in the occurrence of the changed muscarinic receptor-PI breakdown relationship in the remaining ovary.