Cholinergic Receptor Systems Research Articles

Anticipatory attractors, functional neurochemistry and "Throw & Catch" mechanisms as illustrations of constructivism.

This review explores several rarely discussed examples illustrating constructivism principles, generative and selective features of neuronal regulation of behaviour. First, the review highlights Walter Freeman's experiments and mathematical analysis that uncovered the existence of anticipatory attractors, i.e. non-random dynamical patterns in neurodynamics. Since Freeman's work did not extend to neurochemistry, this paper then points to the proposed earlier neurochemical framework summarizing the managerial roles of monoaminergic, cholinergic and opioid receptor systems likely contributing to anticipatory attractors in line with functional constructivism. As a third example, neurochemistry's evidence points to the "Throw & Catch" (T&C) principle in neurodynamics. This principle refers to the pro-active, neurochemically expensive, massive but topical increase of potentials ("Throw") within electrodynamics and neurotransmission in the brain whenever there is an uncertainty in selection of degrees of freedom (DFs). The T&C also underlines the relay-like processes during the selection of DFs. The "Throw" works as an internally generated "flashlight" that, contrarily to the expectations of entropy reduction, increases entropy and variance observed in processes related to orientation and action-formation. The discussed examples highlight the deficiency of structures-oriented projects and excitation-inhibition concepts in neuroscience. The neural regulation of behaviour appears to be a fluid, constructive process, constantly upgrading the choice of behavioural DFs, to ensure the compatibility between the environmental and individual's individuals' needs and capacities.

A novel cholinergic projection from the lateral parabrachial nucleus and its role in methamphetamine-primed conditioned place preference.

Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPBChAT–CeAGABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPBChAT–CeAGABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPBChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPBChAT neurons in vitro or in vivo triggered the excitabilities of the CeAGABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPBChAT neurons or the eLPBChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPBChAT–CeAGABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference.

The Regulation Effect of α7nAChRs and M1AChRs on Inflammation and Immunity in Sepsis.

The inflammatory storm in the early stage and immunosuppression in the late stage are responsible for the high mortality rates and multiple organ dysfunction in sepsis. In recent years, studies have found that the body's cholinergic system can spontaneously and dynamically regulate inflammation and immunity in sepsis according to the needs of the body. Firstly, the vagus nerve senses and regulates local or systemic inflammation by means of the Cholinergic Anti-inflammatory Pathway (CAP) and activation of α7-nicotinic acetylcholine receptors (α7nAChRs); thus, α7nAChRs play important roles for the central nervous system (CNS) to modulate peripheral inflammation; secondly, the activation of muscarinic acetylcholine receptors 1 (M1AChRs) in the forebrain can affect the neurons of the Medullary Visceral Zone (MVZ), the core of CAP, to regulate systemic inflammation and immunity. Based on the critical role of these two cholinergic receptor systems in sepsis, it is necessary to collect and analyze the related findings in recent years to provide ideas for further research studies and clinical applications. By consulting the related literature, we draw some conclusions: MVZ is the primary center for the nervous system to regulate inflammation and immunity. It coordinates not only the sympathetic system and vagus system but also the autonomic nervous system and neuroendocrine system to regulate inflammation and immunity; α7nAChRs are widely expressed in immune cells, neurons, and muscle cells; the activation of α7nAChRs can suppress local and systemic inflammation; the expression of α7nAChRs represents the acute or chronic inflammatory state to a certain extent; M1AChRs are mainly expressed in the advanced centers of the brain and regulate systemic inflammation; neuroinflammation of the MVZ, hypothalamus, and forebrain induced by sepsis not only leads to their dysfunctions but also underlies the regulatory dysfunction on systemic inflammation and immunity. Correcting the neuroinflammation of these regulatory centers and adjusting the function of α7nAChRs and M1AChRs may be two key strategies for the treatment of sepsis in the future.

The Impact of Removal of Ovarian Hormones on Cholinergic Muscarinic Receptors: Examining Prepulse Inhibition and Receptor Binding.

Ovarian hormones, such as estrogens and progesterone, are known to exert beneficial effects on cognition and some psychiatric disorders. The basis of these effects is not fully understood, but may involve altered cholinergic neurotransmission. This study aimed to investigate how a lack of ovarian hormones would impact muscarinic receptor-induced deficits in prepulse inhibition (PPI) and muscarinic receptor density in several brain regions. Adult female rats were either ovariectomized, to remove the source of ovarian hormones, or left intact (sham-operated). PPI is a measure of sensorimotor gating that is typically impaired in schizophrenia patients, and similar deficits can be induced in rats by administering scopolamine, a muscarinic receptor antagonist. Our results revealed no significant effects of ovariectomy on PPI after saline or scopolamine treatment. Autoradiography was performed to measure cholinergic muscarinic receptor binding density using [3H]-pirenzepine, [3H]-AF-DX, and [3H]-4-DAMP, to label M1, M2/M4, and M3 receptors, respectively. We examined the amygdala, caudate putamen, dorsal hippocampus, motor cortex, retrosplenial cortex, and ventromedial hypothalamus. There were no significant group differences in any region for any muscarinic receptor type. These results suggest that removing peripheral ovarian hormones does not influence the cholinergic muscarinic receptor system in the context of PPI or receptor binding density.

CHRM2 Genotype Affects Inhibitory Control Mechanisms During Cognitive Flexibility.

The cholinergic system is one of the most important neurotransmitter systems, but knowledge about the relevance of the cholinergic muscarinergic receptor system for cognitive functions is still scarce. Evidence suggests that the cholinergic muscarinic 2 receptor (CHRM2) plays an important role in the processing of cueing/prior information that help to increase the efficacy of lower-level attentional processes. In the current study, we investigated whether this is also the case for higher-level cognitive flexibility mechanisms. To this end, we tested N = 210 healthy adults with a backward inhibition task, in which prior information needs to be used to guide cognitive flexibility mechanisms. Testing different polymorphisms of the CHRM2 gene, we found that variation in this gene play a role in cognitive flexibility. It could be demonstrated that rs8191992 TT genotype carriers are better able to suppress no longer relevant information and to use prior information for cognitive flexibility, compared to A allele carriers. We further found that rs2350780 GG genotype carriers performed worse than A allele carriers. The results broaden the relevance of the CHRM2 system for cognitive functions beyond attentional selection processes. Corroborating recent theories on the relevance of the cholinergic system for cognitive processes, these results suggest that CHRM2 is important to process of "prior information" needed to inform subsequent cognitive operations. Considering the importance of prior information for adaptive behavioral control, it is possible that CHRM2 also modulates other instances of higher-level cognitive processes as long as these require the processing of "prior information."

Beyond Acetylcholinesterase Inhibitors: Novel Cholinergic Treatments for Alzheimer's Disease.

The major components of the cholinergic receptor system of the human brain include projections from the basal forebrain nuclei, and utilize the two types of receptors that they synapse on, nicotinic and muscarinic acetylcholine receptors. With the widespread cortical and subcortical projections of the basal forebrain, activity of these two receptor systems provide modulation of neurotransmitter activity underlying normal cognitive processes, such as attention, episodic memory, and working memory. Alzheimer's disease (AD) targets and damages cholinergic neurons in the basal forebrain, and as these projections are lost, cognitive performance progressively declines. Currently, the most widely prescribed treatment for AD is acetylcholinesterase inhibitor medications, which work by partially blocking the degradation of acetylcholine in the synapse and enabling more of the neurotransmitter to reach and activate cholinergic receptors. However since these medications have limited effectiveness, alternate treatments that focus on augmenting the activity of the receptors themselves, independent of acetylcholinesterase inhibition, are being explored. This review will discuss: 1) the role of the cholinergic system in modulating cognition, 2) novel cholinergic treatment strategies for AD-related cognitive decline, in particular treatments intended to increase cholinergic system activity by selectively targeting muscarinic and nicotinic acetylcholinergic receptors to improve cognitive performance, 3) risks, and additional considerations for cholinergic cognitive treatments for AD.

Muscarinic, nicotinic and GABAergic receptor signaling differentially mediate fat-conditioned flavor preferences in rats

Rats display conditioned flavor preferences (CFP) for fats. Previous studies demonstrated that whereas expression of an already-acquired corn oil (CO)-CFP was mildly reduced by dopamine (DA) D1, DA D2, NMDA or opioid receptor antagonists, the acquisition or learning of CO-CFP was eliminated by NMDA antagonists, and significantly reduced by DA D1 and D2, but not opioid antagonists. Previous studies of fructose-CFP demonstrated that muscarinic (scopolamine) and nicotinic (mecamylamine) cholinergic receptor antagonists and GABAB (baclofen) receptor agonism reduced the expression of this acquired response, and that scopolamine, but not mecamylamine or baclofen eliminated the acquisition or learning of this response. The present study examined scopolamine, mecamylamine or baclofen effects upon expression or acquisition of CO-CFP. For expression, rats were trained over 10 sessions with CS+ (3.5% CO) and CS− (0.9% CO) flavored solutions without drugs. Two-bottle choice tests with CS+ and CS− flavors in 0.9% CO examined preferences following vehicle, scopolamine (1–10mg/kg), mecamylamine (1–8mg/kg) and baclofen (1.5–5mg/kg). In acquisition, eight groups of rats received vehicle, scopolamine (1, 2.5mg/kg), mecamylamine (4, 6mg/kg), baclofen (3, 5mg/kg) or a limited intake vehicle control 0.5h prior to all 10 CS+ and CS− training sessions followed by six 2-bottle CS+ and CS− choice tests in 0.9% CO. CO-CFP expression (percent CS+ intake) was significantly but marginally reduced by scopolamine (70%), mecamylamine (85%) and baclofen (74%) relative to vehicle (98%). CO-CFP acquisition was eliminated (41%) by scopolamine relative to vehicle (88%) and limited control (98%) conditions. Neither mecamylamine nor baclofen altered CO-CFP acquisition. Thus, the muscarinic cholinergic receptor system is essential for acquisition (learning) of both fat-induced and sugar (fructose)-induced preferences. In contrast, muscarinic, nicotinic and GABAB receptors were minimally involved in the expression (maintenance) of fat- and fructose-CFP.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation.

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

Muscarinic and nicotinic cholinergic receptor antagonists differentially mediate acquisition of fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats

Rats display both conditioned flavor preference (CFP) for fructose, and conditioned flavor avoidance (CFA) following sweet adulteration with quinine. Previous pharmacological analyses revealed that fructose-CFP expression was significantly reduced by dopamine (DA) D1 or D2 antagonists, but not NMDA or opioid antagonists. Fructose-CFP acquisition was significantly reduced by DA D1, DA D2 or NMDA antagonists, but not opioid antagonists. Quinine-CFA acquisition was significantly enhanced and prolonged by DA D1, NMDA or opioid, but not DA D2 antagonists. Cholinergic interneurons and projections interact with DA systems in the nucleus accumbens and ventral tegmental area. Further, both muscarinic and nicotinic cholinergic receptor signaling have been implicated in sweet intake and development of food-related preferences. Therefore, the present study examined whether systemic administration of muscarinic (scopolamine: SCOP) or nicotinic (mecamylamine: MEC) cholinergic receptor antagonists mediated fructose-CFP expression, fructose-CFP acquisition and quinine-CFA acquisition. For fructose-CFP expression, rats were trained over 10 sessions with a CS+ flavor in 8% fructose and 0.2% saccharin and a CS− flavor in 0.2% saccharin. Two-bottle choice tests with CS+ and CS− flavors mixed in 0.2% saccharin occurred following vehicle, SCOP (0.1–10mg/kg) and MEC (1–8mg/kg). For fructose-CFP acquisition, six groups of rats received vehicle, SCOP (1 or 2.5mg/kg), MEC (4 or 6mg/kg) or a limited intake vehicle control 0.5h prior to 10 CS+ and CS− training sessions followed by six 2-bottle CS+ and CS− choice tests in 0.2% saccharin. For quinine-CFA acquisition, five groups of rats received vehicle, SCOP (1 or 2.5mg/kg) or MEC (4 or 6mg/kg) 0.5h prior to 8 one-bottle CS− (8% fructose+0.2% saccharin: FS) and CS+ (fructose+saccharin+quinine (0.030%: FSQ) training sessions followed by six 2-bottle CS− and CS+ choice tests in fructose–saccharin solutions. Fructose-CFP expression was significantly reduced by SCOP (2.5–10mg/kg: 65–68%) and MEC (4–8mg/kg: 67–73%) relative to vehicle (89–90%), that occurred only when antagonist doses reduced total saccharin intake but in which CS+ intake was still significantly higher than CS− intake. Fructose-CFP acquisition was eliminated by SCOP at doses of 1 (40–54%) and 2.5 (45–58%)mg/kg, and was accompanied by a failure to observe CS+ and CS− intake differences during testing relative to vehicle (85–92%) and limited control (74–88%) conditions. In contrast, MEC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was significantly enhanced and prolonged by MEC at 4 (18–24%) and 6 (11–13%) mg/kg relative to vehicle (34–48%). In contrast, SCOP failed to alter quinine-CFA acquisition. These data implicate the cholinergic receptor system in mediating acquisition (learning) of sugar-induced preferences and quinine-induced aversions with muscarinic receptor signaling controlling the former and nicotinic receptor signaling controlling the latter.

Interaction of aqueous leaf extract of Aegle marmelos (L.) Corr. with cholinergic, serotonergic and adrenergic receptors: an ex vivo study.

Objectives:The aim was to study interaction of aqueous leaf extract of Aegle marmelos (AM) with cholinergic, serotonergic, and adrenergic receptor systems using appropriate rat tissues-ileum, fundus and tracheal chain, respectively.Materials and Methods:Cumulative concentration-response curves (CRC) were constructed at various doses on each tissue for AM and respective standard agonist. The CRC was again plotted in presence and absence of respective standard antagonist to confirm the interaction of receptor system and AM.Results:AM induced concentration-dependent contractions in isolated rat ileum (0.2–6.4 mg/ml) and fundus (0.2–3.2 mg/ml) that were inhibited significantly (P < 0.05) in the presence of atropine (10−7 M) and ketanserin (10−6 M), respectively. The relaxant effect, produced by AM (0.2 mg/ml) on carbachol (10−5 M) precontracted rat tracheal chain, was also inhibited significantly (P < 0.05) by propranolol (1 ng/ml).Conclusion:It may be concluded that AM possesses agonistic activity on cholinergic, serotonergic and adrenergic receptors.

Functional neural-bone marrow pathways: implications in hypertension and cardiovascular disease.

Treatment-resistant hypertension (TRHT) is characterized by persistently high arterial blood pressure (BP), partly as a result of a dysfunctional autonomic nervous system (ANS), wherein sympathetic drive/norepinephrine spillover is increased and parasympathetic drive is decreased.1–3 The difficulty in treatment of TRHT arises precisely from this partly neurogenic component because the available drug therapies do not target the central nervous system (CNS) directly. Because of this and despite recent advances in techniques such as renal denervation and carotid baroreceptor activation,4,5 successful treatment and long-term control of TRHT remain challenging.6 In an attempt to develop more effective treatments, many groups are investigating specific causes of TRHT. A large body of experimental evidence implicates both genetic and environmental influences, such as salt sensitivity and elevated systemic renin–angiotensin system (RAS) activity7–14 in the pathophysiology of this disease. Furthermore, a majority of studies point to dysregulations in the activity within the cardiorespiratory brain regions as a reason for increased sympathetic and decreased parasympathetic drive to the peripheral organs,14–21 resulting in end-organ damage,21–25 vascular/endothelial dysfunction,26,27 and hormonal imbalance,28 which perpetuate the pathophysiology and complicate treatment strategies. Despite our increasing understanding of TRHT, the origins of this brain dysregulation remain largely unknown. Recently, the activity of the immune system29–31 and neuroimmune pathways in patients with hypertension and animal models of hypertension has been highlighted.32–36 Studies suggest that both the sympathetic and the parasympathetic arms of the ANS can exert their influence on the activity of the immune organs, tissues, and cells, and that it is the dysfunctional ANS-immune communication that may lead to hypertension and CVD.35–40 The aim of this review is to summarize the latest advances in this …

Alterations in α4β2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology

Nicotinic acetylcholine receptor subtype α4β2 is considered important in the regulation of attention and memory, and cholinergic degeneration is known as one pathophysiology of Alzheimer's disease. Brain amyloid-β protein deposition is also a key pathological marker of Alzheimer's disease. Recent amyloid-β imaging has shown many cognitively normal subjects with amyloid-β deposits, indicating a missing link between amyloid-β deposition and cognitive decline. To date, the relationship between the α4β2 nicotinic acetylcholine receptor and amyloid-β burden has not been elucidated in vivo. In this study we investigated the relation between α4β2 nicotinic acetylcholine receptor availability in the brain, cognitive functions and amyloid-β burden in 20 non-smoking patients with Alzheimer's disease at an early stage and 25 age-matched non-smoking healthy elderly adults by measuring levels of α4β2 nicotinic acetylcholine receptor binding estimated from a simplified ratio method (BPRI) and Logan plot-based amyloid-β accumulation (BPND) using positron emission tomography with α4β2 nicotinic acetylcholine receptor tracer (18)F-2FA-85380 and (11)C-Pittsburgh compound B. The levels of tracer binding were compared with clinical measures for various brain functions (general cognition, episodic and spatial memory, execution, judgement, emotion) using regions of interest and statistical parametric mapping analyses. Between-group statistical parametric mapping analysis showed a significant reduction in (18)F-2FA-85380 BPRI in the cholinergic projection region in patients with Alzheimer's disease with a variety of (11)C-Pittsburgh compound B accumulation. Spearman rank correlation analyses showed positive correlations of (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region with scores of the Frontal Assessment Battery (a test battery for executive functions and judgement) in the Alzheimer's disease group (P < 0.05 corrected for multiple comparison), and also positive correlations of the prefrontal and superior parietal (18)F-2FA-85380 BPRI values with the Frontal Assessment Battery score in the normal group (P < 0.05 corrected for multiple comparison). These positive correlations indicated an in vivo α4β2 nicotinic acetylcholine receptor role in those specific functions that may be different from memory. Both region of interest-based and voxelwise regression analyses showed a negative correlation between frontal (11)C-Pittsburgh compound B BPND and (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region in patients with Alzheimer's disease (P < 0.05 corrected for multiple comparison). These findings suggest that an impairment of the cholinergic α4β2 nicotinic acetylcholine receptor system with the greater amount of amyloid deposition in the system plays an important role in the pathophysiology of Alzheimer's disease.

Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems

Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer’s disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer’s disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer’s disease.

Cholinergic Receptor System as a Target for Treating Alcohol Abuse and Dependence

Alcohol dependence and other alcohol use disorders are major public health problems. Due to the limitations in efficacy with current medications for the management of alcohol abuse and dependence, there is a need for alterantive pharmacotherapies. Emerging preclinical and clinical data indicate that brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of ion channels expressed in the mammalian brain, are critical targets for the development of pharmacotherapies for alcohol abuse and dependence. Evidence suggests that the effects of nAChR partial agonists and antagonists have promise for the management of alcohol dependence and other alcohol use disorders. The present review summarizes information on the most recent pharmacotherapies targeting nAChRs, including cytisine, sazetidine A, varenicline, lobeline mecamylamine, PF-4575180 and CP-601932, that are able to treat alcohol dependence. The role of α4β2*, α3β4* and/or other subtypes associated effects in reducing voluntary alcohol consumption or modulate alcohol drinking behavior in animal models and humans are reviewed. Patents discussed include those targeting α4β2* and α7 subtypes as well as cholinesterase inhibitors. Future research indicating the ability of nAChR based compounds to reduce alcohol consumption or modulate alcohol drinking behavior in preclinical and clinical studies, are also discussed.

Neuropharmacological profile of aqueous extract of &lt;i&gt;Anaphe venata&lt;/i&gt; larva (Notondotidae) in rats

Consumption of Anaphe larva had been reported to cause seasonal ataxia and impaired consciousness. Therefore this study examined the neuropharmacological and mechanism(s) of action of aqueous extract of Anaphe venata in rats. Behavioural effects namely rearing, stretching, sniffing and ataxia were determined after the intraperitoneal administration of aqueous extract of Anaphe larva in rats. Animals were divided into groups and graded doses (100, 200 and 400 mg/kg, i.p.) of extract were administered. The control group was administered normal saline (vehicle). The effects of scopolamine (3 mg/kg, i.p.), flumazenil (2 mg/kg, i.p.), naloxone (2.5 mg/kg, i.p.), and thiamine (1 mg/kg, i.p.) on the observed behavioral changes were also examined. The effects of the extract administered intraperitoneally at a dose of 200 mg/kg on the amphetamine-induced stereotypy and locomotion were evaluated. Aqueous anaphe extract induced significant (p< 0.01) stretching and ataxia behavioural effects while it inhibited rearing behaviour when compared with the vehicle-treated group. However, it had no significant effect on sniffing behaviour. Scopolamine reversed all the effects of the extract on rearing, stretching and ataxia. Both Flumazenil and naloxone only reversed the effects of the extract on stretching and ataxia-induced behaviours significantly. However, thiamine potentiated both stretching and ataxia-induced behaviours. The extract inhibited the amphetamine-induced stereotype behaviour and locomotion. In conclusion, these results showed that these anaphe-induced behavioural effects are mediated via cholinergic, GABAergic, opioidergic and dopaminergic receptor systems with strong muscarinic-cholinergic receptors involvement in ataxia-induced behaviour. We therefore suggest that muscranic-cholinergic like drugs may be of benefit in the management of patients that present with clinical condition of seasonal ataxia.

Alzheimer′s Disease and Metals: A Review of the Involvement of Cellular Membrane Receptors in Metallosignalling

Alzheimer's disease (AD) is a debilitating form of dementia. The hallmark protein associated with the disease is the amyloid beta (Aβ) peptide. Aggregation of Aβ has been shown to depend on interactions with metals. The recent studies now demonstrate that metals also play additional important roles in the disease process. Consequently, there may be benefit from modulating metal homeostasis. However, the role and subcellular location of metals within neurons is not well understood. There is growing evidence to suggest that metals can act at the site of cellular membrane receptors and affect cellular signaling by modulating the signal transduction of those receptors. The glutamatergic and cholinergic receptor systems, both well-known neurotransmitter systems affected in AD, have well-documented metal interactions, as do the tropomyosin-receptor kinase (Trk) family of receptors and the epidermal growth factor (EGF) receptor. In this paper, the metal interactions with these membrane receptor systems will be explored and thus the potential for membrane receptors as an intervention point in AD will be assessed.

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Inhibition of α7‐containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slices

Cys-loop ligand-gated nicotinic ACh receptors (nAChRs) and G protein-coupled muscarinic ACh receptors (mAChRs) are expressed on rat hippocampal interneurones where they can regulate excitability, synaptic communication and cognitive function. Even though both nAChRs and mAChRs appear to co-localize to the same interneurones, it is not clear whether there is crosstalk between them. We utilized patch-clamp techniques to investigate this issue in rat hippocampal CA1 interneurones in slices under conditions where synaptic transmission was blocked. The alpha7 nAChR-mediated currents were activated by choline, and when the activation of this receptor was preceded by the activation of the M(1) mAChR subtype, the amplitude of alpha7 responses was significantly reduced in a rapidly reversible and voltage-independent manner, without any change in the kinetics of responses. This M(1) mAChR-mediated inhibition of alpha7 nAChRs was through a PLC-, calcium- and PKC-dependent signal transduction cascade. These data show that M(1) mAChRs and alpha7 nAChRs are functionally co-localized on individual rat hippocampal interneurones where the activation of these particular mAChRs inhibits alpha7 nAChR function. This information will help to understand how these cholinergic receptor systems might be regulating neuronal excitability in the hippocampus in a manner that has relevance for synaptic plasticity and cognition.

Repeated Exposure to Methamphetamine Causes Long-Lasting Presynaptic Corticostriatal Depression that Is Renormalized with Drug Readministration

Addiction-associated behaviors such as drug craving and relapse are hypothesized to result from synaptic changes that persist long after withdrawal and are renormalized by drug reinstatement, although such chronic synaptic effects have not been identified. We report that exposure to the dopamine releaser methamphetamine for 10 days elicits a long-lasting (>4 month) depression at corticostriatal terminals that is reversed by methamphetamine readministration. Both methamphetamine-induced chronic presynaptic depression and the drug's selective renormalization in drug-experienced animals are independent of corresponding long-term changes in synaptic dopamine release but are due to alterations in D1 dopamine and cholinergic receptor systems. These mechanisms might provide a synaptic basis that underlies addiction and habit learning and their long-term maintenance.

Differential effects of chronic partial sleep deprivation and stress on serotonin‐1A and muscarinic acetylcholine receptor sensitivity

Disrupted sleep and stress are often linked to each other, and considered as predisposing factors for psychopathologies such as depression. The depressed brain is associated with reduced serotonergic and enhanced cholinergic neurotransmission. In an earlier study, we showed that chronic sleep restriction by forced locomotion caused a gradual decrease in postsynaptic serotonin-1A receptor sensitivity, whilst chronic forced activity alone, with sufficient sleep time, did not affect receptor sensitivity. The first aim of the present study was to examine whether the sleep loss-induced change in receptor sensitivity is mediated by adrenal stress hormones. The results show that the serotonin-1A receptor desensitization is independent of adrenal hormones as it still occurs in adrenalectomized rats. The second aim of the study was to establish the effects of sleep restriction on cholinergic muscarinic receptor sensitivity. While sleep restriction affected muscarinic receptor sensitivity only slightly, forced activity significantly hypersensitized the muscarinic receptors. This hypersensitization is because of the stressful nature of the forced activity protocol as it did not occur in adrenalectomized rats. Taken together, these data confirm that sleep restriction may desensitize the serotonin-1A receptor system. This is not a generalized effect as sleep restriction did not affect the sensitivity of the muscarinic cholinergic receptor system, but the latter was hypersensitized by stress. Thus, chronic stress and sleep loss may, partly via different pathways, change the brain into a direction as it is seen in mood disorders.