Role Of Acetylcholine Research Articles

Role of Acetylcholine in the Modulation of Activity of Neocortical Neurons in Awake Animals Performing an Instrumental Conditioned Reflex

We studied modulatory effects of the cholinergic system on the activity of sensorimotor cortex neurons related to realization of an instrumental conditioned placing reflex. Experiments were carried out on awake cats; multibarrel glass microelectrodes were used for extracellular recording of impulse activity of neurons in the sensorimotor cortex and iontophoretic application of synaptically active agents within the recording region. The background and reflex-related activity was recorded in the course of realization of conditioned movements, and then changes of spiking induced by applications of the testing substances were examined. Applications of acetylcholine and carbachol resulted in increases in the intensity of impulse reactions of neocortical neurons evoked by presentation of an acoustic signal and in simultaneous shortening of the response latencies. An agonist of muscarinic receptors, pylocarpine, exerted a similar effect on the evoked activity of sensorimotor cortex neurons. Blockers of muscarinic receptors, atropine and scopolamine, vice versa, sharply suppressed impulse reactions of cortical neurons to afferent stimulation and simultaneously increased latencies of these responses. Applications of an agonist of nicotinic receptors, nicotine, was accompanied by suppression of impulse neuronal responses, an increase in the latency of spike reactions to presentation of a sound signal, and a corresponding increase in the latency of a conditioned motor reaction. In contrast, application of an antagonist of nicotinic receptors, tubocurarine, significantly intensified neuronal spike responses and shortened their latency. The mechanisms underlying the effects of antagonists of membrane muscarinic and nicotinic cholinoreceptors and the role of activation of these receptors in the modulation of activity of pyramidal and non-pyramidal neocortical neurons related to realization of the instrumental motor reflex are discussed.

Cholinergic direct inhibition of N‐methyl‐D aspartate receptor‐mediated currents in the rat neocortex

Acetylcholine (ACh) and N-methyl-D aspartate receptors (NMDARs) interact in the regulation of multiple important brain functions. NMDAR activation is indirectly modulated by ACh through the activation of muscarinic or nicotinic receptors. Scant information is available on whether ACh directly interacts with the NMDAR. By using a cortical brain slice preparation we found that the application of ACh and of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR-mediated currents (I(NMDA)), ranging from 20 to 90% of the control amplitude. The reduction displayed similar features in synaptic I(NMDA) in brain slices, as well as in currents evoked by NMDA application in brain slices or from acutely dissociated cortical cells, demonstrating its postsynaptic nature. The cholinergic inhibition of I(NMDA) displayed an onset-offset rate in the order of a second, and was resistant to the presence of the muscarinic antagonist atropine (10 microM) in the extracellular solution, and of G-protein blocker GDP(beta)S (500 microM) and activator GTP(gamma)S (400 microM) in the intracellular solution, indicating that it was not G-protein dependent. Recording at depolarized or hyperpolarized holding voltages reduced NMDAR-mediated currents to similar extents, suggesting that the inhibition was voltage-independent, whereas the reduction was markedly more pronounced in the presence of glycine (20 microM). A detailed analysis of the effects of tubocurarine suggested that at least this drug interfered with glycine-dependent NMDAR-activity. We conclude that NMDAR-mediated current scan be inhibited directly by cholinergic drugs, possibly by direct interaction within one or more subunits of the NMDAR. Our results could supply a new interpretation to previous studies on the role of ACh at the glutamatergic synapse.

The Intermediate-Conductance Ca2+-Activated K+ Channel (KCa3.1) in Vascular Disease

The intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) was first described by Gardos in erythrocytes and later confirmed to play a significant role in T-cell activation and the immune response. More recently, K(Ca)3.1 has been characterized in numerous cell types which contribute to the development of vascular disease, such as T-cells, B-cells, endothelial cells, fibroblasts, macrophages, and dedifferentiated smooth muscle cells (SMCs). Physiologically, K(Ca)3.1 has been demonstrated to play a role in acetylcholine and endothelium-derived hyperpolarizing factor (EDHF) induced hyperpolarization, and thus control of blood pressure. Pathophysiologically, K(Ca)3.1 contributes to proliferation of T-cells, B-cells, fibroblasts, and vascular SMCs, as well as the migration of SMCs and macrophages and platelet coagulation. Recent studies have indicated that blockade of K(Ca)3.1, by specific blockers such as TRAM-34, could prove to be an effective treatment for vascular disease by inhibiting T-cell activation as well as preventing proliferation and migration of macrophages, endothelial cells, and SMCs. This vasculoprotective potential of K(Ca)3.1 inhibition has been confirmed in both rodent and swine models of restenosis. In this review, we will discuss the physiological and pathophysiological role of K(Ca)3.1 in cells closely associated with vascular biology, and the effect of K(Ca)3.1 blockers on the initiation and progression of vascular disease.

Role of acetylcholine in negative patterning in turtles (Chrysemys picta).

Turtles were run on a negative patterning task involving 2 positive elements, a key with white stripes on a black background, and a solid red key, and a compound stimulus combining the 2 elements, white stripes on a red background. Injections of scopolamine, methylscopolamine, or saline were started at the same time that the compound stimulus was introduced, after the animals had been autoshaped to press the key for each of the elements. Scopolamine disrupted the learning of negative patterning, but methylscopolamine had no effect. In contrast, learning of a simple discrimination between the elements was not affected by scopolamine. These results show that muscarinic cholinergic receptors are involved in the learning of negative patterning in turtles.

Role of the cholinergic system in the pathology and treatment of schizophrenia

Schizophrenia is a devastating psychiatric disorder; the diagnosis probably encompasses a number of illnesses with similar clinical presentations, complicating both treatment and studies into the pathology of the disorder. The development of antipsychotic medications revolutionized treatment for the disorder. However, there are still symptom domains that are relatively untouched by the drugs currently available; these are the cognitive deficits and the negative symptoms. Basic research strongly supports a role of acetylcholine in cognitive processes, making it a primary target for drugs designed to improve this most impairing symptom. In addition, the fact that acetylcholine can modulate dopamine release makes the cholinergic system a target for novel antipsychotic drugs, ideally without the side-effect profiles that contribute to patient noncompliance seen with current antipsychotic drugs. Thus far, the results of clinical trials with cholinomimetics have been equivocal; where beneficial effects are seen they are, by and large, modest rather than compelling. These trials and studies investigating the role of both nicotinic and muscarinic receptors in the pathology of the disorder, published during the last 5 years, are reviewed to ascertain whether there is a role for the cholinergic system in the treatment of schizophrenia.

Cholinergic Enhancement Reduces Spatial Spread of Visual Responses in Human Early Visual Cortex

Animal studies have shown that acetylcholine decreases excitatory receptive field size and spread of excitation in early visual cortex. These effects are thought to be due to facilitation of thalamocortical synaptic transmission and/or suppression of intracortical connections. We have used functional magnetic resonance imaging (fMRI) to measure the spatial spread of responses to visual stimulation in human early visual cortex. The cholinesterase inhibitor donepezil was administered to normal healthy human subjects to increase synaptic levels of acetylcholine in the brain. Cholinergic enhancement with donepezil decreased the spatial spread of excitatory fMRI responses in visual cortex, consistent with a role of acetylcholine in reducing excitatory receptive field size of cortical neurons. Donepezil also reduced response amplitude in visual cortex, but the cholinergic effects on spatial spread were not a direct result of reduced amplitude. These findings demonstrate that acetylcholine regulates spatial integration in human visual cortex.

Role of acetylcholine in Ca2+-dependent regulation of functional activity of the frog Rana temporaria myocardium

To study role of acetylcholine (ACh) in Ca2+-dependent regulation of rhythm and strength of cardiac contractions in the frog Rana temporaria, we studied in parallel experiments the ACh chrono- and inotropic effects on the background of action of blockers of the potential-controlled Ca2+-channels, ryanodine and muscarine receptors. The obtained results indicate participation of acetylcholine in the Ca2+-dependent regulation of the rhythm and strength of the frog cardiac contractions.

64 Role of Acetylcholine and Serotonin Receptors in the Maintenance of Muscle Hypercontractility in a Murine Model of Post-Inflammatory Irritable Bowel Syndrome

64 Role of Acetylcholine and Serotonin Receptors in the Maintenance of Muscle Hypercontractility in a Murine Model of Post-Inflammatory Irritable Bowel Syndrome

Role of acetylcholine in nitric oxide production in the salamander retina

Although acetylcholine is one of the most widely studied neurotransmitters in the retina, many questions remain about its downstream signaling mechanisms. In this study we initially characterized the cholinergic neurotransmitter system in the salamander retina by localizing a variety of cholinergic markers. We then examined the link between both muscarinic and nicotinic receptor activation and nitric oxide production by using immunocytochemistry for cyclic guanosine monophosphate (cGMP) as an indicator. We found a large increase in cGMP-like immunoreactivity (cGMP-LI) in the inner retina in response to muscarinic (but not nicotinic) receptor activation. Based on the amplification of mRNA transcripts, receptor immunocytochemistry, and the use of selective antagonists, we identified these receptors as M2 muscarinic receptors. Using double-labeling techniques, we established that these increases in cGMP-LI were seen in GABAergic but not cholinergic amacrine cells, and that the increases were blocked by inhibitors of nitric oxide production. The creation of nitric oxide in response to cholinergic receptor activation may provide a mechanism for modulating the well-known mutual interactions of acetylcholine-glycine-GABA in the inner retina. As GABA and glycine are the primary inhibitory neurotransmitters in the retina, signaling pathways that modulate their levels or release will have major implications for the processing of complex stimuli by the retina.

Orchidectomy increases the formation of prostanoids and modulates their role in the acetylcholine-induced relaxation in the rat aorta

This study examines the effect of endogenous male sex hormones on thromboxane A2 (TXA2), prostaglandin (PG) I2, PGF(2 alpha), and PGE I2 release, as well as their role in acetylcholine (ACh)-mediated relaxation in the aorta. Aortic segments from orchidectomized and control male Sprague-Dawley rats were used to measure COX-2 protein expression. ACh-induced relaxation of these segments was also determined in the absence and presence of the COX-2 inhibitor NS-398, the TXA2 synthesis inhibitor furegrelate, the PGI2 synthesis inhibitor tranylcypromine (TCP), or the thromboxane-prostanoid (TP) receptor antagonist SQ-29 548. Furthermore, TXA2, PGI2, PGF(2 alpha), and PGE2 release as well as the vasomotor effect of exogenous TXA2, PGI2, PGF(2 alpha), and PGE2 were measured. COX-2 expression was increased in aortas from orchidectomized rats. NS-398 did not modify the ACh-induced relaxation in arteries from both control or orchidectomized rats. Furegrelate did not modify the ACh-induced relaxation in aortas from control animals but, in aortas from orchidectomized rats, it increased that response. TCP decreased the ACh-induced relaxation in both groups. The TP receptor antagonist, SQ29 548 failed to modify ACh-induced relaxation in aortas from either rat group. Pre-incubating arteries from orchidectomized rats with TCP plus furegrelate did not modify the decrease in the ACh response induced by TCP alone, but this response was restored by co-incubation of TCP plus SQ29 548. ACh-induced TXA2, PGI2, PGF(2 alpha), and PGE2 release were increased by orchidectomy. The presence of furegrelate plus TCP increased the ACh-induced PGE2 release more in arteries from orchidectomized than in those from control rats. The contractile responses induced by the TXA2 mimetic U-46619 or by exogenous PGF(2 alpha) were similar in arteries from control and orchidectomized rats, while those induced by exogenous PGE2 were increased in arteries from orchidectomized rats; the vasodilator response induced by exogenous PGI2 was decreased in arteries from orchidectomized rats. These data show that endogenous male sex hormone deprivation increases COX-2 expression, the release of TXA2, PGI2, PGF(2 alpha), and PGE2 and the contractile response induced by exogenous PGE2 and TXA2, while it decreases the relaxation induced by exogenous PGI2. Despite the predominance of vasoconstrictor prostanoids derived from COX-2 in aortas from orchidectomized rats, the ACh-induced relaxation remains increased.

The role of acetylcholine in cocaine addiction.

Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

Comparative roles of acetylcholine and noradrenaline in controlling the spontaneous activity of cortical neurons

The effects of acetylcholine and noradrenaline on the spike activity of neurons recorded in guinea pig parietal cortex slices were studied. Iontophoretic application of these two neurotransmitters to cortical neurons induced similar responses consisting of slowly developing and prolonged increases in spike activity. Differences in the temperature sensitivity of responses to acetylcholine and noradrenaline were identified. When the incubation medium temperature was increased from 32-34 degrees C to 35-36 degrees C, the effects of acetylcholine on neuron spike activity increased sharply, with the result that neurons which showed no spontaneous activity at 32-34 degrees C became sensitive to acetylcholine. The temperature-dependent increases in the extent of responses to acetylcholine were accompanied by stable increases in the level of spontaneous activity. Responses to application of noradrenaline showed no significant change when the temperature increased from 32-34 degrees C to 35-36 degrees C. Since neuron responses to the iontophoretic application of glutamate, the major excitatory neurotransmitter in the cortex, remained constant over this range of temperatures, the data obtained here lead to the conclusion that acetylcholine is the main regulator of the level of spontaneous activity of cortical neurons.

Pharmacology and war: the papers of Sir John Henry Gaddum (1900–65)

The Wellcome Trust’s Research Resources in Medical History has funded a one-year-long project to catalogue the Royal Society’s twentieth-century medical collections. As part of this project, the papers of British pharmacologist Sir John Henry Gaddum FRS have been catalogued. The collection spans Gaddum’s entire career, from school writings and first forays into science to his final post as Director of the Institute of Animal Physiology, Babraham, Cambridge, in 1958. In addition to a wealth of working papers, laboratory notebooks and correspondence, the collection includes material on Gaddum’s war-related research and provides an insight into the role of the medical scientist in World War II. Trained as a physiologist, Gaddum made his first major contributions to the field while working at the National Institute for Medical Research in the laboratory of Sir Henry Hallett Dale FRS (1875–1968). Together with Ulf von Euler ForMemRS, he discovered a previously unknown but vital vasodepressor substance in the brain and intestine (Substance P). Gaddum was able to establish the role of acetylcholine in sympathetic nerve transmission. His later research focused on the mode of action of drugs, and his studies on the effects of lysergic acid diethylamide (LSD) led to a better understanding of serotonin. 1 The laboratory notebooks in the collection chart the course of these discoveries: one day’s entry reads, ‘various unsuccessful attempts to show that sympathetic ganglia act by liberating acetylcholine’; 2 other notable entries include a 1953 self-experiment to record LSD’s physiological effects under the supervision of his research team. 3 Gaddum developed ever more sophisticated methods of testing the pharmacological activity of substances. Among his papers are many diagrams of apparatus and push–pull cannulae, devices for withdrawing fluids from tissue. Extensive correspondence on bioassay techniques shows how widely these methods were taken up by colleagues. Like many of his colleagues working in physiology during the 1940s, Gaddum was called upon to use his expertise in the field of gas warfare research. At Porton Down, he studied how the different dispersal properties of gases used in warfare determined their toxicity. In the company of Sir Joseph Barcroft FRS, Gordon Roy Cameron FRS and Sir Charles Arthur Lovatt Evans FRS, he advised the Porton group on both defensive and offensive war strategies. One such report discusses the feasibility of poisoning enemy water supplies with capsaicin, the active component of hot chillies. 4 Gaddum’s correspondence with physiologists across the globe reveals a different side to the effects of war. Letters from the American pharmacologist Chauncey Leake discuss the

Development of fetal nicotine and muscarinic receptors in utero

The role of acetylcholine in the central and peripheral nervous systems is well established in adults. Cholinergic modulation of vascular functions and body fluid balance has been extensively studied. In the embryo-fetus, cholinergic receptors are widespread in the peripheral and central systems, including smooth muscle and the epithelial lining of the cardiovascular, digestive, and urinary systems, as well as in the brain. Fetal nicotine and muscarinic receptors develop in a pattern (e.g., amount and distribution) related to gestational periods. Cholinergic mechanisms have been found to be relatively intact and functional in the control of vascular homeostasis during fetal life in utero at least during the last third of gestation. This review focuses on the development of fetal nicotine and muscarinic receptors, and provides information indicating that central cholinergic systems are well developed in the control of fetal blood pressure and body fluid balance before birth. Therefore, the development of cholinergic systems in utero plays an important role in fetal vascular regulation, gastrointestinal motility, and urinary control.

The cutaneous non-neuronal cholinergic system and smoking related dermatoses: Studies of the psoriasis variant palmoplantar pustulosis

Palmoplantar pustulosis (PPP) is probably the inflammatory skin disease most strongly associated to smoking. The disease is common in middle-aged, smoking women, and is chronic, sometimes disabling and characterized by pustules, erythema and scaling on the soles and palms. It is often treatment-resistant. PPP patients have a co-morbidity with an increased risk of autoimmune thyroid disease, celiac disease/gluten intolerance, abnormal calcium homeostasis, diabetes type 2, and depression. The sweat gland apparatus is involved in the pathogenesis of PPP since a) the normal structure of the acrosyringium is abolished so the keratin pattern differs to that in normal palmar skin; b) granulocytes migrate outwards in the acrosyringium forming the pustule in the stratum corneum. Acetylcholine (ACh) is the main inducer of sweating. With immunohistochemistry the ACh synthesizing enzyme choline acetyltransferase (ChAT) and the ACh-degrading enzyme acetylcholinesterase (AChE) were found to be strongly expressed in the gland and duct as were the α-3 and α-7 nicotinic acetylcholine receptors (nAChRs). Smoking influenced the staining intensity of the enzymes and the α-3 nAChR in healthy subjects. In involved PPP skin there was a massive infiltration of granulocytes expressing ChAT and α-3 nAChR, and mast cells expressing AChE indicating a role for acetylcholine in inflammation. Cessation of smoking resulted in fewer pustules, and less scaling and erythema. The mechanisms for the effect of nicotine/smoking in PPP are still unknown but nicotine may lead to enhanced inflammation in consideration of the properties of the sweat duct and/or nicotine might facilitate autoimmune reactions.

Role of acetylcholine in neurotransmission of the carotid body

Acetylcholine (ACh) has been considered an important excitatory neurotransmitter in the carotid body (CB). Its physiological and pharmacological effects, metabolism, release, and receptors have been well documented in several species. Various nicotinic and muscarinic ACh receptors are present in both afferent nerve endings and glomus cells. Therefore, ACh can depolarize or hyperpolarize the cell membrane depending on the available receptor type in the vicinity. Binding of ACh to its receptor can create a wide variety of cellular responses including opening cation channels (nicotinic ACh receptor activation), releasing Ca(2+) from intracellular storage sites (via muscarinic ACh receptors), and modulating activities of K(+) and Ca(2+) channels. Interactions between ACh and other neurotransmitters (dopamine, adenosine, nitric oxide) have been known, and they may induce complicated responses. Cholinergic biology in the CB differs among species and even within the same species due to different genetic composition. Development and environment influence cholinergic biology. We discuss these issues in light of current knowledge of neuroscience.

Hypothalamic proopiomelanocortin (POMC) neurons have a cholinergic phenotype

Neuronal networks originating in the hypothalamic arcuate nucleus play fundamental roles in the control of energy balance. Neuropeptide Y (NPY)-producing neurons in the arcuate nucleus stimulate food intake, whereas arcuate nucleus neurons that release the proopiomelanocortin (POMC)-derived peptide alpha-melanocyte-stimulating hormone (alpha-MSH) potently reduce food intake. Relatively little attention has been focused on classical neurotransmitters in regulation of food intake. Here, we have investigated the potential presence of acetylcholine (ACh) in NPY- and POMC-containing neuronal populations of the arcuate nucleus. Antisera to proteins required for cholinergic neurotransmission, including choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT), were employed in double-labeling immunohistochemical experiments. In colchicine-treated rats, ChAT- and VAChT-immunopositive cell bodies were located in the ventral aspect of the arcuate nucleus. ChAT and VAChT immunoreactivities were demonstrated in alpha-MSH- and cocaine- and amphetamine-regulated transcript (CART)-containing cell bodies of the arcuate nucleus, whereas cell bodies containing NPY or agouti-related peptide (AGRP) were distinct from VAChT-immunoreactive neuronal perikarya. VAChT immunoreactivity was also present in a large number of alpha-MSH-containing nerve fiber varicosities throughout the central nervous system. In the commissural part of the nucleus tractus solitarius, no alpha-MSH-containing cell bodies were found to have ChAT or VAChT immunoreactivity. The presence of markers for cholinergic neurotransmission in a subpopulation of hypothalamic POMC/CART neurons suggests co-release of ACh with peptides derived from the POMC precursor and CART. The results indicate a role for ACh in control of energy balance, mediating the effects of peripheral hormones such as leptin and insulin.

II.5 The role of acetylcholine in Parkinson's Disease-related cognitive dysfunction

II.5 The role of acetylcholine in Parkinson's Disease-related cognitive dysfunction

Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse

BackgroundIt has been proposed that serotonin (5-HT)-mediated constriction of the murine trachea is largely dependent on acetylcholine (ACh) released from the epithelium. We recently demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells. Hence, the hypothesis emerged that 5-HT evokes bronchoconstriction by inducing release of ACh from epithelial cells via OCTs.MethodsWe tested this hypothesis by analysing bronchoconstriction in precision-cut murine lung slices using OCT and muscarinic ACh receptor knockout mouse strains. Epithelial ACh content was measured by HPLC, and the tissue distribution of OCT isoforms was determined by immunohistochemistry.ResultsEpithelial ACh content was significantly higher in OCT1/2 double-knockout mice (42 ± 10 % of the content of the epithelium-denuded trachea, n = 9) than in wild-type mice (16.8 ± 3.6 %, n = 11). In wild-type mice, 5-HT (1 μM) caused a bronchoconstriction that slightly exceeded that evoked by muscarine (1 μM) in intact bronchi but amounted to only 66% of the response to muscarine after epithelium removal. 5-HT-induced bronchoconstriction was undiminished in M2/M3 muscarinic ACh receptor double-knockout mice which were entirely unresponsive to muscarine. Corticosterone (1 μM) significantly reduced 5-HT-induced bronchoconstriction in wild-type and OCT1/2 double-knockout mice, but not in OCT3 knockout mice. This effect persisted after removal of the bronchial epithelium. Immunohistochemistry localized OCT3 to the bronchial smooth muscle.ConclusionThe doubling of airway epithelial ACh content in OCT1/2-/- mice is consistent with the concept that OCT1 and/or 2 mediate ACh release from the respiratory epithelium. This effect, however, does not contribute to 5-HT-induced constriction of murine intrapulmonary bronchi. Instead, this activity involves 1) a non-cholinergic epithelium-dependent component, and 2) direct stimulation of bronchial smooth muscle cells, a response which is partly sensitive to acutely administered corticosterone acting on OCT3. These data provide new insights into the mechanisms involved in 5-HT-induced bronchoconstriction, including novel information about non-genomic, acute effects of corticosteroids on bronchoconstriction.

Generalized cortex activation by the auditory midbrain: mediation by acetylcholine and subcortical relays

The inferior colliculus (IC) is a critical component of the ascending projection system carrying auditory information from the brainstem to the forebrain. Recent evidence indicates that, in addition to its role in auditory processing, the IC can exert a generalized, modulatory effect on the forebrain by activating the neocortical electrocorticogram (ECoG). Given the sparse direct projections from the IC to the cortex, it appears that the effect of the IC to produce ECoG activation is indirect, mediated by one or several neuromodulatory systems that have diffuse access to the entire cortical mantle. However, the anatomical relays that permit the IC to influence cortical activity have not been elucidated. In the present experiments, electrical stimulation of the IC suppressed slow, large amplitude oscillations in the ECoG of urethane anesthetized rats, replacing them with higher-frequency cortical activation. This effect was blocked by the muscarinic receptor antagonist scopolamine (0.5-1.0 mg/kg, i.p.), suggestive of a critical role of acetylcholine (ACh) release. Consistent with this hypothesis, localized lidocaine infusions (2%, 1 microl) into the cholinergic basal forebrain complex strongly reduced ECoG activation elicited by IC stimulation. To identify additional relays between the IC and basal forebrain, the effects of lidocaine infusions into the superior colliculus, medial prefrontal cortex, midline thalamus, and dorsal raphe were also studied. Inactivation of the superior colliculus and dorsal raphe reduced IC-induced activation, while prefrontal cortex and thalamic infusions were ineffective. Concurrent basal forebrain and raphe inactivation produced effects similar to that of inactivation of the basal forebrain alone, suggesting that these two areas are arranged in series, rather than acting as independent, parallel pathways. These results suggest that the ability of the IC to induce ECoG activation is mediated, in large parts, by the basal forebrain cholinergic system. Consistent with anatomical evidence, the superior colliculus and dorsal raphe appear to provide important links to functionally connect the IC to the basal forebrain, allowing the IC to indirectly access the entire cortical mantle and enhance processing in neocortical networks.