Effects Of Cholinergic Agents Research Articles

Meningeal mast cell-mediated mechanisms of cholinergic system modulation in neurogenic inflammation underlying the pathophysiology of migraine.

Growing evidence indicates that the parasympathetic system is implicated in migraine headache. However, the cholinergic mechanisms in the pathophysiology of migraine remain unclear. We investigated the effects and mechanisms of cholinergic modulation and a mast cell stabilizer cromolyn in the nitroglycerin-induced in vivo migraine model and in vitro hemiskull preparations in rats. Effects of cholinergic agents (acetylcholinesterase inhibitor neostigmine, or acetylcholine, and muscarinic antagonist atropine) and mast cell stabilizer cromolyn or their combinations were tested in the in vivo and in vitro experiments. The mechanical hyperalgesia was assessed by von Frey hairs. Calcitonin gene-related peptide (CGRP) and C-fos levels were measured by enzyme-linked immunosorbent assay. Degranulation and count of meningeal mast cells were determined by toluidine-blue staining. Neostigmine augmented the nitroglycerin-induced mechanical hyperalgesia, trigeminal ganglion CGRP levels, brainstem CGRP, and C-fos levels, as well as degranulation of mast cells in vivo. Atropine inhibited neostigmine-induced additional increases in CGRP levels in trigeminal ganglion and brainstem while it failed to do this in the mechanical hyperalgesia, C-fos levels, and the mast cell degranulation. However, all systemic effects of neostigmine were abolished by cromolyn. The cholinergic agents or cromolyn did not alter basal release of CGRP, in vitro, but cromolyn alleviated the CGRP-inducing effect of capsaicin while atropine failed to do it. These results ensure for a first time direct evidence that endogenous acetylcholine contributes to migraine pathology mainly by activating meningeal mast cells while muscarinic receptors are involved in CGRP release from trigeminal ganglion and brainstem, without excluding the possible role of nicotinic cholinergic receptors.

Striatal cholinergic transmission. Focus on nicotinic receptors' influence in striatal circuits.

The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic-receptor-mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.

Prokinetic effect of ??-adrenergic antagonist, and ??-adrenergic antagonist on gall-bladder motility in humans with gall-stone disease

The effects of cholinergic agents and vagal control on gall-bladder motility are well defined. Alpha adrenergic antagonists have been found in previous studies to have a prokinetic effect on gall-bladder motility in normal human patients. Their effects have not, however, been fully elucidated in patients with gall-stone disease. Our aim was to determine the effects of alpha-antagonists and beta-antagonists on gall-bladder motility in human patients with gall-stone disease. In this single-blind, three-way crossover study, a slow release formulation of 80 mg propranolol (beta-antagonist), and 25 mg indoramin (alpha-antagonist), and placebo were administered separately to 10 patients with gall-stone disease on three separate days 8 h before assessment of gall-bladder volumes by ultrasonography. Gall-bladder volumes were assessed in the fasting state and at 5 min intervals for 50 min after a standard proprietary enteral feed (Ensure 180 ml, Abbott). Differences between the placebo and postadrenergic antagonist scan volumes were tested using the Wilcoxon-signed rank test. There were no significant differences in the mean fasting gall-bladder volumes after receiving propranolol, indoramin and placebo (23.6+/-3.9, 22.3+/-4.3, 26.8+/-7.2 ml, mean+/-SEM, respectively). In the postprandial period, however, indoramin significantly enhanced postprandial gall-bladder emptying compared with placebo between 5 and 30 min (P<0.05) after which refilling commenced. There were no significant postprandial gall-bladder volume differences between propranolol and placebo. Indoramin, an alpha-adrenergic antagonist, acts as a prokinetic agent enhancing postprandial gall-bladder emptying in patients with gall-stone disease. This effect is similar to its effect on postprandial gall-bladder emptying in healthy individuals.

Cholinergic reversal of isoflurane anesthesia in rats as measured by cross-approximate entropy of the electroencephalogram.

Pharmacologic modulation of the state of consciousness is of interest for clinical practice and for a better understanding of anesthetic mechanisms. The cholinergic activating system is an important regulator of the state of consciousness during general anesthesia. Entropy of the electroencephalogram has been proposed as a promising measure of anesthetic depth. The authors have shown that volatile anesthetics decrease cross-approximate entropy (C-ApEn) of the bihemispheric frontal electroencephalogram in rats. The effect of cholinergic agents on C-ApEn has not been examined. Here, the authors test the hypothesis that cholinergic activation reverses the effect of isoflurane anesthesia on C-ApEn. An electroencephalogram in the 1- to 100-Hz range was recorded bipolarly, with epidural leads from the frontal cortex of both hemispheres, and used to calculate C-ApEn, which reflects statistical independence of bihemispheric electroencephalographic activity. Cholinesterase inhibitor, neostigmine (25 mug), or the muscarinic agonist oxotremorine (25 mug) were infused intracerebroventricularly while the rats were inhaling 1.0% (0.7 minimum alveolar concentration) isoflurane. In other animals, isoflurane was lowered to 0.4% (0.3 minimum alveolar concentration) to assess the electroencephalogram in a sedated, waking state. At 1.0% isoflurane, C-ApEn decreased by 54% compared with that at 0.4%, but the motor reflex response to tail pinch was still present. Cholinergic agents reversed the electroencephalogram-depressant effect of isoflurane, i.e., C-ApEn rose to the level measured at 0.4% isoflurane. The rise in C-ApEn was paralleled by the appearance of spontaneous limb and orofacial explorative movements, suggesting a return of consciousness. In contrast, cholinergic agents fully blocked the motor reflex to tail pinch. C-ApEn of the bihemispheric electroencephalogram correlates with the return of spontaneous motor signs but not with the nociceptive reflex. Cerebral cholinergic activation dissociates central and peripheral anesthetic effects. C-ApEn, a novel measure of interhemispheric electroencephalogram independence, is a promising correlate of depth of sedation and state of consciousness.

Potentiation of imipramine-induced antinociception by nicotine in the formalin test

In this study, the effect of cholinergic agents on imipramine antinociception in mice, in the formalin test, has been investigated. Intraperitoneal (i.p.) administration of different doses of imipramine (2.5, 5, 10, 20 and 30 mg/kg) or nicotine (0.25, 0.5, 0.75 and 1 mg/kg) induced a dose dependent antinociception in both the first and second phases of the formalin test in mice. The combination of imipramine with doses of 0.5 and 0.75 mg/kg of nicotine showed a potentiated response, in both phases of the test. However, neither hexamethonium (5 and 10 mg/kg), atropine (0.25 mg/kg) or mecamylamine (0.25 mg/kg) altered the antinociception induced by imipramine. It is concluded that nicotinic receptor activation but not the cholinergic muscarinic mechanism is involved in the imipramine-induced antinociception.

Rabbit retinal ganglion cell responses mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors.

The responses of many ganglion cells in the rabbit retina are mediated, at least in part, by acetylcholine (ACh) acting on neuronal nicotinic acetylcholine receptors (nAChRs). nAChRs are comprised of alpha and beta subunits; three beta subunits and nine alpha subunits of nAChRs have been identified and these subunits can combine to form a large number of functionally distinct nAChR subtypes. We examined the effects of cholinergic agents on the light-evoked responses of ganglion cells to determine which nAChR subtypes mediate the effects of ACh. Extracellular recordings of retinal ganglion cells were made in intact everted eyecup preparations and nicotinic agonists and antagonists were added to the superfusate. While several ganglion cell classes exhibited methyllycaconitine (MLA) sensitivity, the directionally selective (DS) ganglion cells were most sensitive; exposure to 30 nanomolar MLA, a concentration reportedly too low to affect alphaBgt-insensitive nAChRs, suppressed the stimulus-evoked responses of DS cells without eliminating directional selectivity. Epibatidine, which at low concentrations is an agonist selective for alphaBgt-insensitive nAChRs, stimulated firing of various cell types including DS ganglion cells at low nanomolar concentrations. The effects of the various agents tested persisted under cobalt-induced synaptic blockade. The low nanomolar MLA and epibatidine sensitivity of DS cells suggests that DS ganglion cells express both alphaBgt-sensitive and alphaBgt-insensitive nAChRs. Other ganglion cell types appear to express only alphaBgt-sensitive nAChRs but not alphaBgt-insensitive nAChRs.

Effects of cholinergic agents on the vasopressin-mediated water transport in the isolated toad bladder

The aim of this work was to study the effect of some pharmacological cholinergic agents on the events that follow the interaction of arginine vasopressin with toad bladder membrane receptors related to synthesis of 3′5′ cAMP. The water flow through the membrane was measured gravimetrically in sac preparations of the membrane. In the absence of arginine vasopressin (AVP), carbachol induced a significant increase in the water flow (37%) related to the basal (Ringer's solution). On the other hand, when carbachol and AVP were associated, a significant decrease of AVP hydrosmotic activity occurred (23%). The inhibitory effect of carbachol on the AVP action was almost completely abolished by the cholinergic antagonists atropine, pirenzepine, 4-diphenylacetoxy- N-methylpiperidine methiodide (4-DAMP) and the calcium antagonist lanthanum. Similarly, when carbachol and 3′5′ cyclic adenosine monophosphate (3′5′ cAMP) were associated, a decrease of nucleotide hydrosmotic activity was observed (12.80%). This effect was partially restored by the addition of pirenzepine or 4-DAMP in the bath solution. These results suggest a role for muscarinic receptors of sub-type M 1 and M 3, which are involved in the intracellular calcium release. The increase of calcium concentration in the intracellular medium acts as a negative modulator in the hydrosmotic action of antidiuretic hormone.

Effects of cholinergic agents on spontaneous activity of nucleus basalis magnocellularis neurons in different age rats

The present study investigated the effects of intracerebroventricular (i.c.v.) injection of acetylcholine (Ach), atropine and tubocurarine on the spontaneous activity of nucleus basalis Magnocellularis (nbM) neurons in young, adult and old rats. I.c.v. injection of Ach (1, 10 and 100 mM) dose-dependently increased the spontaneous firing rate in most of the nbM neurons (66.7%). The Ach-induced excitation effect on the spontaneous firing of nbM neurons was decreased with aging. I.c.v. injection of atropine (2.5, 25 and 250 mM) or tubocurarine (0.1, 1 and 10 mM) not only antagonized the Ach-induced excitation, but also inhibited the spontaneous firing of nbM neurons. The inhibitory effects were gradually decreased with aging. These results suggested that there might be some functional changes in nbM neurons with aging, which impair their responsive ability to stimuli of drugs.

Cholinergic modulation of synaptic transmission and plasticity in entorhinal cortex and hippocampus of the rat

Effects of cholinergic agents on synaptic transmission and plasticity were examined in entorhinal cortex and hippocampus. Bath application of carbachol (0.25–0.75 μM) induced transient depression of field potential responses in all cases tested (24/24 in layer III of medial entorhinal cortex slices and 24/24 in CA1 of hippocampal slices; 11.0±1.9% and 7.8±2.5%, respectively) and long-lasting potentiation in some cases (4/24 in entorhinal cortex and 12/24 in hippocampus; 33.7±3.7% and 32.1±9.9%, respectively, in successful cases). Carbachol (0.5 μM) induced transient depression, but not long-lasting potentiation, of N-methyl- d-aspartate receptor-mediated responses in entorhinal cortex. At 5 μM, carbachol induced transient depression only (55.9±4.7% in entorhinal cortex and 41.4±2.9% in hippocampus), which was blocked by atropine. Paired-pulse facilitation was not altered during carbachol-induced potentiation but enhanced during carbachol-induced depression. These results suggest that the underlying mechanisms of carbachol-induced depression and potentiation are decreased transmitter release and selective enhancement of non- N-methyl- d-aspartate receptor-mediated responses, respectively. Long-term potentiation could be induced in the presence of 10 μM atropine by theta burst stimulation. The magnitude was significantly lower (15.2±5.2%, n=9) compared with control (37.2±6.1%, n=8) in entorhinal cortex, however. These results demonstrate similar, but not identical, cholinergic modulation of synaptic transmission and plasticity in entorhinal cortex and hippocampus.

Influence of nitric oxide on transepithelial transport in toad skin: effects of cholinergic agents and morphine

The effects induced by l-arginine ( l-Arg) on the short-circuit current and potential difference of Pleurodema thaul skin were investigated. l-Arg, but not d-Arg significantly increased the short-circuit current and potential difference when applied to the serosal surface. The effects of l-Arg were antagonized by amiloride, N G-nitro-methyl- l-arginine ( l-NAME) and by methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of l-Arg and antagonized by l-NAME or methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of l-Arg and antagonized by l-NAME or methylene blue. Addition of dibutyryl cyclic guanosyl monophosphate (db cGMP) or dibutyryl cyclic adenosine monophosphate (db cAMP) increased short-circuit current and potential difference. The effects of db cGMP, but not those of db cAMP were antagonized by l-NAME. The consecutive application of db cGMP and db cAMP induced additive effects. These results suggest that l-Arg increases transport in toad skin presumably acting through the formation of nitric oxide, which then stimulates cytoplasmic guanylate cyclase and leads to increased Na + and K + transport. The effects of l-Arg and carbachol were antagonized by acute application of morphine; however, a rebound response was observed when carbachol or noradrenaline were given after prolonged exposure of the skin to morphine, which suggests an adaptive response of the skin involving both cGMP and cAMP. Responses to both nucleotides were unchanged by morphine.

Effects of cholinergic agents on locomotor activity of P and NP rats.

Experiments were undertaken to compare the selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines for differences in the locomotor activity (LMA) response to intracerebroventricular infusions of muscarinic- and nicotinic-cholinergic agents. Scopolamine, a nonselective muscarinic antagonist (40 to 120 micrograms/0.5 microliters), dose-dependently increased LMA in both P and NP rats (up to 90 to 100% above baseline; p < 0.05). On the other hand, pirenzepine, a selective M1 muscarinic antagonist (10 to 80 micrograms/0.5 microliters), decreased LMA in P and NP rats (as much as 35 to 40% below control values; p < 0.05). Mecamylamine, a nicotinic antagonist (20 to 80 micrograms/0.5 microliters), also decreased LMA in P and NP rats (as much as 30 to 40% below baseline; p < 0.05). The agonist nicotine (20 to 80 micrograms/0.5 microliters) dose-dependently decreased LMA in both P and NP rats (to a maximum of approximately 60 to 65% below control values; p < 0.05). Based on standardized z-scores, NP rats were more sensitive (p < 0.05) to the locomotor depressant effects of nicotine than P rats, whereas no differences were observed for standardized z-scores between the P and NP lines on the effects of scopolamine, pirenzepine, or mecamylamine on LMA. The results suggest that subtypes of muscarinic and nicotinic receptors are involved in regulating LMA in a complex manner, with the M1 subtype possibly mediating behavioral activation, and that P and NP rats may possess innate differences in CNS nicotinic receptors regulating LMA.

The effects of physostigmine and scopolamine on memory for food caches in the black-capped chickadee

The possible effects of anticholinesterases on the central nervous systems and, in particular, on learning and memory, have generated considerable interest. Food caching in the black-capped chickadee is an excellent natural paradigm of spatial working memory. Its susceptibility to cholinergically active drugs was explored in the present study. Our ultimate objective was to use food caching as a natural paradigm for the study of the consequences in birds of sublethal exposure to anticholinesterase insecticides. Biochemical analyses showed that administration of the anticholinesterase physostigmine (eserine) led to a short-lived effect, with recovery of brain cholinesterase levels already underway 5 min after an intramuscular injection. Birds administered the anticholinergic scopolamine before caching demonstrated significantly impaired recall compared to birds given physostigmine. Birds given saline only had an intermediate performance. Giving the drugs between caching and recovery had no measurable effect. These findings suggest that effects of cholinergic agents on cache recovery in chickadees are comparable to their effects in tests of working memory in mammals.

Stimulated pancreatic exocrine secretion does not require pancreatic hyperemia in rats

Although blood flow and cholinergic tone influence gastric and salivary gland secretion, their role in pancreatic secretion is poorly defined. The purpose of the present study was: (1) to test the hypothesis that an increase in pancreatic blood flow accompanies stimulated pancreatic exocrine secretion, and (2) to examine the effects of cholinergic agents on basal and stimulated blood flow using hydrogen gas clearance. Stimulated pancreatic exocrine secretion (secretin 0.4, 0.8, 1.6 micrograms/kg/hr) resulted in a significant (P < 0.005) increase in secretory volume; however, pancreatic blood flow was not significantly changed, and a negative correlation between blood flow and secretion was observed. A pharmacologic dose of secretin (5.0 micrograms/kg/hr) resulted in a significant (P < 0.05) increase in pancreatic blood flow, which was inhibited by atropine (5.0 micrograms/kg/hr) infusion. Although 2-deoxyglucose caused a significant decrease (P < 0.03) in basal pancreatic blood flow, atropine had no effect on basal blood flow levels. These observations suggest that: (1) under physiologic conditions, secretin- or 2-deoxyglucose-stimulated pancreatic secretion does not require pancreatic hyperemia; (2) a pharmacologic dose of secretin does produce pancreatic hyperemia, perhaps through a local cholinergic mechanism; (3) peripheral cholinergic tone does not contribute significantly to basal pancreatic blood flow; and (4) basal pancreatic blood flow may be influenced by central mechanisms.

Effects of Cholinergic Agents on the Metabolism of Choline in Muscle from Ascaris suum

The incorporation of [methyl-14C]choline into the choline-containing compounds of Ascaris suum muscle and the effects of acetylcholine and its agonists, carbachol and levamisole, on this incorporation were studied. Previous experiments reported a stimulation of phosphatidylcholine (lecithin) metabolism upon the administration of acetylcholine. Acetylcholine administered in vitro to A. suum muscle and body wall preparations resulted in a stimulation of phospholipase C activity that, in turn, produced an increased rate of hydrolysis of phosphatidylcholine to the corresponding diacylglyceride (DAG). The DAG, in turn, may act as a second messenger as it is required for the activation of an A. suum protein kinase C. Evidence presented here is in accordance with this hypothesis. The administration of cholinergics resulted in a stimulation of phosphatidylcholine turnover. Acetylcholine also stimulated isotope incorporation into glycerophosphorylcholine, presumably as a consequence of enhanced phospholipid turnover. These events appear to be associated with the ligand binding to the acetylcholine receptors of the A. suum muscle. Choline kinase activity is suggested in order to maintain the observed high ratio of phosphorylcholine to choline. Findings indicate that in the parasite's muscle phosphatidylcholine metabolism may be linked to receptor-dependent responses and subsequent signal transduction.

Cholinergic regulation of the phosphoinositide second messenger system in the guinea pig organ of Corti

The effect of cholinergic agents on the phosphoinositide second messenger system was investigated in the cochlea of the adult guinea pig in vivo and in vitro. In vivo, phospholipids were labeled with [ 32P]-orthophosphate by perilymphatic perfusion and their hydrolysis assayed in llschase’ experiments with non-radioactive orthophosphate. Carbachol (1 mM) reduced the content of 32P-labeled phosphatidylinositol 4,5-bisphosphate in the organ of Corti from 31% to 21% of total 32P-lipids, indicating stimulated hydrolysis. The pharmacology of this effect was studied in detail in vitro via the release of inositol phosphates from phosphoinositides pre-labeled with 3H-inositol. Release was increased 2-fold by 1 mM carbachol, 1.6-fold by 1 mM muscarine, but was unaffected by dimethylphenylpiperazinium; the stimulation was blocked by 1 μM atropine but not mecamylamine. These responses indicate the coupling of phosphoinositides to a muscarinic receptor. Furthermore. stimulated inositol phosphate release was higher in the base of the organ of Corti than in the apex which correlates with the increased cholinergic efferent innervation of outer hair cells in the basal region. These results suggest that muscarinic-stimulated inositol phosphate release occurs at the level of the outer hair cell and thus may have an important modulatory role in auditory transduction.

Cholinergic effect on rat proximal convoluted tubule

The effect of cholinergic agents on proximal tubular absorption of bicarbonate and fluid were examined to investigate the possible role of the cholinergic receptor in the regulation of renal function. Proximal convoluted tubule (PCT) and peritubular capillaries were perfused with bicarbonate-Ringer's solution containing radioactive inulin. Bicarbonate (total CO2) was determined by microcalorimetry. The rates of bicarbonate absorption (JHCO3) and fluid absorption (Jv) were 143.3 +/- 7.2 pEq/min.mm and 2.52 +/- 0.23 nl/min.mm, respectively. Addition of carbachol (10(-8) M) to the capillary perfusate reduced JHCO3 by 17% and Jv by 32%. A higher dose of carbachol (10(-6) M) did not further inhibit JHCO3 or Jv. Simultaneous perfusion of atropine (10(-5) M) together with carbachol (10(-8) M) abolished the inhibitory effect of carbachol on PCT transport. Atropine itself, however, had no effect on PCT transport. The inhibitory effect of carbachol was also diminished by lanthanum chloride (10(-4) M). Carbachol (10(-6) M) had no effects from the luminal side. W-7, a calmodulin antagonist, inhibited carbachol-induced effects. Ionophore A-23187 also inhibited Jv and JHCO3. However, there was no additive effect when A-23187 and carbachol were combined in the capillary perfusate. These results suggest that there are functional cholinergic receptors on the basolateral side of the PCT that can regulate JHCO3 and Jv. Calcium influx may play a role in mediating the cholinergic effects on PCT transport.

Acetylcholine is an indirect inhibitory transmitter in the canine ileocolonic junction

The effects of cholinergic agents, electrical stimulation and vasoactive intestinal polypeptide (VIP) were studied on transverse muscle strips of the canine ileum, ileocolonic junction and colon. Acetylcholine, methacholine and carbachol caused concentration-dependent contractions in the three gut tissues. Only acetylcholine (> 10 −5 M) evoked transient relaxations in the ileum and the ileocolonic junction before the onset of contractions. During contractions by noradrenaline, acetylcholine induced relaxations, which were enhanced by atropine; electrical stimulation also caused frequency-dependent relaxations. Propranolol or naloxone did not affect the relaxations. Hexamethonium, cocaine or lidocaine inhibited the relaxations induced by acetylcholine but not those evoked by electrical stimuli. Tetrodotoxin inhibited all relaxations. VIP did not evoke relaxation in the ileocolonic junction. These data indicate that acetylcholine stimulates nicotinic receptors on non-adrenergic non-cholinergic neurons, which do not release VIP or opioids. It is thus suggested that there is a nicotinic inhibitory innervation at the canine ileum and ileocolonic junction.

Effect of cholinergic agents on human spermatozoa motility

The effect of various cholinergic agents on human spermatozoa motility was studied. Both direct-acting (e.g., acetylcholine, pilocarpine) and indirect-acting (e.g., physostigmine) cholinergic agonists stimulated human spermatozoa motility. All the cholinergic antagonists (e.g., atropine, hyoscine, hexamethonium, d-tubocurarine, and succinylcholine) inhibited the spermatozoa motility. At 1 × 10 −4 m, muscarinic antagonists, atropine and hyoscine, did not influence motility, whereas nicotinic antagonists, hexamethonium, d-tubocurarine and succinylcholine, depressed motility. These observations suggest that a nicotinic-type receptor is present in spermatozoa. However, these studies did not exclude the possibility of the presence of a muscarinic receptor in spermatozoa.

Effects of nerve growth factor on the expression and post-translational processing of the beta-amyloid precursor proteins in PC12 cells

236 Alzheimer’s disease (AD) is characterized by extensive cholinergic denervation in both cortex and hippocampus. However, cholinergic therapies are of limited value. We investigated choline@ mechanisms in hippocampus which was denervated by a fimbriafomix lesion. Denervated pyramidal cells were found to be hypersensitive to carbachol, responding to a given dose with larger depolarizing currems and with a more pronounced blockade of the after-hyperpolarizing (AHP) current. Also, in denervated hippocampus, depolarization blockade was induced by lower concentrations of carbachol. In some cells this blockade could be reversed by addition of clonidine. It is suggested that treatment failure in AD is due to the induction of depolarization blockade and that combined treatment with a hyperpolarizing agent may enhance the therapeutic effects of cholinergic agents in this disease.

Theta in hippocampal slices: Relation to synaptic responses of dentate neurons

The effects of cholinergic agents on isolated dentate neurons were studied to characterize cellular mechanisms underlying carbachol-induced ‘theta’ EEG activity. Carbachol, eserine, and acetylcholine produced a synchronization of slow wave activity (theta) accompanied by depression of perforant path to dentate field potentials. These effects were antagonized by atropine but not d-tubocurarine. The results suggest that muscarinic receptors mediate theta activity resulting from a depolarization of dentate neurons.