Involvement Of Central Cholinergic Mechanisms Research Articles

Involvement of central cholinergic mechanisms on sodium intake induced by gabaergic activation of the lateral parabrachial nucleus

Bilateral injections of the GABAA agonist muscimol into the lateral parabrachial nucleus (LPBN) disrupt satiety and induce strong ingestion of water and 0.3M NaCl in fluid-replete rats by mechanisms not completely clear. In the present study, we investigated the effects of the blockade of central muscarinic cholinergic receptors with atropine injected intracerebroventricularly (i.c.v.) on 0.3M NaCl and water intake induced by muscimol injections into the LPBN in fluid-replete rats. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the LPBN and unilaterally into the lateral ventricle (LV) were used. Bilateral injections of muscimol (0.5nmol/0.2μL) into the LPBN induced 0.3M NaCl (32.2±9.9mL/4h, vs. saline: 0.4±0.2mL/4h) and water intake (11.4±4.4mL/4h, vs. saline: 0.8±0.4mL/4h) in fluid-replete rats previously treated with i.c.v. injection of saline. The previous i.c.v. injection of atropine (20nmol/1μL) reduced the effects of LPBN-muscimol on 0.3M NaCl (13.5±5.0mL/4h) and water intake (2.9±1.6mL/4h). The i.c.v. injection of atropine did not affect 0.3M NaCl (26.8±6.2mL/2h, vs. saline i.c.v.: 36.5±9.8mL/2h) or water intake (14.4±2.5mL/2h, vs. saline i.c.v.: 15.6±4.8mL/2h) in rats treated with furosemide+captopril subcutaneously combined with bilateral injections of moxonidine (α2-adrenoceptor/imidazoline agonist, 0.5nmol/0.2μL) into the LPBN, suggesting that the effect of atropine was not due to non-specific inhibition of ingestive behaviors. The results show that active central cholinergic mechanisms are necessary for the hypertonic NaCl and water intake induced by the blockade of the inhibitory mechanisms with injections of muscimol into the LPBN in fluid-replete rats. The suggestion is that in fluid-replete rats the action of LPBN mechanisms inhibits facilitatory signals produced by the activity of central cholinergic mechanisms to maintain satiety.

Involvement of Central Cholinergic Mechanisms in the Effects of Oxytocin and an Oxytocin Receptor Antagonist on Retention Performance in Mice

Oxytocin (OT, 0.10 μg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH2)5[Tyr(Me)2, Thr4, Thy-NH92] OVT (AOT, 0.30 μg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training–treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 μg/kg, sc) on retention were prevented by AOT (0.03 μg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, ip), but not its quaternary analogue neostigmine (150 μg/kg, ip), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, ip) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, ip), but not methylatropine (0.5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.

Involvement of central cholinergic mechanism in RU-24969-induced behavioral deficits

The present study was undertaken to investigate the role of cholinergic mechanisms in the behavioral effects of RU-24969, a compound with serotonin 1B (5-HT 1B) receptor agonist properties. RU-24969 caused an increase in locomotion (2−5 mg/kg IP) and an impairment of spontaneous alternation (SA) behavior in a T-maze (0.5−2.0 mg/kg IP) in mice, effects that were also induced by the cholinergic hypofunction with scopolamine treatment (0.5−5.0 mg/kg IP), an acetylcholine (ACh) receptor antagonist. The impairment of the SA behavior by RU-24969 was enhanced by scopolamine. Both the hyperlocomotion and the SA impairment by RU-24969 were markedly reduced by propranolol (20 mg/kg IP) which has 5-HT 1A/5-HT 1B receptor antagonist properties, as well as by physostigmine (0.05−0.2 mg/kg IP), an ACh esterase inhibitor, and oxotremorine (0.005−0.01 mg/kg IP), an ACh receptor agonist. Moreover, these behavioral deficits of RU-24969 were diminished in mice pretreated intracerebroventricularly with AF64A (30 nmol/body), a presynaptic cholinergic neurotoxin, whereas scopolamine induced the deficits even in animals with the same treatment. These results suggest that the serotonergic behavioral deficits observed after RU-24969 treatment may be caused by an inhibition of ACh release through its action on the presynaptic receptor (particularly RU-24969-sensitive sites) localized on the cholinergic terminals.

D1 agonist SKF 38393 antagonizes pentobarbital-induced narcosis and depression of hippocampal and cortical cholinergic activity in rats

SKF 38393 (5 mg/kg), but not quinpirole, shortened the duration of loss of righting reflex produced in pentobarbital-narcotized rats. This effect was blocked by atropine (2 mg/kg), but not by atropine methylbromide, suggesting involvement of central cholinergic mechanisms. The analeptic effect was also blocked by SCH 23390 (0.2 mg/kg) or raclopride (2 mg/kg). SKF 38393 also increased sodium dependent high affinity choline uptake (HACU) in cortical and hippocampal synaptosomes that had been depressed by pentobarbital. SCH 23390 or raclopride prevented the SKF 38393 reversal of the depressed HACU, indicating that both D1 and D2 mechanisms were involved mediating the analeptic effect. These results provide neurochemical evidence that cortical and hippocampal D1-mediated cholinergic activation results in a behavioral arousal (analeptic) response. They also suggest that DA mechanisms may be involved in regulation of cortical and hippocampal cholinergic neurons.

Plasma corticosterone is increased and correlated with brain acetylcholine in physostigmine- but not in neostigmine-treated rats

Rats were given intraperitoneal injections of physostigmine (PHYSO), neostigmine (NEO) or saline (SAL). Either 15 or 30 min later the number and intensity of observable cholinomimetic effects (OCE) was determined, plasma was collected for corticosterone (Cst) measurement, and the cerebral cortex, striatum, hippocampus and hypothalamus were removed after microwave treatment for the measurement of tissue acetylcholine (ACh) and choline (Ch) concentrations. Plasma Cst correlated with the number of OCEs at both 15 and 30 min in both NEO- and PHYSO-treated animals. Although the number and intensity of OCE were the same in NEO- and PHYSO-treated animals 15 min after injection, plasma Cst was significantly higher in the PHYSO-treated group. ACh levels in the cortex were also increased in PHYSO- compared with NEO-treated animals 15 min after injection. Ch levels remained unchanged. Plasma Cst correlated positively with ACh levels in the cortex and striatum in PHYSO-treated rats both 15 and 30 min after injection. These data support the involvement of central cholinergic mechanisms in the regulation of the HPA axis.

Differential involvement of central cholinergic mechanisms in the aversive stimulus properties of morphine and amphetamine.

Previously, it was reported that pretreatment with the centrally-acting cholinergic antagonist atropine, but not the peripherally-acting antagonist, methyl-atropine, may serve to attenuate the positive reinforcing properties of morphine and conversely, to enhance those of amphetamine as evidenced within a drug self-administration paradigm in rats. In parallel, evidence from several sources would suggest that there may be a functional relationship between the neurochemical mechanisms mediating these drugs' positive reinforcing properties and their seemingly paradoxical capacity to act as aversive stimuli, as evidenced within a conditioned taste aversion (CTA) paradigm. Accordingly, the present study undertook to examine whether a similar differential involvement of central cholinergic mechanisms established for these drugs' positive reinforcing effects may be obtained for morphine and amphetamine-induced CTA. Using a conventional CTA paradigm, animals were pretreated with either intraperitoneal (IP) atropine or methyl-atropine (0.6 mg/kg) 40 minutes prior to consuming a novel 0.1% saccharin solution. This taste stimulus was paired with IP injection of 15 mg/kg morphine or vehicle. Results showed that atropine (but not methyl-atropine) pretreatment served to attenuate the morphine CTA. In a second experiment, atropine-pretreatment failed to attenuate, and may have slightly potentiated, a CTA induced by 1 mg/kg amphetamine. Atropine pretreatment did not affect a CTA induced by the emetic agent, lithium chloride. Pretreatment with the peripherally-acting methyl-atropine had no effect on the amphetamine CTA and served, if anything, to slightly attenuate the lithium chloride CTA.(ABSTRACT TRUNCATED AT 250 WORDS)

COMPARISON OF THE EFFECTS OF ATROPINE AND GLYCOPYRROLATE ON COGNITIVE FUNCTION FOLLOWING GENERAL ANAESTHESIA

Tests of orientation, concentration and short-term visual memory were used to assess 72 patients 1 day before, and 2 days after, elective major surgery. Patients were premedicated with papaveretum and either atropine or glycopyrrolate, before receiving a standard general anaesthetic. Those who had received atropine showed significant postoperative short-term memory deficit (P less than 0.01), but no change in orientation or concentration. Those who had been given glycopyrrolate showed no significant cognitive changes after surgery. As glycopyrrolate does not cross the blood-brain barrier freely, these findings support the involvement of central cholinergic mechanisms in the deterioration of cognitive function in the postoperative period.

The involvement of central cholinergic mechanisms in cardiovascular responses to intracerebroventricular and intravenous administration of thyrotropin-releasing hormone

Intracerebroventricular (i.c.v.) administration of thyrotropin-releasing hormone (TRH) in a range from 0.1 to 100 μg induced a dose-related increase in blood pressure in conscious rats, whereas TRH-free acid (TRH-OH) and histidyl-proline diketopiperazine (His-Pro-DKP), metabolites of TRH, did not. The blood pressure responses to intravenous (i.v.) injection of 5mg/Kg TRH were similar to those induced by TRH (i.c.v.). Pretreatment with atropine (50 μg, i.c.v.) significantly reduced the pressor effect of TRH administered through either route. Hemicholinium-3 (50 μg, i.c.v.), an inhibitor of choline uptake, also prevented the increase in blood pressure induced by TRH (10 μg, i.c.v.). These results indicate that both centrally and peripherally administered TRH have pressor effects that are mediated by central cholinergic mechanisms, probably by activating cholinergic neurons.

O-75 - Involvement of central cholinergic mechanism in serotonergic behavioral deficits

O-75 - Involvement of central cholinergic mechanism in serotonergic behavioral deficits

Effect of gonadal hormones on luteinizing hormone in plasma and on choline acetyltransferase activity and acetylcholine levels in discrete nuclei of the rat brain.

In order to assess the possible involvement of central cholinergic mechanisms in the feedback actions of gonadal hormones, the activity of choline acetyltransferase (ChAT) and the concentration of acetylcholine (ACh) were measured in microdissected brain nuclei of male and female rats after castration and gonadal hormone replacement. Castration of male rats significantly elevated plasma levels of LH and also increased ChAT activity and ACh level in the medial preoptic nucleus. Castration also increased ChAT activity but not ACh concentration in the posteromedial amygdala. In the rostral part of the nucleus tractus diagonalis and in the ventral tegmental area. ACh concentrations were elevated by castration, but ChAT activity was unaffected. Daily administration of testosterone propionate (TP) to castrated males attenuated the postcastration rise of plasma LH and also partially prevented the increases of ACh in the medial preoptic and rostral tractus diagonalis nuclei and of ChAT in the posteromedial amygdala. In addition, TP treatment significantly decreased ChAT acivity in the rostral nucleus tractus diagonalis. Treatment of ovariectomized female rats with estradiol benzoate lowered plasma levels of LH, but did not affect cholinergic parameters. Administration of progesterone to estrogen-primed females produced a surge in plasma LH and decreased the activity of ChAT and the concentration of ACh in the periventricular nucleus. Such treatment also reduced ChAT activity in the caudal nucleus tractus diagonalis and decreased ACh levels in the ventral tegmental area. The combined estradiol/progesterone treatment elevated ChAT activity in the supraoptic nucleus. These results demonstrate that cholinergic activity in several discrete brain regions known to be targets for testicular and ovarian hormones is altered by gonadectomy and gonadal hormone treatment and suggest involvement of cholinergic systems in the feedback effects of estadiol, progesterone and testosterone.

Involvement of central cholinoceptors in Metrazol-induced convulsions.

Atropine sulphate (10 mg/kg IP) afforded 90% protection against clonic convulsions induced by standard doses of metrazol (80 mg/kg SC) in mice, whereas atropine methonitrate (10 mg/kg IP) did not offer any protection. Furthermore, physostigmine (1 mg/kg IP) caused recurrence of convulsions in atropinzed metrazol-treated mice and converted the subconvulsive dose of metrazol (40 mg/kg SC) into a 100% convulsive dose. However, neostigmine (1 mg/kg IP) did not antagonize the protection afforded by atropine sulphate against metrazol. The results of the study suggest an involvement of central cholinergic mechanisms in metrazol-induced convulsions.

Neurochemical correlates of alcohol preference in inbred strains of mice

C 5 7 B1 6 J , a specific inbred strain of mice with high alcohol preference and DBA/2J, a specific inbred strain with poor preference for alcohol were studied. Brain content of acetylcholine, uptake of 14C-Choline by whole brain homogenate were significantly higher in the C 5 7 B1 6 J mice whereas brain acetylcholinesterase was higher in the DBA/2J mice. No significant difference was found for the level of brain serotonin, uptake of 3H-norepinephrine or 3H-dopamine. Treatment with a specific inhibitor of choline transferase, 4-(1-napthylvinyl) pyridine salt (10 mg/kg, twice daily) shifted the selection of alcohol to water in the C 5 7 B1 6 J mice. These findings suggest a direct involvement of central cholinergic mechanism in alcohol preference.