CARDIOVASCULAR RESPONSES ELICITED BY MICROINJECTION OF CHOLINERGIC AGENTS INTO NUCLEUS DORSALIS RAPHE IN CATS

The effect of cholinomimetics and cholinoceptor blocking agents microinjected into nucleus dorsalis raphe (NDR) has been studied on heart rate and blood pressure to identify the nature and role of these cholinoceptors in cardiovascular regulation. Microinjection of the cholinoceptor agonists, pilocarpine and carbachol into NDR elicited bradycardia and hypotension accompanied by salivation which could be blocked by local pretreatment with ethybenztropine (a muscarinic receptor blocker), but not by chlorisondamine (a nicotinic receptor blocker). Pretreatment with atropine methylnitrate (i.v.), which blocks only peripheral muscarinic receptors, did not prevent these cardiovascular responses evoked by carbachol microinjection. These cholinergic receptors seem to be localized in NDR since, microinjection of carbachol into neural structures adjoining NDR, failed to induce any cardiovascular responses. Muscarinic cholinoceptors are present in NDR which modulate cardiovascular activity by influencing sympathetic preganglionic neurons in the intermediolateral columns of the spinal cord.     

Interrelation between monoaminergic and cholinergic mechanisms in the hypothalamic thermoregulatory centre of rabbits

The intracerebroventricular injection of acetylcholine, carbachol and physostigmine induced hyperthermia in rabbits while muscarinic agents, pilocarpine and oxotremorine produce a biphasic thermal response consisting of an immediate hyperthermia followed by a delayed hypothermia. An involvement of central nicotinic receptors in the acetylcholine-induced hyperthermia is suggested, since it is blocked by intracerebroventricular pretreatment with chlorisondamine and (+)-tubocurarine and not by atropinization. On the other hand, stimulation of central muscarinic receptors in the hypothalamus are concerned in the delayed hypothermia induced by pilocarpine as it is blocked by prior central atropinization. Intracerebroventricular injection of catecholamines, viz. noradrenaline, adrenaline and dopamine, results in a hyperthermic response due to activation of α-adrenoceptors in the hypothalamus, since norepinephrine hyperthermia is blocked by intracerebroventricular pretreatment with phenoxybenzamine and not by propranolol. Furthermore, a blockade of norepinephrine hyperthermia by pretreatment with chlorisondamine and not by prior atropinization suggests that the activation of central α-adrenoceptors in turn stimulates the cholinergic system which is nicotinic in nature. On the contrary, intracerebroventricular 5-hydroxytryptophan and 5-hydroxytryptamine caused hypothermia which is due to an activation of central muscarinic receptors since it is found to be blocked by prior intracerebroventricular administration of ethybenztropine and not by chlorisondamine pretreatment. On the basis of these observations, an interaction between adrenergic and nicotinic mechanisms as well as between tryptaminergic and muscarinic systems is suggested in the hypothalamic thermoregulation in rabbits for the hyperthermic and hypothermie responses, respectively.     

Central adrenoceptors and cholinoceptors in cardiovascular control.

1. In cats anaesthetized with chloralose, adrenoceptor and cholinoceptor agonists and antagonists were localized to the posterior hypothalamus (PH), lateral medullary pressor area (LMPA) and spinal autonomic loci to delineate the role of central cholinoceptors and adrenoceptors in cardiovascular control. 2 All along the neuroaxis, the alpha-adrenoceptors seem to subserve an inhibitory and the beta-adrenoceptors a facilitatory role in cardiovascular control. There appear to be a predominance of alpha-adrenoceptors at the medullary level and beta-adrenoceptors at the hypothalamic level. 3 The nicotinic cholinoceptors at the hypothalamic, medullary and spinal levels were facilitatory, whereas muscarinic cholinoceptors were inhibitory for cardiovascular control. However, muscarinic receptors were undetectable at the posterior hypothalamus. 4 The central cardiovascular effects of nicotine are attributed to nicotinic receptor activation and release of central catecholamines. 5 There appears to be a relationship between central cholinergic and adrenergic mechanisms in cardiovascular control.     

Effect of dithiothreitol on agonist and antagonist actions in frog muscle

The effects of the disulphide bond reducing agent dithiothreitol (DTT) in the frog rectus abdominis preparation have been investigated. DTT, 1 mM, reduced the potency of the monoquaternary agonists acetylcholine, carbachol and tetramethylammonium and the response to electrical field stimulation; the same applied to nicotine, but the action of edrophonium was unaffected and that of the bisquaternary agonist, decamethonium, was increased. The potency of tubocurarine and gallamine as antagonists was unaltered or slightly reduced by DTT when monoquaternary agonists were used and increased when decamethonium was used as agonist. All these effects of DTT were reversed by the oxidizing agent 5-5'dithiobis(2-nitrobenzoic acid) and can be explained by a reduction of a disulphide bond in the vicinity of the anionic site of the nicotinic cholinoceptor. Comparison between these results and published data indicate that there are species differences between nicotinic cholinoceptors and motor endplates. In the guinea-pig ileum preparation DTT reduced the potency of nicotine acting at ganglionic nicotinic cholinoceptors, but had no effect on the agonist response mediated via muscarinic cholinoceptors.     

Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

Intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP), induced hyperthermia in guinea-pigs which was not mediated through prostaglandins (PG) or norepinephrine since a prostaglandin synthesis inhibitor, indomethacin, and an alpha-adrenergic receptor blocking agent, phenoxybenzamine did not antagonize the hyperthermia. In contrast, the hyperthermic response to dibutyryl cyclic AMP was attenuated by central administration of a beta-adrenergic receptor antagonist, sotalol, indicating that cyclic AMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production/conservation. Central administration of dibutyryl cyclic GMP (Db-cGMP) produced hypothermia which was not mediated via histamine H1- or H2-receptors and serotonin since the H1-receptor antagonist, mepyramine, the H2-receptor antagonist, cimetidine, and the serotonin antagonist, methysergide, had no antagonistic effects. The antagonism of hypothermia induced by dibutyryl cyclic GMP and acetylcholine + physostigmine, by central administration of a cholinergic muscarinic receptor antagonist, atropine, and not by a cholinergic nicotinic receptor antagonist, d-tubocurarine, suggests that cholinoceptive neurons and endogenous cyclic GMP may regulate heat loss through cholinergic muscarinic receptors. These results support a regulatory role in thermoregulation provided by a balance between opposing actions of cyclic AMP and cyclic GMP in guinea-pigs.     

Participation of cytoskeleton in the effect of antilaminin IgG on cardiac cholinoceptors.

1. We have previously demonstrated a molecular relationship between laminin and cardiac cholinoceptors. 2. We have now explored the participation of cytoskeletal proteins in the interaction between an antilaminin IgG with cardiac cholinoceptors. 3. Antilaminin IgG, whilst it specifically reacts with laminin molecules was able to induce cardiac cholinoceptor activation; acting like an agonist, decreasing cyclic AMP concentrations, reducing heart contractility and increasing phosphoinositide turnover. 4. Antilaminin IgG also interfered with the binding of a radiolabelled muscarinic antagonist, [3H]-quinuclidinyl benzilate. Colchicine and cytochalasin B, drugs that are able to prevent microfilament and microtubule polimerization, impaired the binding of antilaminin IgG to muscarinic cholinoceptors. 5. Cytochalasin B but not colchicine modified the muscarinic cholinoceptor effects mediated by regulatory G proteins (cyclic AMP and contractility) induced by antilaminin IgG. 6. It was demonstrated, by immunofluorescence, that none of these disrupting drugs altered the specific recognition of the antibody by its antigen. 7. These data indirectly suggest the participation of the cytoskeleton in the laminin and cholinergic receptor association.     

Effects of locally and systemically administered cholinoceptor antagonists on the secretory response of human eccrine sweat glands to carbachol.

Eleven healthy male volunteers participated in a study comparing the effects of locally and systemically administered cholinoceptor antagonists on the secretory response of sweat glands to intradermally injected carbachol chloride. Atropine sulphate administered locally into the skin antagonised the response to carbachol: the dose-response curve for carbachol was shifted to the right without any depression of the maximum of the curve. The nicotinic receptor antagonists hexamethonium bromide and (+)-tubocurarine chloride, however, had little effect on the response to carbachol. Atropine sulphate, administered systemically by intramuscular injection, caused a non-surmountable antagonism of the response to carbachol: the maximum of the dose-response curve was depressed with little change in the value of ED50. Atropine methonitrate (a mixed muscarinic/nicotinic receptor antagonist), and hexamethonium bromide (a nicotinic receptor antagonist), both with poor access to the central nervous system, were injected intramuscularly: both caused non-surmountable antagonism of the response to carbachol. It is concluded that the response to carbachol is mediated by muscarinic rather than nicotinic receptors. The effect of atropine sulphate on the response to carbachol depends on the route of administration: while locally applied atropine sulphate appears to act as a competitive antagonist, systemically applied atropine sulphate, like atropine methonitrate and hexamethonium bromide, appears to act in a non-competitive manner. It is suggested that the systemically administered cholinoceptor antagonists reduce the response to carbachol by interacting with cholinoceptors in sympathetic ganglia: such an interaction would reduce the impulse flow in sudomotor fibres resulting in decreased sensitivity of the sweat glands to carbachol.     

Effects of alpha(1)-adrenoceptors and muscarinic cholinoceptors on water intake in rats

The present study investigated the effects of alpha(1)-adrenoceptors and muscarinic cholinoceptors on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24-h deprivation of water. After deprivation, the volume of consumed water was measured for 1 h. Administration of pilocarpine, a muscarinic cholinoceptor agonist (0.5-1 microg/rat), and prazosin, the alpha(1)-adrenoceptors antagonist (2 microg/rat), increased, while scopolamine, a muscarinic cholinoceptor antagonist (5-10 microg/rat), and phenylephrine, an alpha(1)-adrenoceptor agonist (30 microg/rat), decreased water intake in rats. The activation of muscarinic cholinoceptors by pilocarpine attenuated the inhibitory effect induced by phenylephrine. Blockade of muscarinic cholinoceptors did not change the phenylephrine-induced response. Pretreatment with prazosin decreased the pilocarpine-induced response. However, pharmacological blockade of muscarinic cholinoceptors by scopolamine decreased the prazosin-induced effect on water intake. It is concluded that muscarinic cholinoceptors and alpha(1)-adrenoceptors may interact on water intake.     

Central muscarinic M2 cholinoceptors involved in cholinergic hypertension

Cholinomimetic agents increase blood pressure and heart rate via central muscarinic cholinoceptors in various aspects. It was reported that i.c.v. injection of the muscarinic M₁ and M₃ cholinoceptor selective antagonist, 4-DAMP (4-diphenylacetoxy-N-methyl-piperidine methiodide, inhibited the pressor response to physostigmine, while the M₁ selective antagonist, pirenzepine, was ineffective. In the present study, the involvement of muscarinic M₂ cholinoceptors in central cholinergic hypertension and tachycardia was investigated. Physostigmine (10–80 μg/kg i.v.), a cholinesterase inhibitor, and oxotremorine (20–40 μg/kg i.v.), a direct muscarinic cholinoceptor agonist, caused a dose-dependent increase in blood pressure. Additionally, physostigmine induced dose-dependent tachycardiac responses. I.c.v. administration of the muscarinic M₂ cholinoceptor antagonists, AF-DX 116 and methoctramine, inhibited both physostigmine (60 μg/kg) and oxotremorine (20 μg/kg)-induced pressor responses at their lower doses used in this study (100 nmol/rat and 10 nmol/rat, respectively). These findings indicate the partial involvement of postsynaptic muscarinic M₂ cholinoceptors. The higher doses of the antagonists (AF-DX 116 300 nmol/rat and methoctramine 30 nmol/rat) potentiated the blood pressure increase due to physostigmine but did not affect that due to oxotremorine. The physostigmine-induced tachycardiac responses were influenced similarly by these antagonists. These results suggest the presence and tonic influence of presynaptic inhibitory muscarinic M₂ cholinoceptors.     

Muscarinic cholinoceptor subtypes mediating tracheal smooth muscle contraction and inositol phosphate generation in guinea pig and rat.

The effects of the muscarinic cholinoceptor antagonists atropine (non-selective), pirenzepine (M1-selective), methoctramine (M2-selective) and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; M3-selective) were examined on the responsiveness of guinea pig and rat tracheal tissue to acetylcholine and carbachol. Results indicate that smooth muscle contraction in isolated tracheal tissue from both species was mediated primarily by muscarinic M3 cholinoceptors. The effects of atropine, pirenzepine and 4-DAMP were similar against the contractile actions of acetylcholine and carbachol in both species and in epithelium-intact and epithelium-denuded tissue. In contrast, differences in the effects of methoctramine in antagonising contractile responses to acetylcholine and carbachol were observed between the two species and following epithelium removal in the guinea pig. Thus, whilst this study has found that tracheal smooth muscle contraction in the guinea pig and rat is mediated primarily by muscarinic M3 cholinoceptors, anomalies in the functional inositol phosphate generation results obtained with the muscarinic cholinoceptor antagonists highlight species differences in the actions of acetylcholine and carbachol in eliciting smooth muscle contraction suggesting the possible existence of functional non-M3 muscarinic cholinoceptors.     

Newly synthesized alpha 1-adrenoceptor blockers (SM911 and SM2470) and characterization of alpha-adrenoceptors in rat aortic strips, rat vas deferens preparations and rabbit aortic strips

Alpha 1-adrenergic potencies of SM911 and SM2470, whose chemical structures are similar to that of prazosin, a selective alpha 1-adrenoceptor blocker, were tested in rabbit aortic strips, rat aortic strips and rat vas deferens preparations. SM2470 was as potent as prazosin in alpha 1-adrenoceptor blocking effects, though SM911 was 0.5-0.1 as potent as prazosin. The pA2-values for prazosin, SM911 and SM2470 were approximately one order of magnitude lower in rabbit aortic strips and rat vas deferens preparations than in rat aortic strips, suggesting that alpha 1-adrenoceptors in these tissues may not be identical. SM911 and SM2470 as well as prazosin did not interact with alpha 2- and beta-adrenoceptors, muscarinic and nicotinic cholinoceptors, and histamine and serotonin receptors in doses up to 10(-5) M.     

The role of nicotinic and muscarinic acetylcholine receptors in attention

Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing. Received: 21 March 1999 / Final version: 3 August 1999     

Muscarinic cholinoceptors in the rabbit's myometrium: a study of the relationship between binding and response

The relationship between [3H](-)-quinuclinidyl benzilate [( 3H](-)QNB) binding and muscarinic cholinoceptors in the myometrium of the oestrogen treated rabbit was studied. [3H](-)QNB binding was specific, saturable and reversible. The ability of muscarinic agonists and antagonists and some of their stereoisomers to inhibit [3H](-)QNB binding and to stimulate or inhibit contraction of the myometrium were almost identical suggesting that [3H](-)QNB binds specifically to the muscarinic cholinoceptor in this tissue. There appeared to be no receptor reserve in this tissue and whilst structural and stereospecific requirements for binding were almost identical to those for the muscarinic cholinoceptor in the guinea pig ileum requirements for activation were not. Competition binding experiments with pirenzepine suggested that antagonist binding sites were heterogeneous whilst those with 4-diphenylacetoxy-N-methyl-piperidine MeBr did not. Results were discussed with regard to simple and complex models of muscarinic cholinoceptor interactions.     

Endogenous calcitonin gene-related peptide (CGRP) mediates adrenergic-dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat

1. The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. 2. Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. 3. In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1 - 100 microM) for 1 min caused a concentration-dependent vasodilator response without vasoconstriction. 4. The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 microM) and blocked by guanethidine (adrenergic neuron blocker, 5 microM). 5. Either denervation by cold storage (4 degrees C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. 6. Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml(-1), for 30 s) nor treatment with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor, 100 microM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (beta-adrenoceptor antagonist, 100 nM) affected the nicotine-induced vasodilation. 7. In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 microM) or human CGRP[8 - 37] (CGRP receptor antagonist, 0.5 microM) markedly inhibited the nicotine-induced vasodilation. 8. These results suggest that, in the mesenteric resistanc artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve.     

A1 adenosine receptors and muscarinic cholinoceptors in myocardial ischemia

The regulation of cardiac A₁ adenosine receptors and M₂ muscarinic cholinoceptors was investigated in ischemic rat hearts. Ischemia was induced in isolated, perfused hearts either by stop (stop-flow) or by reduction (low-flow) of perfusion flow. Receptor densities and affinities were determined by radioligand binding. The mRNA concentrations of the receptors and of control messages were measured by quantitative polymerase chain reactions (PCR). Second messenger coupling of the receptors was evaluated by measuring their inhibition of adenylate cyclase activity.Up to 60 min of stop-flow ischemia and 6 h of lowflow ischemia, cardiac A₁ adenosine receptor density and affinity, and adenosine receptor-mediated inhibition of adenylate cyclase, did not change significantly, compared to non-ischemic hearts. Receptor down-regulation, however, could be induced by perfusion with the A₁ receptor agonist R-phenyl-isopropyl-adenosine (R-PIA) during normal flow. After 6 h of perfusion with R-PIA (0.1 mol/l), A₁ adenosine receptor density was reduced. Agonist-induced receptor down-regulation was not found after perfusion with R-PIA in low-flow ischemia. The density and the affinity of muscarinic cholinoceptors were not affected during stop-flow ischemia up to 1 h either, whereas the density was down-regulated to 75% of controls (P<0.05) after 6 h of low-flow ischemia. This intervention also reduced inhibition of adenylate cyclase via muscarinic cholinoceptors. In non-ischemic hearts, perfusion with carbachol (10 µmol/l) suppressed receptor densities to 72% of control values.No significant changes in the concentration of A₁ adenosine receptor or M₂ cholinoceptor mRNAs occurred during normal flow, stop-flow and low-flow ischemia. Likewise, agonist stimulation with R-PIA or carbachol during normal flow did not change the respective receptor mRNA concentrations significantly. Conclusion: Although a down-regulation of A₁ adenosine receptor density was demonstrated after receptor agonist perfusion with normal flow, adenosine did not affect the density or functional activity of cardiac A₁ adenosine receptors in the ischemic myocardium. In contrast, muscarinic cholinoceptor density and function was down-regulated after prolonged ischemia. The lack of an agonist-induced down-regulation of A₁ adenosine receptors in the presence of decreasing activity of m-cholinoceptors suggests a growing importance of the adenosine system in myocardial ischemia.     

Nicotinic receptors modulating somatodendritic and terminal dopamine release differ pharmacologically

Ascending dopaminergic and noradrenergic neurons possess somatodendritic and terminal nicotinic cholinoceptors in the rat. Each neuronal population expresses mRNA for several types of nicotinic cholinoceptor subunit, including alpha6 and beta3. In superfused rat striatal synaptosomes, epibatidine evoked release of [3H]dopamine with similar efficacy to ACh, whereas nicotine and cytisine were weaker (70+/-6% and 58+/-6%, respectively). The four agonists were equi-efficacious in evoking [3H]noradrenaline release from hippocampal synaptosomes. Nicotine-evoked synaptosomal release was tetrodotoxin-insensitive. Somatodendritic nicotinic cholinoceptors on dopaminergic neurons were studied using a dendrosomal [3H]dopamine release assay and also in locomotor activity tests. In both assays, nicotine appeared more efficacious than epibatidine. Furthermore, with repeated nicotine exposure, the acute locomotor stimulant response to nicotine increased, whereas the epibatidine response became undetectable. In conclusion, somatodendritic nicotinic cholinoceptors located on dopaminergic neurons appear to differ pharmacologically from those on striatal dopaminergic terminals and hippocampal noradrenergic terminals.     

Cholinergic effects on spike-density and burst-duration of medullary respiration-related neurones in the rabbit: an iontophoretic study

Cholinoceptive properties of 180 medullary respiration-related neurones (RRN) were studied in urethane-anaesthetized rabbits. Acetylcholine (ACh) and agonists, as well as antagonists of muscarinic receptors and nicotinic receptors, were administered iontophoretically. Respiration-related neurons were classified with respect to the correlation of their activity with the activity of the phrenic nerve: phase-bound inspiratory (I) and expiratory (E) neurones and phase-spanning expiratory-inspiratory and inspiratory-expiratory neurones were discriminated. Acetylcholine altered the activity of 170 respiration-related neurones. In 49 cells the discharge-rate (f) alone was affected. In 44 respiration-related neurones the burst-duration (tbd) only was altered. In 77 respiration-related neurones the discharge rate and burst duration were affected simultaneously. Inhibitory actions of ACh prevailed over excitatory actions on inspiratory neurones. In expiratory neurones the discharge rate was increased or decreased in about the same number of cases. In most phase-spanning neurones the discharge rate was increased. Cholinergic inhibition of burst duration was observed in most respiration-related neurones. In all phase-types of respiration-related neurones muscarinic as well as nicotinic actions of ACh were demonstrated. In inspiratory and expiratory-inspiratory neurones muscarinic effects on the discharge rate prevailed over nicotinic effects. More nicotinic than muscarinic effects on discharge rate were observed in expiratory and inspiratory-expiratory neurones. Cholinergic effects on burst duration in about the same number of respiration-related neurones were mediated by muscarinic or by nicotinic receptors, respectively. Various types of cholinoceptors may be involved in these effects. The results suggest that cholinergic mechanisms play an important role in the control of the central regulation of respiratory movements. The functional significance of cholinergic effects on respiration-related neurones is discussed with special emphasis of effects on burst duration.     

Involvement of M1-muscarinic receptors in the excitation of neocortical neurones by acetylcholine

The technique of microelectrophoresis was used to investigate the cholinoceptor pharmacology of spontaneously active single neurones in the parietal cortex of the rat. Acetylcholine, carbachol and the selective M1-muscarinic receptor agonist, McN-A-343, were each potent excitants (rank order of apparent potency: carbachol greater than acetylcholine greater than McN-A-343). When measured in vitro, the apparent mobilities of carbachol and acetylcholine were similar although significantly less than that of McN-A-343, suggesting that the lower potencies of acetylcholine and McN-A-343 probably reflect a genuine biological phenomenon. In addition to excitation, carbachol also evoked biphasic (excitation/depression) and depressant responses. In contrast to the other cholinoceptor agonists, nicotine produced weak and inconsistent excitations. Excitatory responses to acetylcholine and carbachol were significantly attenuated by the selective M1-muscarinic receptor antagonist, pirenzepine, at a time when the excitatory response to McN-A-343 was also significantly reduced. Responses to phenylephrine were not diminished. On several cells an excitatory response to carbachol was converted to a depression by pirenzepine. These results suggest that the excitatory responses of cortical neurones to cholinoceptor agonists are mediated predominantly by M1-muscarinic receptors. The identity of the receptor mediating the depressant response to carbachol remains uncertain, although nicotinic cholinoceptors do not appear to be involved.     

NICOTINIC AGONIST MODULATION OF FELINE BRONCHOMOTOR TONE

1. The bronchomotor actions of three nicotinic cholinoceptor agonists were investigated in anaesthetized, mechanically ventilated cats. The agonists were administered intravenously after increasing baseline airways smooth muscle tone with an infusion of 5-hydroxytryptamine. 2. Acetylcholine induced a biphasic change in lung resistance, characterized by initial bronchoconstriction followed by bronchodilation. The specific nicotinic cholinoceptor agonists, nicotine and dimethylphenylpiperazinium (DMPP), principally induced bronchodilator responses, although initial bronchoconstrictor phases were observed occasionally. 3. All bronchoconstrictor phases were sensitive to muscarinic cholinoceptor blockage with atropine. DMPP-induced bronchodilator responses were adrenergic in nature, whereas those induced by either nicotine or acetylcholine resulted from a combination of adrenergic and non-adrenergic influences. 4. It is concluded that intravenously administered nicotinic cholinoceptor agonists exert varying actions on feline bronchomotor tone and that these actions result from activation of different autonomic inputs.     

Potentiation of morphine hyperthermia in cats by pimozide and fluoxetine hydrochloride

Administration of morphine sulfate (1--4 mg/kg i.v.) to cats produces changes in body temperature, with hyperthermia appearing with larger doses. Since the central neurotransmitters dopamine and serotonin have been implicated in thermoregulation, studies were done to determine whether morphine's action could be mediated via these transmitters. Temperature responses were measured in freely moving cats by means of rectal thermometer probes. Either pimozide, 0.5 mg/kg i.p., a specific DA receptor blocker, or fluoxetine HCl, 10 mg/kg i.p., a specific inhibitor of 5-HT uptake, was administered 2--3 h prior to morphine injection. Temperatures were monitored for 3.5 h after morphine administration. Both agents were found to enhance the hyperthermic response to morphine with the maximum morphine effect occurring in most cases by 2 h. The results indicate that a balance in the ratio of 5-HT : DA may be involved in cat thermoregulation and that the hyperthermic response in the cat to morphine may be effected by shifting this 5-HT : DA ratio.