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Biomedical subjects

A J Gower

Publications and source records attributed to A J Gower.

33 records · Page 2Linked to original sources
PubMed1987

Effects of acetylcholine agonists and antagonists on yawning and analgesia in the rat.

The ability of acetylcholine muscarinic agonists, injected subcutaneously (s.c.) to elicit yawning and analgesia (tail-flick response) in rats was examined. Yawning was elicited by physostigmine, RS86 and pilocarpine with an inverted 'U'-shaped dose-response relationship; maximal effects occurred at 0.1, 0.5 and 2.0 mg/kg respectively. Neostigmine (0.05-0.2 mg/kg); arecoline (0.5-2.0 mg/kg); bethanecol (0.1-10 mg/kg) and McN-A-343 (5-20 mg/kg) had marginal or no activity. In contrast, dose-related analgesia was obtained following oxotremorine (0.01-0.3 mg/kg) and arecoline (0.5-4.0 mg/kg) and physostigmine (0.1-0.4 mg/kg), RS86 (0.25-2.5 mg/kg) and pilocarpine (0.5-8.0 mg/kg). The effects of acetylcholine antagonists on physostigmine-induced yawning and physostigmine-induced analgesia were also investigated. Following their s.c. injection, trihexyphenidyl, atropine, dicyclomine, secoverine and methylatropine but not pirenzepine, inhibited both yawning and analgesia; there were clear differences in their potencies on the two responses. Pirenzepine, intracerebroventricularly (i.c.v.), inhibited yawning (ED50 value 5.7 micrograms/rat) but not analgesia (3-100 micrograms/rat). The results are discussed in terms of a possible functional differentiation of central muscarinic receptors.

Acetylcholine↗
PubMed1987

Enhancement by secoverine and physostigmine of retention of passive avoidance response in mice.

A one-trial passive avoidance test in the mouse, in which drugs were injected intraperitoneally immediately after the shocked acquisition trial, was used. The effects of enhancing central cholinergic transmission on retention of passive avoidance was investigated using secoverine, which blocks muscarinic autoreceptor-mediated inhibition of acetylcholine release, and using physostigmine, an acetylcholinesterase inhibitor. Secoverine (1.0-5.0 mg/kg) and physostigmine (0.1-0.4 mg/kg) were found to improve retention of the avoidance response measured 24 h after acquisition. These effects were augmented when the two drugs were given in combination. In contrast, atropine (5.0 mg/kg) tended to impair retention of passive avoidance and blocked the facilitatory effects of physostigmine. The results support the hypothesis of a novel approach to treatment of memory disorders based on blockade of muscarinic autoreceptors, to augment central cholinergic activity.

Animals↗
PubMed1986

Antagonism of drug-induced yawning and penile erections in rats.

A number of centrally active drugs were tested for antagonism of physostigmine- or apomorphine-induced yawning and for apomorphine-induced penile erections. The alpha 2-adrenoceptor antagonists piperoxan and idazoxan inhibited the yawning response without affecting the penile erections. The 5HT agonist quipazine and the histamine antagonist dexchlorpheniramine inhibited the yawning response more effectively than the penile erections. Dexchlorpheniramine even enhanced the apomorphine-induced penile erections and induced penile erections in physostigmine-treated rats. The 5HT antagonists metergoline and methysergide blocked the apomorphine-induced penile erections without affecting the yawning response. The alpha 2-adrenoceptor agonist clonidine, the dopamine antagonist sulpiride, the antihistaminic mepyramine and the benzodiazepine chlordiazepoxide inhibited both yawning and penile erections at the same dose level. The alpha 1-adrenoceptor antagonists prazosin and phenoxybenzamine were inactive. It is concluded that yawning and penile erections can be differentially affected by drug treatments. Also, while concomitant yawning and penile erections can be selectively induced by a class of dopamine receptor agonists, the same selectivity does not apply to antagonism of these induced behaviours.

Adrenergic alpha-Agonists↗
PubMed1986

The effects of cholinergic drugs support an avoidance learning hypothesis of brief footshock-induced analgesia.

Rats were tested for tail-flick responses and then immediately subjected to footshock for 30 sec. This procedure induced analgesia, i.e. prolonged the latency of the tail-flick response, which was maximal immediately after the shock and decayed to normal levels within 2 hr. No analgesia occurred if either the analgesia test before the shock or the shock itself was omitted. The dependence of the analgesia on the association between the test before the shock plus the shock, suggests that this was a form of avoidance learning. The effects of drugs injected immediately after the shock were determined on latency of the tail-flick response, measured 2 hr later. Drugs known to improve memory, including physostigmine, pramiracetam and the muscarinic agonists, oxotremorine and RS 86, selectively induced analgesia in rats subjected to test before the shock plus the shock, thereby supporting a hypothesis of avoidance learning. Neostigmine and atropine methyl nitrate had no effect, indicating that the effects were mediated centrally. The learning effects were distinguishable from analgesia induced by drugs, since morphine increased analgesia regardless of the presence or absence of the test before shock or the shock. Also, naloxone, which had no effect per se, blocked analgesia induced by morphine but enhanced physostigmine-induced analgesia. Neither chlordiazepoxide nor D-amphetamine produced any changes in the latency of the tail-flick responses indicating that neither anxiolytic/muscle relaxant nor stimulant actions were involved.

Analgesia↗
PubMed1986

Effects of ACTH and related peptides on medial septal self-stimulation.

The effects of ACTH1-24, ACTH4-10, the ACTH4-9 analog Org 2766 and [D-Phe7] ACTH4-10 on medial septal self-stimulation were determined in the rat following intracerebroventricular (ICV) injections. Self-stimulation rates were increased by 0.01-10 micrograms ACTH1-24 or 0.1-10 micrograms ACTH4-10, but not by Org 2766 or [D-Phe7] ACTH4-10. A dose of 1 microgram ACTH1-24 ICV did not affect open field behaviour. Subcutaneous administration of 1 microgram ACTH1-24 did not influence self-stimulation in the septum. Thus, the ACTH1-24 effect appears to be a central effect and provides evidence for an influence of ACTH containing pathways on structures involved in maintaining self-stimulation behavior. A possible role of opiate receptors and dopaminergic neurons in this effect of ACTH1-24 is also discussed.

Adrenocorticotropic Hormone↗
PubMed1986

Opiate-androgen interactions in drug-induced yawning and penile erections in the rat.

The effects of pretreatment with drugs on drug-induced yawning and penile erection in intact and chronically castrated rats were investigated. Naloxone partially blocked yawning in intact rats and in castrated rats pretreated with dihydro-testosterone propionate (DHTP) but not in control castrates. In contrast, naloxone potentiated apomorphine-induced penile erections in intact rats. Morphine, haloperidol and atropine blocked yawning and penile erections. Methyl naloxone, methyl atropine and domperidone at doses which are selectively peripheral-acting had no effect on drug-induced yawning or penile erection indicating that both effects are mediated centrally. Pretreatment with morphine did not change the naloxone effects in intact rats. The results indicate a naloxone-androgen interaction in drug-induced yawning but the results with morphine are not consistent with a role of opiates in this interaction. The penile erection data support a direct opiate-dopamine receptor interaction in this response. The haloperidol and atropine effects support a cholinergic-dopaminergic interaction in both yawning and penile erections.

Animals↗
PubMed1985

Dopaminergic agents including 3-PPP and its enantiomers on medial septal self-stimulation.

The effects of several dopamine agonists were determined on medial septal self-stimulation in rats and compared with selected dopamine antagonists and with the psychostimulants, d-amphetamine and nomifensine. Apomorphine, 3-PPP, TL-99, N,N-dipropyl-5,6-ADTN and N,N-dipropyl-6,7-ADTN inhibited self-stimulation at dose ranges selective for the dopamine autoreceptor as indicated by biochemical studies. Haloperidol and molindone produced dose-related inhibition but sulpiride increased self-stimulation. D-amphetamine and nomifensine also increased responding. The agonist-induced inhibition differed from neuroleptic-induced inhibition of self-stimulation. Both (+) and (-) 3-PPP inhibited responding by a similar amount over the dose range 0.25-1.0 mg/kg. At higher doses, (-) 3-PPP further decreased responding whereas the effects of (+) 3-PPP plateaued at approximately 55% of controls. These studies show that dopamine agonists, like neuroleptics, inhibit medial septal self-stimulation. This effect appears to be mediated via autoreceptor activation. Differences between neuroleptic- and agonist-induced inhibition and the 3-PPP stereoisomer data accord with the hypothesis that behavioural inhibitory effects caused by autoreceptor activation are less severe than those caused by dopamine postsynaptic blockade.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

The yawning-penile erection syndrome as a model for putative dopamine autoreceptor activity.

The efficacy of several drugs to elicit yawning and penile erections were determined in rats. The dopamine agonists, N-propylnorapomorphine, apomorphine, pergolide, (+/-)-3-PPP, TL-99 and N,N-dipropylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (N,N-dipropyl A-5,6-DTN) all elicited yawning accompanied by an increase in spontaneous penile erections. The potencies of these drugs in causing yawning closely resemble published data concerning their actions in biochemical tests reputedly indicative of autoreceptor activity. In contrast, SK&F 38393, A-5,6-DTN and clonidine produced no yawning and few or no penile erections. Although physostigmine also caused yawning, the effect was not accompanied by penile erections. Studies with the optical isomers of 3-PPP showed that (+)-3-PPP was considerably more potent than (-)-3-PPP. Haloperidol antagonised dopamine agonist-induced yawning and penile erections. Apomorphine-induced yawning and penile erections were also antagonised by sulpiride and atropine but not by domperidone. The suitability of elicitation of the combined syndrome of yawning plus penile erections as useful behavioural model for dopamine autoreceptor agonists is discussed.

Animals↗
PubMed1983

Synthesis of exo-3-phenylbicyclo[3.2.1]oct-3-en-2-amine and related compounds as potential analgesics.

Several analogues (21 and 29-50) of exo-3-phenylbicyclo[3.2.1]oct-3-en-2-amine (1) were prepared, a compound that had been found to have marked antinociceptive activity in the inflamed-paw pressure test in rats. Two synthetically versatile methods leading to these compounds are described. In this series, antinociceptive activity increases with increasing size of the amine substituent, reaching an optimum with N(Me)Et (32), but this is always associated with central nervous system (CNS) stimulant activity. The antinociceptive activity of these compounds is most likely due to an action that is similar to that of amphetamine rather than to an interaction with an opiate receptor. The endo diastereoisomer 22 and the benzo analogue 11 were both devoid of antinociceptive and CNS stimulant activity.

Acetylcholine↗
PubMed1982

Pharmacological evidence for the subclassification of central dopamine receptors in the rat.

1 The relative potencies of dopamine receptor agonists in causing stereotypy in rats when injected into the olfactory tubercles, and contralateral rotation when injected unilaterally into the caudate nucleus of rats with lesions of the nigro-striatal dopamine pathway, were determined. The actions of some agonists in eliciting these responses following peripheral injection, and the relative potencies of dopamine receptor antagonists in inhibiting them were also determined. 2 Dopamine, apomorphine and 2-amino-5,6 and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5, 6 DTN, A-6, 7 DTN) and N,N dipropyl A-5, 6DTN induced both responses. In contrast, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine HCl (SK & F 38393) whether injected intracerebrally or peripherally, induced contralateral rotation but not stereotypy. 3 Contralateral rotation and stereotypy induced by apomorphine or N,N dipropyl A-5, 6 DTN were inhibited by haloperidol, pimozide and fluphenazine but these drugs failed to inhibit rotation induced by SK & F 38393. Clozapine inhibited rotation induced by SK & F 38393, apomorphine or N,N dipropyl A-5,6 DTN but failed to inhibit stereotypy. Loxapine was more potent in inhibiting stereotypy than rotation,, whereas clothiapine inhibited rotation and stereotypy at similar doses irrespective of the agonist used to elicit the response. 4 Contralateral rotation induced by SK & F 38393 was not inhibited by yohimbine, prazosin, atropine, methysergide, mepyramine or propranolol. 5 The results provide evidence that contralateral rotation induced by dopamine receptor agonists is mediated by two different classes of dopamine receptors and that these receptors differ from those mediating the stereotypy response. 6 The receptors mediating these responses appear classifiable in terms of their sensitivity to the agonist actions of SK & F 38393 or apomorphine respectively. SK & F 38393-sensitive receptors are susceptible to blockade by clozapine but are not blocked by haloperidol, pimozide or fluphenazine. Apomorphine-sensitive receptors are susceptible to blockade by haloperidol, pimozide and fluphenazine but appear divisible into two sub-classes depending on whether or not they are blocked by clozapine and on their sensitivity to blockade by loxapine.

Animals↗
PubMed1979

Alpha 2-adrenoceptors mediate clonidine-induced sedation in the rat.

1 The central alpha-adrenoceptors responsible for mediating clonidine-induced sedation in rats have been characterized according to their sensitivity to alpha-adrenoceptor agonists and antagonists.2 Clonidine, injected intraperitoneally or intracerebroventricularly, caused dose-dependent sedation, both in terms of a reduction in the time that rats could remain on an accelerating rotarod and in terms of overt sedation assessed visually. Following intracerebroventricular injection, xylazine, naphazoline and methoxamine, but not phenylephrine, produced similar effects.3 The sedation caused by intraperitoneal injection of clonidine was antagonized by intracerebroventricularly injected phentolamine, yohimbine, piperoxan and tolazoline but not by labetalol, thymoxamine or prazosin.4 The relative potencies of the agonists in causing sedation and of the antagonists in inhibiting the sedative effect of clonidine clearly demonstrated that the central alpha-adrenoceptors mediating clonidine-induced sedation are the same as the peripheral presynaptic alpha(2)-adrenoceptors.5 All the alpha-adrenoceptor agonists caused hypothermia after intracerebroventricular injection, but their order of potency was different from that in producing sedation. The hypothermic effect of intraperitoneally injected clonidine was little affected by any of the antagonists administered intracerebroventricularly. No conclusions could be drawn concerning the type of receptor responsible for mediating hypothermia.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Cholinergic modulation of spatial learning in mice in a Morris-type water maze.

Injection of the centrally active muscarinic antagonist scopolamine i.p. 20 min pre-test at 3 mg/kg but not at 1 mg/kg, impaired spatial learning of a Morris-type water maze adapted for mice. Both doses caused hyperactivity. D-amphetamine (3 mg/kg, i.p.), which also caused hyperactivity, did not impair spatial learning nor did methylscopolamine (3 mg/kg, i.p.). In a cued version of the water maze, apart from a temporary disturbance on day 1, scopolamine (3 mg/kg) and control groups behaved similarly, indicating that scopolamine-induced place learning deficits are not due to changes in swimming ability, motivation or ability to use proximal cues. Physostigmine (0.1 and 0.2 mg/kg, i.p.) and oxotremorine (0.02 mg/kg but not 0.01 mg/kg, i.p.) antagonized the deficits in the swimming maze. Neither drug affected the scopolamine hyperactivity despite causing hypoactivity per se. In contrast, the peripherally acting cholinergic drug neostigmine was inactive against scopolamine in either test at 0.1 mg/kg. THA (2-8 mg/kg, i.p.), RS86 (0.25-1 mg/kg, i.p.) and nicotine (1 and 3 mg/kg, i.p.) were also unable to antagonize the scopolamine effect. These studies show that scopolamine disrupts acquisition of spatial rather than cued learning in mice in a Morris-type water maze and that this effect appears to be mediated centrally and can be dissociated from drug-induced hyperactivity. Moreover, this deficit can be reversed with certain cholinergic agents.

Animals↗
PubMedDate not supplied

Pharmacological evaluation of in vivo tests for alpha 2-adrenoceptor blockade in the central nervous system and the effects of the enantiomers of mianserin and its aza-analog ORG 3770.

A series of compounds with actions on the central nervous system was tested for antagonism of clonidine-induced sleep in chicks and clonidine-induced mydriasis in rats for the purpose of evaluating these methods as tests for demonstrating an in vivo alpha 2-adrenoceptor blocking effect of a novel compound. Clonidine-induced mydriasis was found to be the most selective method. The order of potency for compounds fully antagonizing clonidine-induced mydriasis was MSD 26 greater than physostigmine = idazoxan greater than aptazapine greater than piperoxan greater than yohimbine greater than mianserin greater than tolazoline. Partial antagonism was found for quipazine and sulpiride. Misleading results can arise from the involvement of cholinergic mechanisms in the control of the pupil diameter. The order of potency for compounds antagonizing clonidine-induced sleep in chicks was apomorphine greater than yohimbine greater than idazoxan greater than aptazapine = MSD 26 greater than quipazine greater than methysergide greater than piperoxan = mianserin = bepridil = metergoline = cyproheptadine = desipramine greater than tolazoline greater than dexchlorpheniramine, although antagonism was not complete for all of these compounds. Misleading results can arise from effects on arousal of the chicks but cholinergic mechanisms do not play a disturbing role so that the method with chicks can be a useful supplement to the mydriasis method. The enantiomers of mianserin and of a compound related to mianserin, Org 3770, were tested in the 2 methods and the alpha 2-blocking effect of these compounds was found to be residing in the S(+)-enantiomers.

Adrenergic alpha-Antagonists↗