Biomedical subjects

C L Broekkamp

Publications and source records attributed to C L Broekkamp.

At least 55 records · Page 3Linked to original sources

PubMed1988

Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine.

The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s.c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

The relative potencies of cholinomimetics and muscarinic antagonists on the rat iris in vivo: effects of pH on potency of pirenzepine and telenzepine.

The effects of cholinomimetics and muscarinic antagonists were compared following topical administration to the eyes of anaesthetized rats. For tests with cholinomimetics, clonidine (0.3 mg/kg) was used to induce mydriasis via central inhibition of parasympathetic tone. Full, dose-dependent miosis was induced by acetylcholinesterase inhibitors [physostigmine greater than neostigmine greater than tetrahydroaminoacridine (THA)] and by membrane channel blockers (4-aminopyridine greater than 3,4-diaminopyridine). Oxotremorine was the most potent direct agonist tested [oxotremorine greater than arecaidine propargylester (APE) greater than arecoline greater than carbachol greater than ethoxyethyltrimethyl-ammonium iodide (EOE) greater than RS 86]. Some putative M1 selective agonists were weakly active or behaved as partial agonists (pilocarpine greater than AH6405 greater than Mc-A-343 greater than isoarecoline). Of the antagonists, compared in non-clonidine treated rats, scopolamine hydrochloride was the most potent. Of the receptor selective antagonists the M2 (ileal) selective compounds hexahydrosiladifenidol and 4-DAMP were more potent than either M1 selective (pirenzepine, telenzepine) or M2 (atrial) selective (AF DX 116) drugs. These data tentatively suggest the involvement of an M2 (ileal) type muscarinic receptor. Potency was lower for quaternary structures, probably due to impaired corneal penetration. The potency of pirenzepine and telenzepine was increased 60-fold at low pH following topical administration. Acid induced corneal damage does not appear to account for this potency shift as the effects of scopolamine and several agonists (oxotremorine, pilocarpine and McNA-343) were not substantially altered by acid media. For pirenzepine the potency shift appears to be related to protonation of the second amino group (N1) in the piperazine tail (pKa = 2.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha 2-adrenolytic activity.

(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906) is a potential new antidepressant agent, with a neurochemical profile quite different from that of the classical tricyclic antidepressant drugs. The compound was found active in behavioural tests which are considered to be predictive for antidepressant activity, such as the muricidal test in the rat and the acquired immobility model. Neurochemical studies showed that Org 6906 was an inhibitor of the reuptake of monoamines both in vitro and ex-vivo without having appreciable anticholinergic, antihistaminergic or alpha 1-adrenolytic activity. The facilitatory effect on monoaminergic neurotransmission was confirmed by the reversal of hypothermia induced by reserpine. The drug Org 6906 appeared to have selective alpha 2-adrenolytic properties. It facilitated potassium-stimulated release of noradrenaline from slices of cortex, displaced [3H]rauwolscine and [3H]dihydroergocryptine from their binding sites but only weakly blocked alpha 1-adrenoceptors. The alpha 2-adrenolytic properties were also apparent in behavioural interaction models. The compound antagonized the sleep-inducing effects of clonidine in chicks and mice and it antagonized the mydriasis induced by clonidine in the rat. Finally, it was shown that the two enantiomers of Org 6906 contributed almost equally to the relevant neurochemical and behavioural properties.

Adrenergic alpha-Antagonists↗

PubMed1988

Prodrug behaviour of nicotinoylmorphine esters.

Morphine and its nicotinoyl esters, dinicotinoylmorphine (nicomorphine), 6-mononicotinoylmorphine (6-MNM) and 3-mononicotinoylmorphine (3-MNM) were tested in mice for central activity to obtain time-effect profiles of these compounds in rats. Two effects, analgesia with the hot plate test and locomotor stimulation in activity cages were measured and nicomorphine, 6-MNM and 3-MNM were found to have a faster onset of action compared with morphine. The effects of 3-MNM and morphine lasted longer than the effect of nicomorphine and 6-MNM. The prodrug behaviour of 3-MNM and nicomorphine for morphine and 6-MNM, respectively, is discussed.

Animals↗

PubMed1988

Selective behavioural impairment after acute intoxication with trimethyltin (TMT) in rats.

A series of experiments was conducted to characterize the long term behavioural consequences of acute intoxication with trimethyltin (TMT) (5,6,7, mg/kg p.o.). The acute toxicity syndrome, including weight loss, convulsions, irritability and hyper-reactivity was confirmed in treated rats. These symptoms subsided to reveal marked increases in locomotor activity in a novel environment but no lasting effects on consummatory behaviour or sensorimotor integration. Neither two-way active avoidance nor passive avoidance learning were impaired by doses of up to 7 mg/kg p.o. although intertrial activity was elevated in the shuttle box and extinction responding was increased. Place navigation in a water maze was impaired, particularly at the highest dose of TMT (7 mg/kg p.o.) and when a brief training phase (8 trials) was used. Finally, TMT lesioned rats were compared with controls on spatial and non-spatial discrimination tasks. Following 7 mg/kg p.o. TMT rats were highly impaired on the spatial discrimination but not the non-spatial discrimination despite the greater difficulty of the latter task. Histological studies confirmed the pathological effects of TMT in limbic structures, particularly the pyramidal cells of CA1 and CA4, and also revealed increased acetylcholinesterase activity within the molecular layer of the dentate gyrus. The selective, long term behavioural impairments caused by TMT are discussed in the light of their qualitative similarity to the effects of hippocampectomy or hippocampal denervation. TMT lesioned rats may provide a suitable functional model for the partial hippocampal and temporal lobe pathology characteristic of Alzheimer's disease.

Animals↗

PubMed1987

Facilitation of amphetamine-induced rotation by muscarinic antagonists is correlated with M2 receptor affinity.

This study examined the relationship between the affinity of cholinergic drugs for muscarinic receptor subtypes and their potency in potentiating or inhibiting amphetamine-induced rotation. The ascending nigrostriatal dopaminergic pathway was unilaterally lesioned in male Wistar rats using 6-hydroxydopamine. In these rats, ipsiversive rotation induced by amphetamine sulphate (1 mg/kg, s.c.) was dose-dependently inhibited by the cholinergic agonists oxotremorine, RS86 and pilocarpine and by the acetylcholinesterase inhibitor physostigmine. In contrast the cholinergic antagonists scopolamine, secoverine and dicyclomine facilitated amphetamine-induced rotation. Agonist and antagonist potencies were then compared with M1 and M2 binding site affinities estimated by displacing [3H]pirenzepine from forebrain and [3H]QNB from brainstem homogenates. The data suggest a relationship between antagonist potency and M2 binding site affinity.

Animals↗

PubMed1987

Drug-induced penile erections in rats: indications of serotonin1B receptor mediation.

The induction of penile erections by a variety of compounds with a direct or indirect effect on serotonin (5HT) receptors was investigated in rats. L-5-Hydroxy-tryptophan (L-5HTP) induced penile erections when co-administered with nialamide and the peripheral decarboxylase inhibitor benserazide, indicating that the site of action for inducing penile erections is within the central nervous system. Penile erections were also induced by the 5HT uptake inhibitors zimelidine, fluoxetine, citalopram, Org 6997, by the 5HT-releasing agent fenfluramine and by the putative 5-HT1B receptor agonist 1-(3'-chlorophenyl)-piperazine (mCPP). The 5HT1A-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) did not induce penile erections. The less selective 5HT receptor agonists 5-methoxy-N,N-dimethyl-tryptamine (5MeODMT), 5-methoxytryptamine (5MeOT), dl-lysergic acid diethylamide (LSD) and Ru 24969 were also ineffective. Induction of penile erections by quipazine appeared only when this compound was co-administered with the 5HT2 receptor antagonist pirenperone. Receptor antagonists were tested against penile erections induced by Org 6997. The beta-adrenoceptor antagonists that also have 5HT1 antagonistic properties, (S)-pindolol and dl-propranolol, antagonized Org 6997-induced penile erections but butoxamine and metoprolol did not. Spiperone and pirenperone in doses selective for 5HT1A and 5HT2 receptors respectively were also inactive. Haloperidol, 0.46 mg/kg, partially attenuated penile erections induction. The data are discussed in the light of the hypothesis that penile erections induction by serotonin-mimetic compounds is mediated by 5HT1B receptors in the striatum.

5-Hydroxytryptophan↗

PubMed1987

Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine.

Two experiments were conducted to determine the effects of the M1 muscarinic receptor antagonist pirenzepine on place navigation in a water maze. In the first experiment rats were required to learn the location of a hidden platform following intracerebroventricular injections of equimolar doses of pirenzepine or scopolamine methylbromide. Both drugs dose-dependently impaired spatial learning according to both escape latency data and transfer test analysis. Pirenzepine was approximately 3 times less potent than scopolamine, a potency ratio which suggests M1 receptor mediation of the impairment. In the second experiment pirenzepine (1 approximately 92.3 micrograms/rat ICV) was injected prior to training on a simultaneous place discrimination task in the water maze. Impairments of choice accuracy were found with a dose of 20 micrograms/rat in the absence of any marked increases in either errors of omission or choice latency. These data suggest that M1 receptor blockade impairs processes which are involved in spatial learning.

Animals↗

PubMed1987

Cholinergic stimulation of drinking from the lateral hypothalamus: indications for M2 muscarinic receptor mediation.

Available evidence suggests that muscarinic receptor binding sites may exist in at least two heterogenous subclasses (M1 and M2), distinguished by their affinity for the antagonist pirenzepine. In order to evaluate the role of these receptors in comsummatory behaviour a series of conventional and putatively receptor selective drugs were tested for their effects on water consumption following injection (0.5 microliter/30 sec) into the perifornical hypothalamic area of non-deprived rats. Of the conventional agonists tested, carbachol and oxotremorine were approximately equipotent and arecoline was about 16 X weaker. Of the putative M1 agonists tested, pilocarpine was about 50 X weaker than carbachol and the remainder (MCNA343, AHR602, AH6405) were inactive. Inhibition of carbachol (1 microgram) induced drinking was subsequently measured. The most potent inhibition was found using scopolamine, a non selective antagonist. 4-DAMP was approximately 7 X weaker than scopolamine, but was more potent than the putative M1 antagonists pirenzepine, telenzepine or dicyclomine. In a separate series of experiments the affinity of these drugs for [3H]pirenzepine forebrain receptors (M1) and [3H]QNB brainstem receptors (M2) was determined to confirm their receptor binding selectivity. No systematic relationship was found between agonist potency and M1 or M2 affinities. M2 receptor involvement was indicated by the antagonist data which show a close relationship between rank potency order and M2 receptor affinity. An important role for M1 receptors is excluded by the absence of a clear relationship between potency order and M1 affinity. The data therefore suggest an important role for M2 receptors in mediating drinking stimulated by muscarinic receptor activation.

Animals↗

PubMed1986

Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim-induced grooming in mice.

The effects of psychotropic compounds on grooming and burying were compared in mice. Burying behaviour was provoked by glass marbles and grooming was observed after 3 min swimming. Compounds with minor tranquilizing properties, such as diazepam, chlordiazepoxide, flunitrazepam, clonazepam, meprobamate and ethyl alcohol, were more effective in reducing burying than grooming. Drugs with an anticholinergic effect, e.g. scopolamine and atropine were also more effective against burying. A number of neuroleptic drugs, such as haloperidol, chlorpromazine, perphenazine and trifluperidol reduced grooming more effectively than burying. Non-selective inhibitory effects were observed with clozapine, thioridazine, diphenhydramine, imipramine, mianserin and apomorphine. It is concluded that, with certain limitations, the burying-grooming test described offers a simple tool for identifying novel compounds as potential major or minor tranquilizers.

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

Corticosterone, choline acetyltransferase and noradrenaline levels in olfactory bulbectomized rats in relation to changes in passive avoidance acquisition and open field activity.

Consequences of olfactory bulbectomy in two behavioural situations, passive avoidance acquisition and activity in a brightly lit open field, were measured in the same animals for which data on four biochemical measures were also obtained. The biochemical measurements were on plasma corticosterone levels, noradrenaline (NA) levels in the midbrain and amygdala + pyriform cortex and the choline acetyltransferase (CAT) levels in the olfactory tubercle. Experimental variation in age groups of rats (7 weeks and 3 months) and in post-bulbectomy periods (1, 2 and 4 weeks) was made. The deficit in passive avoidance as a consequence of olfactory bulbectomy was evident in all groups of young animals and in older animals one and two weeks post-bulbectomy but not in older animals four weeks after bulbectomy. An increase in open field activity was similarly observed in all groups except in the older animals four weeks after bulbectomy. In contrast to reports by other investigators the basal plasma corticosterone levels were not increased in bulbectomized animals nor did we observe any diminution of NA levels in the amygdala (+ pyriform cortex). CAT levels were slightly increased in older animals two weeks after bulbectomy. The absence of a change in the plasma corticosterone level after bulbectomy is discussed in relation to the notion that the olfactory bulbectomized rat is in some way relevant as a test model for predicting efficacy of potential antidepressant drugs.

Animals↗

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↗

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

Akinesia after locally applied morphine near the nucleus raphe pontis of the rat.

Morphine (10 micrograms/microliter) was injected into different sites within the pontine brainstem in different groups of rats with indwelling guide cannulae. The rats were tested for the persistence of abnormal postures as a measure for the degree of akinesia. Local morphine was most effective in inducing akinesia at a site identical or close to the nucleus raphe pontis. Midline injections were effective in contrast to bilateral injections. Fenfluramine, a serotonin releaser, strongly potentiated morphine akinesia.

Animals↗

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↗

PubMed1984

The comparative effects of benzodiazepines, progabide and PK 9084 on acquisition of passive avoidance in mice.

Acquisition of passive avoidance following aversive conditioning to a dark compartment was measured in mice under the influence of one of seven benzodiazepines, the GABA-mimetic drug progabide or PK 9084, a nonbenzodiazepine ligand on benzodiazepine receptors. The drugs were administered prior to the training trial and retention was measured in the absence of the drug 24 h later. Oral administration (dose in mg/kg in parentheses) of flunitrazepam (0.1), lorazepam (1.0), nitrazepam (3.0), diazepam (10), flurazepam (10) and chlordiazepoxide (30), all prevented retention whereas progabide (100-800) and PPK 9084 (10-100) were ineffective. In comparison to effects on motor capacity none of the benzodiazepines was outstanding in its acquisition interfering effects.

Animals↗

PubMed1984

Ethyl alcohol on escape from electrical periaqueductal gray stimulation in rats.

In a procedure to measure the escape latency and threshold for aversive electrical stimulation of the Peri-Aqueductal Gray (PAG) the effect of ethyl alcohol was tested in order to validate aversive PAG stimulation further as a model for testing potential anxiolytics. Doses of 0.2-1.6 g/kg were given orally in an ascending sequence and were found to increase escape latency and threshold. A second dose of 0.8 g/kg had no effect, suggesting development of tolerance. Spontaneous activity in the test environment was not changed by alcohol. These results indicate specific effects of alcohol on aversive stimulation and reinforce the suggestion to use this phenomenon as a model for human anxiety.

Animals↗