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At least 577 records · Page 32Linked to original sources
PubMed1990

Phase-dependent modulation of dorsal root potentials evoked by peripheral nerve stimulation during fictive locomotion in the cat.

To help elucidate the role of presynaptic mechanisms in the control of locomotor movements, the transmission of PAD pathways was investigated by recording dorsal root potentials (DRPs) evoked by electrical stimulation of cutaneous and muscle nerves of both hindlimbs at various phases of the fictive step cycle. Fictive locomotion occurred spontaneously in decorticate cats or by stimulating the mesencephalic locomotor region (MLR) as well as in low spinal cats injected with nialamide and L-DOPA. Evoked DRPs were superimposed on a fluctuating DRP accompanying the fictive locomotor rhythm (locomotor DRP) which typically consisted of two peaks of depolarization per cycle, the largest peak occurring during the flexor phase. The amplitude of evoked DRPs was substantially modulated throughout the locomotor cycle and followed a similar modulation pattern for all stimulated nerves whether ipsilateral (i-) or contralateral (co-). The amplitude of evoked DRPs decreased at the beginning of the flexor phase, dropped to a minimum later in the flexor phase and then increased during the extensor phase where it became maximum. Results were comparable in decorticate and spinal preparations and for L6 and L7 rootlets with cutaneous and muscle nerve stimulation. It is noteworthy that the modulation pattern for a given rootlet was similar for i- and co- stimulation, even though the bilateral locomotor DRPs fluctuate out-of-phase with each other, subjecting the stimulated fibres to opposite presynaptic polarization changes. This suggests that the modulation may depend more on the presynaptic mechanisms of the receiving fibres than on those of the stimulated fibres. These results demonstrate that the transmission in spinal pathways involved in primary afferent depolarization (PAD) is phasically modulated by the activity in the spinal locomotor network. It is further suggested that the presynaptic inhibition associated with PAD evoked by movement-related sensory feedback during real locomotion could be modulated in a similar way.

Animals↗
PubMed1976

Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens.

Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.

Animals↗
PubMed1976

Antagonism of the hyperactivity induced by dopamine applied intracerebrally to the nucleus accumbens septi by typical neuroleptics and by clozapine, sulpiride and thioridazine.

Dopamine administered intracerebrally to the nucleus accumbens septi was shown to induce a dose-dependent hyperactivity following pretreatment with nialamide. This effect was optimum following the injection of 50 mug dopamine. The hyperactivity induced by this dose of dopamine was inhibited by the i.p. injection of both the typical neuroleptic agents, haloperidol, fluphenazine, pimozide and clothiapine (0.05--0.5 mg/kg i.p.), and the atypical neuroleptics clozapine, sulpiride and thioridazine (0.5--20 mg/kg i.p.) although, generally, the doses required ot the latter were in the order of 20--100 times those of the typical agents to produce an equivalent effect. In contrast, cataleptic doses of metoclopramide (10--30 mg/kg i.p.) failed to reduce the dopamine-induced hyperactivity: aceperone and propranolol were similarly ineffective. However, inhibition of hyperactivity was recorded following the peripheral administration of the antimanic drug, IB503. It is suggested that the ability of a drug to antagonise the hyperactivity induced by the injection of dopamine into the nucleus accumbens septi may be of value in the detection of antipsychotic activity.

Animals↗
PubMed1976

A comparison of the abilities of typical neuroleptic agents and of thioridazine, clozapine, sulpiride and metoclopramide to antagonise the hyperactivity induced by dopamine applied intracerebrally to areas of the extrapyramidal and mesolimbic systems.

Dopamine injected directly into the caudate--putamen, nucleus accumbens or tuberculum olfactorium of rat brain, following a nialamide pretreatment, caused dose-dependent hyperactivity. The hyperactivity was more intense after injections into the nucleus accumbens, but was limited by the development of stereotyped biting when larger doses of dopamine were injected into the caudate--putamen or tuberculum olfactorium. Haloperidol, fluphenazine and pimozide were shown to antagonise, in a dose-dependent manner, the hyperactivity induced by dopamine from all 3 areas. Pimozide appeared equieffective against the 3 hyperactivity mediated from the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium. Sulpiride, clozapine and thioridazine also caused dose-dependent reductions in the hyperactivity induced by dopamine injections into the caudata--putamen, nucleus accumbens and tuberculum olfactorium, although the doses required to effect this inhibition were notably larger than for the typical neuroleptics. Generally, these atypical agents were also least effective as antagonists of the hyperactivity following intrastriatal dopamine. Metoclopramide differed from all other agents tested in failing to antagonise the hyperactivity induced by dopamine injections into the nucleus accumbens. However, the responses to dopamine from the caudate-putamen and tuberculum olfactorium were both antagonised by metoclopramide, the striatal response being the least sensitive. The alpha- and beta-adrenergic blocking agents, aceperone and propranolol, failed to reduce the hyperactivity induced by dopamine injections into the caudate-putamen, nucleus accumbens or tuberculum olfactorium. The abilities of the agents tested to antagonise a hyperactivity induced by dopamine in the striatum or in the mesolimbic areas, the nucleus accumbens and tuberculum olfactorium, are compared with the potential of these agents to induce extrapyramidal side effects and to exert an antipsychotic action in man.

Animals↗
PubMed1977

The influence of adrenergic agonists and their antagonists on isolated salivary glands of ixodid ticks.

Various drugs elicit fluid secretion by isolated salivary glands of two species of ixodid ticks (Dermacentor andersoni Stiles and Amblyomma hebraeum Koch). Among catecholamines, the following order of potency was observed: dopamine, epinine, noradrenaline = adrenaline and isoprenaline. The following drugs, in order of potency, were also agonists on this preparation: ergonovine, ergotamine, 6-hydroxydopamine, apomorphine, phenylephrine, norphenylephrine, beta-phenylethylamine, tyramine, D, L-dopa and octopamine. Nialamide increased the response to near-threshold concentrations of dopamine but had no intrinsic activity. Dopamine-induced secretion was depressed by phenoxybenzamine, alpha-flupenthixol, phentolamine, propranolol and dichloroisoprenaline, but only at conce,trations 10- to 1000-fold that of the agonist. Pimozide and spiperone (10(-6) M) augmented the maximum response of dopamine. The tick salivary gland, thus appears to contain one or several receptors differing pharmacologically from mammalian alpha-adrenergic, beta-adrenergic and dopamine receptors.

Animals↗
PubMed1979

GABA-mediated potentiation of amine release from nigrostriatal dopamine neurones in vitro.

The uptake and release of 3H-dopamine was studied in slices of corpus striatum and substantia nigra in the presence of nialamide. High potassium triggered the outflow of tritium in both brain structures and this release was potentiated by GABA in a dose related fashion, whereas the spontaneous overflow of radioactivity was unchanged. This action of GABA was mimicked by the GABA-T antagonists aminooxyacetic acid and ethanolamine-O-sulphate, but not by the GABA analogues muscimol, 3-aminopropanesulphonic acid, gamma-hydroxybutyrate or beta-(p-chlorophenyl)-GABA. The response to GABA was not blocked by picotoxin, which itself facilitated the evoked release of 3H-dopamine, nor by bicuculline or the omission of calcium ions from the bathing medium. GABA facilitation of K+-evoked 3H-dopamine release was increased significantly on reducing tissue thickness and following prolonged incubation with GABA. GABA also potentiated the depolarization induced outflow of 3H-noradrenaline, 3H-5-hydroxytryptamine and 3H-histamine without affecting their initial accumulation. Veratridine, amphetamine and cold dopamine also raised the output of 3H-dopamine, but none of these releases was altered by GABA. The uptake of 3H-dopamine, but not that of 14C-GABA, was considerably attenuated in 6-hydroxydopamine lesioned corpora striata. The possible mechanism(s) of this stimulatory action of GABA is discussed.

4-Aminobutyrate Transaminase↗
PubMed1982

Effects of inhibitors of 5-hydroxytryptamine uptake on plasma glucose and their interaction with 5-hydroxytryptophan in producing hypoglycaemia in mice.

The effects of various inhibitors of 5-HT uptake on plasma glucose have been studied in normal and monoamine oxidase inhibitor pretreated mice. Additionally their interaction with 5-hydroxytryptophan (5-HTP) in producing hypoglycaemia was studied. Clomipramine, fenfluramine, fluoxetine, ORG 6582 (dl-8-chloro-11-anti-amino-benzo-(b)-bicyclo[3.3.1]nona-3, 6 alpha(10 alpha)-diene hydrochloride), ORG 6997 (dl-4-exo-amino-8-chloro-benzo-(b)-bicyclo[3.3.1]nona-2-6 alpha(10 alpha)-diene hydrochloride), MK 212 and mazindol did not modify the plasma glucose in normal mice but produced hypoglycaemia in mice pretreated with either nialamide or pargyline. Dexamphetamine did not influence plasma glucose in either normal or monoamine oxidase inhibitor pretreated mice. Each of the above drugs except ORG 6997 but including dexamphetamine augmented the hypoglycaemic effect of 5-HTP in normal mice. These responses did not appear to be mediated by insulin since none of the drugs increased the plasma immunoreactive insulin concentration or augmented the hyperinsulinaemic effect of 5-HTP. Moreover, fenfluramine, fluoxetine and ORG 6582 did not augment the hypoglycaemic action of injected insulin although such an augmentation was produced by mazindol.

5-Hydroxytryptophan↗
PubMed1982

Mechanism of action of histamine in the estrogen-primed rat uterus.

Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10(-8)-10(-8) M), a specific H2-receptor antagonist. Propranolol, a selective beta-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10(-8)-10(-6) M). The pA2 value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 X 10(-6) M), the monoamine oxidase inhibitor, and cocaine (4.3 X 10(-6) M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 X 10(-5) M), and adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H2-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic beta-receptors and produces relaxation of the rat uterus.

Animals↗
PubMed1986

Increased gastric cholinergic activity evoked by 5-hydroxy-L-tryptophan in the rat.

In gastrointestinal tissues such as rat stomach, exogenous 5-hydroxytryptamine (5HT) has little or no ability to affect nerve activity. However, endogenous 5HT might act differently, and this was investigated by stimulating 5HT synthesis using 5-hydroxy-L-tryptophan (5HTP). In longitudinal strips of rat forestomach, 5HTP (50 and 500 microM) increased cholinergically mediated contractions evoked by electrical field stimulation, probably by facilitating acetylcholine release; contractions evoked by exogenous acetylcholine were unaffected by 5HTP. The ability of 5HTP to increase electrically evoked contractions was long-lasting, required the presence of pyridoxal (a monoamine decarboxylase cofactor) and was reduced by the decarboxylase inhibitor carbidopa, but not by 6-hydroxydopamine. In the presence of paroxetine and nialamide, the 5HTP-induced increase in cholinergically mediated contractions was short-lasting. In anaesthetised rats 5HTP caused stimulation of gastric motility, which was blocked or reduced by atropine. These findings suggest that in the rat 5HTP stimulates gastric cholinergic activity, by increasing the concentration of 5HT at sites which normally synthesise 5HT.

5-Hydroxytryptophan↗
PubMed1986

The St 587-induced flexor reflex in pithed rats: a model to evaluate central alpha 1-receptor blocking properties.

A combination of reserpine, nialamide and the specific alpha 1-adrenoceptor agonist St 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine] induced a marked increase of the electrically stimulated flexor reflex in pithed rats. This increased reflex - which lasted for more than 3 h - could be inhibited by the alpha 1-receptor antagonist prazosin but not by the alpha 2-adrenoceptor antagonist idazoxan (RX 781094). A range of different drugs was tested, including 17 neuroleptics. Most of the neuroleptics showed marked inhibition of the St 587-induced reflex. Bromperidol, butaclamol and fluperlapine were weak inhibitors while pimozide was without effect. The results showed close correlation to alpha 1-receptor affinities in vitro (r = 0.84, P less than 0.001) while no correlation was found to either D-2 receptor affinities or to 5-HT2 receptor affinities in vitro (r = 0.43, P less than 0.2 and r = 0.41, P less than 0.05, respectively). It is concluded that inhibition of the St 587-induced flexor reflex in pithed rats is an in vivo test model for central alpha 1-receptor blocking properties.

Adrenergic alpha-Antagonists↗
PubMed1987

Effects of drugs affecting noradrenergic neurotransmission in rats with spontaneous petit mal-like seizures.

Wistar rats of a strain displaying spontaneous petit mal-like seizures and spike-wave EEG discharged (SWD) were injected i.p. with drugs affecting noradrenergic neurotransmission. The EEG and behavior were recorded. Drugs which decrease alpha-noradrenergic neurotransmission, prazosin (alpha 1-antagonist) and clonidine (alpha 2-agonist), increased SWD and were sedative in a dose-dependent manner. Drugs which increase alpha-noradrenergic neurotransmission, ST 587, cirazoline (alpha 1-agonists) and yohimbine (alpha 2-antagonist), reduced SWD and the latter two caused agitation. Drugs which interact with beta-noradrenergic transmission (salbutamol, isoprenaline and propranolol), monoamine oxidase inhibitors (nialamide and iproniazid), and a noradrenaline reuptake inhibitor (desipramine), did not affect SWD. These findings suggest that noradrenaline participates in the control of petit mal-like seizures in the rat, as in other types of seizures and other animal models.

Animals↗
PubMed1979

Enhancement by transition metals of unscheduled DNA synthesis induced by isoniazid and related hydrazines in cultured normal and xeroderma pigmentosum human cells.

In combination with transition metals (Mn(II), Cu(II), and Fe(III)), isoniazid and related hydrazine compounds induced unscheduled DNA synthesis (DNA repair) in cultured human fibroblasts. Manganese at 10(-5) and 10(-4) M strongly enhanced DNA repair induced by isoniazid, iproniazid, nialamide and hydrazine. Peak levels of DNA repair occurred at 5 x 10(-4)--10(-3) M of the 4 hydrazine compounds. Copper caused less enhancement of DNA repair while iron had no detectable effect. Without added metal, unscheduled DNA synthesis was not observed in cells treated with any of the 4 freshly-prepared hydrazine compounds. However, following preincubation in medium for 6--12 h, isoniazid alone at high concentrations (10(-2) M--10(-1) M) induced DNA repair. With isoniazid/manganese mixtures, preincubation did not further enhance DNA repair except at low concentrations of isoniazid (2--5 x 10(-4) M). Catalase reduced the DNA damage caused by preincubated isoniazid and by the isoniazid/metal mixtures. Exposure of repair-deficient xeroderma pigmentosum cells to isoniazid plus manganese resulted in a DNA-repair profile similar to that of normal cells. The results are consistent with hydrogen peroxide being a critical intermediate for the production of free radicals which cause the observed DNA damage.

Cells, Cultured↗
PubMed1984

Discrimination of the amphetamine cue. Effects of A, B and mixed type inhibitors of monoamine oxidase.

Rats were trained to discriminate between the effects of 0.6 mg/kg of (+)-amphetamine given intraperitoneally saline in a two-lever operant task, according to a fixed ratio ( FR10 ) schedule of food reinforcement. Once trained (greater than 90% responding on the appropriate lever during sessions with drug and saline, respectively over 2 weeks), they were given tests of generalization with various type A, type B or mixed type monoamine oxidase inhibitors (MAOI). Generalization was tested during the first 100 sec of a 15 min trial during which no reinforcements were given (extinction) followed by reinforcement on both levers for the rest of the session. Generalization to amphetamine was estimated using both the percentage of responding on the "drug lever" and a measure of choice of lever. None of the type A MAOI's tested [ cimoxatone (MD 780515), clorgyline, LY 51641, moclobemide (Ro 11-1163), toloxatone] showed generalization towards the lever for amphetamine. Clear or partial amphetamine-like responding was observed with the B type MAOI (+/-)-deprenyl and LY 54761 but not with two other type B MAOI's MD 240928 or pargyline. (+/-)-Tranylcypromine, but not nialamide (mixed type MAOI's), induced dose-dependent responding on the lever for amphetamine. It was concluded that amphetamine-like activity was not an intrinsic property of A or B type MAOI's.

Amphetamine↗
PubMed1985

Myoclonus in the rat induced by p,p'-DDT and the role of altered monoamine function.

Administration of p,p'-DDT to rats produced myoclonus, but unlike previous studies in mice, this was not decreased by administration of clonazepam. Precursors of 5-hydroxytryptamine (5-HT) (L-tryptophan and L-5-HTP) reduced the intensity of myoclonus, but the 5-HT agonists, quipazine and Org 6582 did not. Antagonists of 5-HT (methergoline, methysergide and cinanserin) did not potentiate the myoclonus induced by p,p'-DDT. Drugs altering the function of dopamine and noradrenaline (apomorphine, clonidine or phenoxybenzamine) also had no effect on this myoclonus. Administration of monoamine oxidase inhibitors (MAOIs; pargyline, nialamide and tranylcypromine) markedly attenuated the myoclonus, an effect that could not be attributed to an action on any one monoamine system. No observable changes in cerebral biochemical parameters of 5-HT occurred at the onset of myoclonus, although tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in brain were increased following periods of prolonged myoclonus. Electrophysiological analysis of the myoclonus in the rat induced by p,p'-DDT revealed changes in EEG and EMG activity which suggested an origin for the myoclonus in the brainstem. Although this was similar to electrophysiological findings in some human patients with post-anoxic action myoclonus, the pharmacological studies suggest that the myoclonus induced by p,p'-DDT in the rat is not a suitable model for screening potential drugs to be used in the treatment of this disorder.

Animals↗
PubMed1986

An in vivo pharmacological method for the quantitative evaluation of the central effects of alpha 1 adrenoceptor agonists and antagonists.

A new in vivo pharmacological method for the quantitative evaluation of alpha 1-adrenoceptor agonists and antagonists has been developed. It consists of recording the myoclonic twitch activity (MTA) of the suprahyoideal muscle of rats anesthetized with urethane. In these animals, the isomers of amphetamine elicited myoclonic twitch activity; their effects were dose-related and the d-isomer was approximately 3.5 times more effective than the l-isomer. While pimozide did not block this response, the postsynaptic alpha 1-antagonist prazosin fully blocked the myoclonic twitch activity induced by d-amphetamine. Other postsynaptic alpha 1-antagonists, such as haloperidol, phenoxybenzamine and clozapine, were also effective in blocking this response to d-amphetamine. Since d-amphetamine elicited myoclonic twitch activity in rats pretreated with reserpine and alpha-methyl-p-tyrosine, it was concluded that d-amphetamine exerted a direct alpha 1-adrenoceptor stimulation. In rats pretreated with nialamide and pimozide, l-DOPA elicited myoclonic twitch activity which was dose-related. This effect of l-DOPA was promptly and fully blocked by prazosin. It was concluded that this response to l-DOPA resulted from stimulation of alpha 1-adrenoceptors. The relative potencies of four alpha 1-adrenoceptor stimulants, namely, cirazoline, St-587, (-)SKF 89748A and Sgd 101/75 were determined using this method. The results correlated very well with their relative potencies to increase the diastolic blood pressure of pithed rats. Evidence that myoclonic twitch activity is a centrally-mediated response has also been presented. It appears that the method is a simple, sensitive, versatile and easily quantifiable procedure for the evaluation of the central effects of alpha 1-adrenoceptor agonists and antagonists.

Adrenergic alpha-Agonists↗
PubMed1985

Some behavioral effects of microinjections of noradrenaline and serotonin into the amygdaloid body of the rat brain.

The effects of microinjections of noradrenaline (NA) and serotonin (5HT) into the basomedial part of the amygdaloid body (BM AB) on various forms of behavior were studied in rats. NA as well as 5HT administered to the BM AB had dose-related and general inhibitory influence on the rats' behavior in the open field test. The reactivity of rats to pain (tail compression) was attenuated by 5HT injections. The effect of NA in this test was less clear, though some inhibitory tendency was also present. Pretrial injections of NA (40 micrograms) and 5HT (40 micrograms) significantly impaired the retention of a passive avoidance reaction. NA injections also produced some disinhibitory effects on shock-suppressed drinking in the conflict test. The effects of intra-amygdalar administration of NA and 5HT on open field behavior were potentiated by pretreatment of rats with nialamide, a monoaminooxidase inhibitor. The results are discussed in terms of an involvement of the amydalar NA and 5HT in the regulation of animal behavior.

Amygdala↗
PubMedDate not supplied

Profile of drug effects on temporally spaced responding in rats.

A differential reinforcement of low rate schedule was used with rats to test 15 psychotropic drugs. The computer analysis was based on interresponse time (IRT). Mean IRT, IRT standard deviation, median IRT, IRT midrange, modal IRT, frequency of modal IRT, and an efficiency index, in addition to numbers of responses and reinforcements and the IRT histogram were obtained for each rat in each drug test. An increase in number of responses and a peak shift to shorter IRTs in the histograms were observed with amphetamine, methamphetamine, priradrol and nicotine, as reported by many other investigators. Decrease in IRT midrange and less change in number of responses were observed with diazepam and chlordiazepoxide. Long pauses were found with LSD-25, 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. In a factor analysis, the following main factors were obtained. High values in factor loading a1 were observed with chlorpromazine, chlordiazepoxide, pentobarbital, imipramine, nialamide, LSD-25, DOM and mescaline. With these drugs, mean IRT and IRT standard deviation were also high. Values for a2, were high with amphetamine, methamphetamine, pipradrol and nicotine. High a3 values were observed in some rats with chlorpromazine, diazepam, chlordiazepoxide, pentobarbital, pipradrol and caffeine. The changes in a3 values were correlated with changes in the IRT midrange. These results may be valuable in classifying new compounds in drug screening programs as being of the amphetamine type, nicotine type, diazepam type of LSD-25 type.

Animals↗