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Biomedical subjects

T Archer

Publications and source records attributed to T Archer.

At least 91 records · Page 5Linked to original sources
PubMed1988

Comparison of desipramine, amitriptyline, zimeldine and alaproclate in six animal models used to investigate antidepressant drugs.

In the present paper the acute actions primarily of the tricyclic antidepressants amitriptyline and desipramine, the atypical antidepressant zimeldine and the potential antidepressant alaproclate were evaluated in six models used for studying antidepressant agents. These included the forced swim test, a modified learned helplessness procedure, the clonidine hypothermia test, the social dominance test (using the interaction with clonidine), a differential-reinforcement-of-low-rates (DRL-72s) schedule and conditioned avoidance response. The results showed desipramine to be effective in all the tests employed. Zimeldine was effective in the learned helplessness, DRL-72s and domination tests, but also caused notable deficits in two-way active avoidance response. Alaproclate was effective in all the tests except the domination paradigm. Amitriptyline was effective in all tests employed. The results are discussed in relation to the possible mechanism of action of these compounds in the test models employed.

Alanine↗
PubMed1987

Impaired performance of rats in the Morris swim-maize test late in abstinence following long-term sodium barbital treatment.

Rats were tested for place learning in the Morris swim maze on days 110-114 of abstinence following 48 weeks of treatment with sodium barbital. A retarded acquisition of the swim-maze task, that could not be ascribed to motor impairments, was found in the barbital-treated rats. There was a significant difference in brain weight, but there were no significant differences between the control and barbital-treated rats in the frontal cortical concentrations of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), nor in the intra- and extrasynaptosomal activities of cerebral cortical monoamine oxidase towards NA and 5-HT. Postsynaptically, neither the cerebral cortical inositol phospholipid breakdown responses to carbachol and NA (mediated by muscarinic and alpha 1-adrenergic receptors, respectively), nor the striatal and cortical densities of muscarinic receptors labelled by [3H]quinuclidinyl benzilate [( 3H]QNB) were found significantly to be altered in the barbital-treated rats. A strong correlation between the density of striatal and cortical [3H]QNB binding sites was seen for the barbital-treated (r = 0.91) but not for the control (r = -0.05) rats. It is suggested that the deficit in performance of the barbital-treated rats in the Morris maze may be related to a cholinergic dysfunction.

Animals↗
PubMed1987

Increased antinociception by alpha-adrenoceptor drugs after spinal cord noradrenaline depletion.

Animals depleted of the bulbospinal NA fiber tracts have been reported to be supersensitive to antinociceptive effects of intrathecally administered noradrenaline (NA) in vivo. In the present investigation, the antinociceptive effects were determined after systemic or intrathecal injections of noradrenergic agents. NA and the selective alpha 2-adrenoceptor agonists guanfacine and clonidine were used. NA depletion was performed by treatment neonatally with 6-hydroxydopamine (6-OHDA), or in adult animals by intrathecal 6-OHDA administration or systemic N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4). The neurotoxins were found to cause a severe depletion of spinal NA without affecting dopamine (DA) or 5-hydroxytryptamine (5-HT) levels. The antinociceptive effects of intrathecal injection of NA, clonidine and guanfacine were more strongly enhanced in the depleted than in the control rats. It was also found that clonidine and guanfacine given systemically had a stronger effect in depleted than in control animals. In conclusion, depletion of descending NA pathways induces functional supersensitivity both to intrathecally administered NA and to the selective alpha 2-adrenoceptor agonists clonidine and guanfacine. It was also found that systemically administered clonidine and guanfacine had a stronger effect in NA-depleted than in control animals.

Adrenergic alpha-Agonists↗
PubMed1987

(+)-8-OH-DPAT and 5-MeODMT induced analgesia is antagonised by noradrenaline depletion.

In experiments with both rats and mice the 5-HT agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT) were shown to produce reliable analgesic effects after acute administration (1 mg/kg SC) in the tail-flick, hot-plate and shock-titration tests of nociception. Prior treatment with the noradrenaline neurotoxin, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), systemically administered to both rats and mice abolished the analgesic effects of both the 5-HT agonist compounds in all the tests of nociception used. Intrathecal 6-hydroxydopamine (6-OHDA) treatment also abolished the analgesic effects of 8-OH-DPAT and 5-MeODMT; in the tail-flick test the analgesia induced by 8-OH-DPAT was reversed to an hyperalgesia. Biochemical analyses confirmed notable noradrenaline depletions in the spinal cord. It is concluded that an important interaction between presynaptic noradrenergic terminals and serotonergic receptor sites, possibly 5-HT1A, mediates spinal nociception processes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

5-Hydroxytryptamine antagonists and the 5-methoxy-N,N-dimethyltryptamine-induced changes of postdecapitation convulsions.

The ability of various compounds to antagonise the 5-MeODMT induced prolongations of latency and duration of postdecapitation convulsions (PDCs) were compared. The 5-hydroxytryptamine (5-HT) receptor antagonists, mianserin, methergoline, cinanserin and methysergide antagonised the 5-MeODMT (0.5 to 4.0 mg/kg) induced prolongations of latency to onset of convulsions substantially and to a lesser extent the prolongation of duration. The efficacy of the 5-HT antagonists for blocking 5-MeODMT changes of PDCs was roughly of the order mianserin greater than cinanserin greater than methysergide greater than methergoline. Pirenperone, the 5-HT2 antagonist, and pimozide, the dopamine receptor antagonist did not antagonise the 5-MeODMT induced changes. Mianserin, methergoline, cinanserin and methysergide, by themselves, prolonged the duration of PDCs but did not affect latency. Pirenperone (0.25 mg/kg) prolonged both the latency and duration of the PDCs while pimozide (0.5-2.0 mg/kg) had no effect upon PDCs. This evidence suggests that 5-MeODMT induced changes of PDCs are mediated via 5-HT1 receptors and thus a reliable model to combine with other measures of spinal function is suggested.

Animals↗
PubMed1987

Chronic treatment with antidepressant drugs and ECT differentially modifies the hypothermic action of clonidine and guanfacine.

The hypothermia inducing action of clonidine and guanfacine was abolished by yohimbine and idazoxan pretreatment which suggests an alpha 2-adrenoceptor involvement in this effect. The effects of acute and chronic treatment with the antidepressant drugs desipramine (DMI), amitriptyline (AMI), maprotiline (MAP), mianserin (MIAN), iprindol (IPR), alaproclate (ALA) and electroconvulsive treatment (ECT) on the hypothermic action of the alpha 2-adrenoceptor agonists clonidine and guanfacine were studied. Acute administration of MIAN potentiated clonidine induced hypothermia whereas acute MIAN, IPR and ALA potentiated guanfacine induced hypothermia. Repetitive DMI, AMI and MAP treatment attenuated clonidine-induced hypothermia whereas guanfacine-induced hypothermia was potentiated by chronic treatment with DMI, AMI, MAP and MIAN, ECT applied without anaesthesia attenuated both clonidine and guanfacine hypothermia, however, under ethyl ether anaesthesia ECT was effective only towards guanfacine hypothermia. This discrepancy is discussed in terms of the relative selectivity of the agonists used, the reliability of agonist studies for indexing receptor function, and possible pharmacokinetic interaction.

Animals↗
PubMed1987

Antinociceptive effects and spinal cord tissue concentrations after intrathecal injection of guanfacine or clonidine into rats.

In the present study, the antinociceptive effects of intrathecal injections of the alpha 2-adrenoceptor agonists clonidine and guanfacine in rats was determined to establish their dose-response curves. Spinal cord tissue concentrations were also determined in a separate group of animals. Guanfacine was found to be more potent than clonidine and had a considerably longer duration of action. Thus, whereas the analgesic effect of clonidine declined to baseline by 4 hr after injecting doses of up to 50 micrograms, guanfacine still showed a considerable effect 18 hr after injecting both 25 and 50 micrograms. With both compounds, concentration gradients existed within the spinal cord. In the experiments with guanfacine, the region in the spinal cord tissue with the highest concentrations 10 min after injection contained around 30 pmol/mg wet weight. At 3 hr, this figure was around 20 pmol/mg. With clonidine, on the other hand, the concentration decreased from the maximal level of 200 pmol/mg at 10 min to 10 pmol/mg at 3 hr. On all occasions, except 10 min after injecting clonidine, it was found that the maximal tissue concentrations for both drugs remained below the cervical spinal cord, i.e., the rostral spread was less than expected, especially with drugs with such a long duration of action. The present investigation demonstrates analgesic effects of both clonidine and guanfacine after intrathecal administration, with guanfacine proving more potent and longer acting; the difference in duration of action is probably attributable to differences in rates of elimination of the drugs from spinal cord tissue.

Adrenergic alpha-Agonists↗
PubMed1987

Lack of effects of prenatal exposure to lidocaine on development of behavior in rats.

The objective of this investigation was to study the effects of lidocaine upon postnatal development of the rat. Lidocaine, 6 mg/kg (21 mumol/kg), was given to a group of 12 rats. Injections were administered intramuscularly, bilaterally in the masseter muscles, once a day on days 10 and 11 of pregnancy. Twelve control rats were given physiologic saline. Clinical signs, mortality, body weight, and food consumption were recorded during pregnancy and lactation. The duration of gestation was also recorded. The development of the offspring was monitored by tests of spontaneous activity, nociception, learning ability, and physical development. No clinical signs of adverse reactions were seen in any of the groups. In the majority of the learning ability tests, the control and lidocaine-treated groups showed similar results. However, in the schedule of differential reinforcement of low rates of responding (DRL 20), the lidocaine-exposed males received more reinforcements than the controls and made fewer responses. In the tests of nociception, a significant difference between sexes was recorded, in that the females were more sensitive than the males in the shock-titration test. Physical development, as monitored by swimming ability and spontaneous activity, showed no inter-group difference. The present results indicate that prenatal exposure to lidocaine fails to result in postnatal impairment of the development of behavioral performance of a wide range of tasks.

Animals↗
PubMed1986

Selective lesioning of forebrain noradrenaline neurons at birth abolishes the improved maze learning performance induced by rearing in complex environment.

The effect of selective destruction of forebrain noradrenaline (NA) neurons induced by 6-hydroxydopamine (6-OHDA) at Day 1 after birth on Hebb-Williams maze performance was investigated in adult rats housed after weaning in a complex environment (EC) or an isolated (IC) environment for 35 days. Saline treated control rats raised in the EC made fewer errors than those raised in the IC. This effect of EC was completely abolished in 6-OHDA treated rats; for these animals no improved performance due to the housing condition was obtained. Protection of the NA neurons against 6-OHDA neurotoxicity by pretreatment with desipramine (DMI) resulted in an effect of EC identical to that seen in saline-treated controls. Postweaning housing in the IC led to an increased locomotion as compared to housing in EC, but this effect was not affected by neonatal 6-OHDA and/or DMI treatment. Neurochemical analysis confirmed cortical NA and metabolite depletion as well as a good protection by the DMI pretreatment. The present results indicate that central NA neurons are involved critically in mediating mainly the cognitive components of behavioral alterations induced by EC.

Animals↗
PubMed1986

Noradrenaline-serotonin interactions in the control of sexual behavior in the male rat: DSP4-induced noradrenaline depletion antagonizes the facilitatory effect of serotonin receptor agonists, 5-MeODMT and lisuride.

The present communication reports how depletion of central noradrenaline neurons of DSP4 treatment antagonizes the facilitatory actions of 5-MeODMT and lisuride on male rat sexual behavior. In males with intact noradrenaline, 5-MeODMT facilitated sexual behavior by reducing the number of intromissions required for ejaculation; inhibitory actions were also noted, since 5-MeODMT prolonged intromission and ejaculation latencies. In DSP4-pretreated animals the inhibitory effect of 5-MeODMT remained unchanged, whereas its facilitatory action was abolished. Consistent with previous research, lisuride also reduced intromission frequency prior to ejaculation. This facilitation of sexual behavior was not observed in DSP4-treated animals. In the male rat, ejaculations following the first have a lower latency and are preceded by a lower number of intromissions. This naturally occurring facilitation of sexual behavior was not prevented by DSP4-induced noradrenaline depletion. Our results suggest that serotonin and noradrenaline interact in the control of sexual behavior in the male rat.

Animals↗
PubMed1986

The effect of selective noradrenergic lesions upon the stimulation by noradrenaline of inositol phospholipid breakdown in rat hippocampal miniprisms.

The breakdown of inositol phospholipid (PI) stimulated by hippocampal noradrenaline in rat miniprisms in vitro was used as an index of alpha 1-adrenoceptor function after selective noradrenergic denervation. Selective denervation was produced by microinjections of 6-hydroxydopamine (6-OHDA) into either the dorsal noradrenergic bundle (DNAB) or the locus coeruleus (LC), or by systemic treatment with the noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). Fourteen days after these treatments, there was a large depletion of cortical noradrenaline but no change in the stimulation of hippocampal PI breakdown by noradrenaline. It is concluded that selective noradrenergic denervation under the conditions used here does not lead to hippocampal alpha 1-adrenoceptor supersensitivity as assessed by noradrenaline-stimulated PI breakdown.

Animals↗
PubMed1986

Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior.

Male rats were given 6-hydroxydopamine-induced lesions of the locus coeruleus (LC) or the dorsal noradrenergic bundle (DNAB), prior to the measurement of locomotor and rearing activity induced by D-amphetamine. The increased locomotor activity induced by D-amphetamine (1.8 mg/kg) was significantly attenuated by both the LC and the DNAB lesions. The stimulatory effect of the 7.2 mg/kg dose of amphetamine was attenuated by the LC lesion, whereas the DNAB lesion potentiated this effect. The LC lesion also attenuated rearing induced by the 7.2 mg/kg dose of amphetamine. These results suggest some involvement of central noradrenergic neurons in the activity induced by amphetamine in the rat.

Animals↗
PubMed1986

Spinal noradrenergic neurotransmission and the analgesia induced by brief footshock.

Antinociception induced by brief footshock as well as by 5-methoxy-N,N-dimethyltryptamine was antagonized by lesions of the descending bulbospinal noradrenergic (NA) pathways by intrathecal injections of 6-hydroxydopamine. The alpha 2-adrenoceptor antagonist, yohimbine, injected intrathecally also blocked both types of nociceptive effects in the tail-flick and hot-plate tests. 5-Methoxy-N,N-dimethyltryptamine (1 mg/kg) potentiated shock-induced antinociception and this potentiation was also antagonized by decreased NA neurotransmission. These findings suggest an important role for spinal NA innervation, and possibly alpha 2-adrenoceptors in antinociception induced by brief footshock and serotonergic receptor stimulation induced analgesia in rats.

Afferent Pathways↗
PubMed1986

Noradrenergic-serotonergic interactions and nociception in the rat.

Spinal noradrenaline (NA) depletion in rats, via either systemic N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) or intrathecal 6-hydroxydopamine (6-OHDA), reversed and/or abolished the analgesic effects of the 5-hydroxytryptamine (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA), in shock titration, hot-plate and tail-flick measures of pain sensitivity. Spinal NA depletion also abolished the analgesic effects of 5-HT itself, administered intrathecally, in all three nociception tests and potentiated the analgesic effects of intrathecal NA, a demonstration of receptor supersensitivity. Spinal 5-HT depletion, via intrathecal 5,7-dihydroxytryptamine (5,7-DHT), only attenuated 5-MeODMT-induced analgesia in the tail-flick test but potentiated the 5-MeODMT effect in the hot-plate test. Intrathecal 5,7-DHT treatment caused a drastic potentiation of NA-induced analgesia in the shock titration and tail-flick tests but not in the hot-plate test. Biochemical analyses confirmed the NA and 5-HT depletion. The spinal noradrenergic system appears to be an important tonic factor modulating the function of the descending 5-hydroxytryptaminergic pathway.

5,7-Dihydroxytryptamine↗
PubMed1986

Analgesia induced by 5-hydroxytryptamine receptor agonists is blocked or reversed by noradrenaline-depletion in rats.

The antinociceptive effect of acute administration of 5-HT receptor agonists and agents releasing 5-HT from neuronal terminals was studied in rats by using the hot-plate, tail-flick and shock-titration tests. Noradrenaline depletion by the noradrenaline-neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4, 2 X 50 mg/kg) blocked the analgesia induced by the 5-hydroxytryptamine (5-HT) receptor agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and quipazine, as well as that induced by acute release of 5-HT by p-chloroamphetamine (PCA) and increased 5-HT synthesis by 5-hydroxytryptophan (5-HTP). Analgesia in the tail-flick test was partly blocked by both methergoline and mianserin, whereas the analgesic effects of 5-MeODMT in the hot-plate and shock-titration tests were unaffected by the 5-HT antagonists. In the shock-titration test it was found that the DSP4-pretreated animals were made hyperalgesic by acute 5-MeODMT, and this hyperalgesia was blocked by both mianserin and methergoline, implying that this effect was 5-HT receptor mediated. It is therefore concluded that a functional central noradrenergic system is required for eliciting 5-HT receptor mediated analgesia, and that these interactions, at least in part, are probably spinally located.

5-Hydroxytryptophan↗
PubMed1986

Central noradrenaline depletion antagonizes aspects of d-amphetamine-induced hyperactivity in the rat.

The effects of noradrenaline (NA) depletion upon amphetamine-induced hyperactivity were examined in five experiments. Central NA depletion via either systemic DSP4 or neonatal 6-OHDA antagonised the amphetamine-induced (2 mg/kg SC) increase in rearing behaviour, whereas lesions of the dorsal noradrenergic bundle using 6-hydroxydopamine antagonised the increase in locomotor activity. Peripheral NA depletion following systemic 6-hydroxydopamine to adult rats did not cause any changes in motor activity after acute amphetamine administration. Desipramine, the selective NA uptake inhibitor, blocked the effects of DSP4 upon amphetamine-induced rearing. NA depletion antagonised hyperactivity produced by the 2 mg/kg dose of amphetamine, but not the hyperactivity (rearing or locomotion) effects of amphetamine at 1, 4 or 8 mg/kg.

Animals↗
PubMed1986

The inhibition of the cage-leaving response--a model for studies of the serotonergic neurotransmission in the rat.

It was observed that rats that had been given drugs that enhance serotonergic neurotransmission, e.g. the serotonin releasing compounds p-chloroamphetamine (PCA) and fenfluramine, the MAO-A inhibitors and serotonin releasing agents amiflamine and alpha-ethyltryptamine and the serotonin agonists 5-methoxy-N, N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT), m-chlorophenyl piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl)1H-indole (RU 24969), did not leave their home-cages when the grid-covers were removed in contrast to normal rats who almost immediately left the cages. The association between the serotonin neurotransmission and the inhibitory effect of PCA on the cage-leaving response was indicated by the findings that 1. Serotonin uptake inhibitors (alaproclate and citalopram) antagonized the effect of PCA. 2. High, neurotoxic doses of PCA antagonized the effect of PCA when tested one week after the former administration. The serotonin uptake inhibitor zimeldine counteracted the effect of neurotoxic PCA. 3. Depletion of brain serotonin with p-chlorophenylalanine counteracted the effect of acute PCA. 4. Repeated treatment of rats for 7 days with zimeldine, amiflamine, alpha-ethyltryptamine or clorgyline plus a low dose of PCA counteracted the effect of acute PCA probably due to a functional down-regulation at postsynaptic receptors. Clorgyline or a low dose of PCA by themselves had no effect. 5. Compounds interacting with dopamine or noradrenaline mechanisms, e.g. alpha-methyltyrosine, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP 4), pimozide, remoxipride and prazosin did not antagonize the effect of PCA nor did (+)-amphetamine inhibit the cage-leaving response. None of the serotonin receptor antagonists (cinanserin, ketanserin, metergoline, methysergide, metitepine, mianserin, pirenperone) blocked the inhibition of the cage-leaving response produced by PCA, indicating that the receptors involved may not be of the S1- and S2- types. Observation of the cage-leaving response may be a valuable technique in studies of drugs that enhance the serotonin neurotransmission in the rat brain.

Animals↗