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Biomedical subjects

D J Heal

Publications and source records attributed to D J Heal.

At least 91 records · Page 5Linked to original sources
PubMed1985

Intracerebroventricular administration of 5,7-dihydroxytryptamine to mice increases both head-twitch response and the number of cortical 5-HT2 receptors.

5-Hydroxytryptamine-containing (5-HT) neurones in brain of the mouse were selectively destroyed by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 50 micrograms). Sham-lesioned controls received vehicle (2 microliters, i.c.v.). Two weeks later the head-twitch response induced by 5-methoxy-N,N-dimethyltryptamine (2.0 mg/kg) and mediated by 5-HT2 receptors was markedly enhanced in the lesioned mice. Furthermore, lesioning also increased 5-HT2 binding sites in the cortex, assessed by the binding of [3H]ketanserin in these animals, and decreased levels of 5-HT in the cortex (70%) and mid/hindbrain (64%) regions. A second group of mice, lesioned with less 5,7-DHT (5-20 micrograms, i.c.v.) showed unaltered head-twitch responses to 5-methoxy-N, N-dimethyltryptamine (2.0 mg/kg) and did not have increased 5-HT2 receptor binding in the cortex. Depletions of 5-HT were 32 and 40% in the cortex and mid/hindbrain, respectively. Comparison of the extent of depletion of 5-HT in the mid/hindbrain after lesioning, with the increase in head-twitch response, suggested that depletions of less than 40% did not affect this behaviour. However, depletions greater than 40% produced marked increases in this response and there was a good correlation between these two variables (r=0.701, P less than 0.01). In conclusion, these data suggest that enhanced head-twitch responses occurring after lesioning with 5,7-DHT may result from increased 5-HT2 receptors in brain. Moreover, the magnitude of the observed behavioural enhancement was dependent upon the extent of depletion of 5-HT produced by the lesioning.

5,7-Dihydroxytryptamine↗
PubMed1984

Effects of thyroid status on clonidine-induced hypoactivity responses in the developing rat.

Clonidine-induced hypoactivity was studied in rats made neonatally hypo- and hyperthyroid (PTU or T4 administered between 1-27 days postnatally) as an indication of central presynaptic alpha 2-adrenoceptor function. Paradoxically, at 28 days postnatally both treatments caused an increase in clonidine-hypoactivity compared with untreated control animals, which was not due to sex differences amongst littermates in the various groups. It is proposed that whereas the hyperthyroid neonate data perhaps reflect an enhancement of presynaptic alpha 2 function similar to that seen in the adult rat brain, the result obtained for the hypothyroid neonates could perhaps be due to a retardation of the ontogeny of central noradrenergic neurones.

Animals↗
PubMed1984

Effects of thyroid status on presynaptic alpha 2-adrenoceptor function and beta-adrenoceptor binding in the rat brain.

The effect of thyroid status on noradrenergic synaptic function in the mature rat brain was examined by measuring presynaptic alpha 2- and post-synaptic beta-adrenoceptors. Repeated triiodothyronine (T3) administration to rats (100 micrograms/kg X 14 days: hyperthyroid) caused an 18% increase in striatal beta-adrenoceptors as shown by [3H]-dihydroalprenolol binding with no change in membranes from cerebral cortex or hypothalamus. In contrast, hypothyroidism (propylthiouracil, PTU X 14 days) produced significant 12% and 30% reductions in striatal and hypothalamic beta-adrenoceptors respectively with no change in the cerebral cortex. Presynaptic alpha 2-adrenoceptor function was measured in the two dysthyroid states using the clonidine-induced hypoactivity model. Experimental hyperthyroidism increased the degree of clonidine-induced hypoactivity, and suggests increased presynaptic alpha 2-adrenoceptor function compared with control rats, whereas hypothyroidism suppressed presynaptic alpha 2-adrenoceptor function. These results show firstly that changes in thyroid status in the mature rat may produce homeostatic alterations at central noradrenergic synapses as reflected by changes in pre- and post-synaptic adrenoceptor function. Secondly, there appear to be T3-induced changes in beta-adrenoceptors in the striatum where changes in dopaminergic neuronal activity have previously been demonstrated.

Animals↗
PubMed1984

Phenylephrine-induced activity in mice as a model of central alpha 1-adrenoceptor function. Effects of acute and repeated administration of antidepressant drugs and electroconvulsive shock.

Intracerebroventricular injection of the alpha 1-agonists phenylephrine (10-100 micrograms) or methoxamine (10-50 micrograms) produced a dose-dependent increase in locomotor activity and behavioural excitation in mice. The syndrome induced by phenylephrine was inhibited by prazosin but not yohimbine, RX 781094 or propranolol. Methoxamine-induced responses were, however, also reduced by yohimbine. Activity induced by phenylephrine was not affected by metergoline or pirenperone but was reduced by haloperidol and spiroperidol. This latter effect, however, may have been due to inhibition of alpha 1-adrenoceptors and/or dopamine receptors. Pretreatment with alpha-methyl-p-tyrosine or FLA-63 reduced responses to phenylephrine by respectively inhibiting either the locomotor activity or the other behavioural components of the syndrome. This suggests that some residual noradrenergic and possibly also dopaminergic function may be necessary for the behavioural expression of the effects of phenylephrine. The activity was inhibited by mianserin and amitriptyline but not by desmethylimipramine. When these antidepressant drugs were given twice daily for 14 days, mianserin alone affected the activity induced by phenylephrine, tested either 12 or 60 hr after the final injection. This behaviour was also not altered 24 hr after the mice had received an electroconvulsive shock under halothane anaesthesia, once daily for 10 days. In conclusion, the data suggest that the behavioural syndrome induced by phenylephrine probably provides a specific and quantifiable assessment of central alpha 1-adrenoceptor function and that in general this is unaltered following repeated administration of antidepressant drugs or electroconvulsive shock.

Adrenergic alpha-Agonists↗
PubMed1983

Hypophysectomy alters both 5-hydroxytryptamine- and alpha 2-adrenoceptor-mediated behavioural changes in the rat.

Hypophysectomy, but not sham-hypophysectomy, reduced tranylcypromine/L-tryptophan hyperactivity when compared with unoperated controls although brain 5-hydroxytryptamine concentrations were not different. Hypophysectomy also reduced quipazine locomotor activity but did not alter spontaneous locomotion. Hypophysectomy potentiated clonidine hypoactivity but did not itself produce sedation. Furthermore, noradrenaline concentrations were not altered in either hypothalamus or nucleus accumbens. This suggests that pituitary function is necessary for the normal manifestation of behaviours mediated by postsynaptic 5-hydroxytryptamine receptors and presynaptic alpha 2-adrenoceptors.

Animals↗
PubMed1983

Studies on the mechanisms by which clenbuterol, a beta-adrenoceptor agonist, enhances 5-HT-mediated behaviour and increases metabolism of 5-HT in the brain of the rat.

The head twitch response in mice produced by injection of 5-hydroxytryptophan (100 mg/kg i.p.) and carbidopa (25 mg/kg i.p.) was enhanced by administration of clenbuterol (0.5 mg/kg i.p.), a beta-adrenoceptor agonist. Clenbuterol also enhanced the hyperactivity syndrome in rats produced by quipazine (25 mg/kg i.p.), a 5-hydroxytryptamine (5-HT) agonist. This enhancement was not prevented by depletion of 5-HT in brain with p-chlorophenylalanine or after pretreatment with prazosin. The behavioural responses of the rats to administration of the alpha 2-adrenoceptor agonist, clonidine, was unaltered by acute or longer-term administration of clenbuterol. Following chronic administration of clenbuterol (5 mg/kg daily for 14 days), a procedure resulting in down-regulation of central beta-adrenoceptors, a larger dose of clenbuterol was necessary to enhance the quipazine-induced hyperactivity, suggesting that the mechanism of enhancement involved central post-synaptic beta-adrenoceptors. Further evidence for this conclusion was that a lesion of central noradrenaline pathways produced by 6-hydroxydopamine did not abolish the clenbuterol-induced enhancement of the quipazine-mediated behaviour. The binding characteristics of 5-HT2-receptors were unchanged by acute or chronic administration of clenbuterol. Clenbuterol (5 mg/kg) increased the percentage of plasma free (non-albumin bound) tryptophan, plasma free fatty acid concentration and the concentration of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The increase in 5-HT turnover in brain was prevented by pretreatment with the beta 1-adrenoceptor antagonist atenolol, which enters the brain poorly. It is therefore suggested that the clenbuterol-induced increase in 5-HT metabolism results from the increase in the concentration of plasma free fatty acid which increases plasma free tryptophan and thus increases the concentration of tryptophan in brain and 5-HT synthesis in brain. The clenbuterol-induced enhancement of 5-HT-mediated behaviour is therefore not associated with its effect on 5-HT metabolism. The data are discussed in relation to that obtained after administration of antidepressant drugs.

Animals↗
PubMed1983

The effects of acute and repeated administration of various antidepressant drugs on clonidine-induced hypoactivity in mice and rats.

Small doses of clonidine produce hypoactivity in mice and rats, probably by stimulating pre-synaptic alpha 2-adrenoceptors in the brain. When mice were injected with desmethylimipramine (DMI, 5 mg/kg) before clonidine it attenuated the hypoactivity, while pretreatment with amitriptyline (5 mg/kg) or mianserin (5 mg/kg) potentiated this behaviour. In rats, desmethylimipramine (20 mg/kg) inhibited and mianserin (5 mg/kg) potentiated the clonidine-induced hypoactivity. Amitriptyline (20 mg/kg), however, had no effect on this behaviour in rats. Mice were also given repeated injections of these 3 antidepressant drugs (5 mg/kg twice daily for 14 days) and were tested with clonidine 12 and 60 hr after the final treatment. At 12 hr desmethylimipramine and amitriptyline both attenuated the hypoactivity responses while the reduction by mianserin was marginal (potency DMI greater than amitriptyline greater than mianserin). At 60 hr, however, amitriptyline and mianserin both decreased the clonidine-induced responses while the attenuation by desmethylimipramine was slight (potency amitriptyline congruent to mianserin greater than DMI). In rats, repeated injections of desmethylimipramine (20 mg/kg), administered twice daily for 14 days, attenuated the clonidine-induced hypoactivity 12 hr after the final treatment and this effect persisted for at least 72 hr. Furthermore, the degree of inhibition of the behavioural responses did not correlate with plasma concentrations of desmethylimipramine and persisted after disappearance of the drug from plasma. In conclusion, these data suggest that after repeated injection, desmethylimipramine, amitriptyline and mianserin all produce an adaptive decrease in the function of central alpha 2-adrenoceptors but the time course of this change differs with the individual antidepressant drug administered.

Amitriptyline↗
PubMed1983

Antidepressant treatments: effects in rodents on dose-response curves of 5-hydroxytryptamine- and dopamine-mediated behaviours and 5-HT2 receptor number in frontal cortex.

The effects of repeated electroconvulsive shock (ECS) administration, repeated desmethylimipramine injection (5 mg kg-1, twice daily for 14 days) and acute administration of the beta-adrenoceptor, clenbuterol, on 5-hydroxytryptamine (5-HT)- and dopamine-mediated behaviours in mice have been examined. All three treatments enhanced the carbidopa/5-hydroxytryptophan (5-HTP)-induced head-twitch response at all doses of 5-HTP examined, producing a parallel shift in the dose-response curve. A single ECS administration or single dose of desmethylimipramine had no effect. Only repeated ECS enhanced the locomotor response to injection of apomorphine. The dose-response curve shift was not parallel. A single ECS had no effect. A 6-hydroxydopamine lesion of brain dopamine terminals also enhanced the apomorphine response, but again did not produce a parallel shift in the dose-response curve. Both repeated ECS and repeated desmethylimipramine administration to rats increased the number of 5-HT2 receptor sites in rat brain. Clenbuterol had no effect. The enhancing effects of repeated ECS and clenbuterol administration on the 5-HTP-induced head-twitch response were additive. Enhanced 5-HT-mediated behavioural responses are seen in both mice and rats after these treatments. If it is assumed, therefore, that similar receptor changes occur in both species it appears that there is no relationship in either behavioural system between the ability of the treatment to alter receptor number and the change in the dose-response curve (parallel or non-parallel). All three antidepressant treatments (ECS, a tricyclic and a beta-adrenoceptor agonist) increase 5-HT-mediated behavioural responses although clenbuterol did not increase 5-HT2 receptor number. Only ECS increased dopamine-mediated responses.

5-Hydroxytryptophan↗
PubMed1982

Repeated administration of subconvulsant doses of GABA antagonist drugs. II. Effect on monoamine-mediated behaviour.

The effect on monoamine-medical behaviour of repeated daily subconvulsive doses of the GABA antagonist drugs pentylenetetrazol (PTZ) (30 mg/kg for 8 days), picrotoxin (5 mg/kg for 4 days) and bicuculline (3.5 mg/kg for 16 days) was investigated. None of the drugs, administered chronically, increased behavioural responses to the 5-hydroxytryptamine agonist quipazine (25 mg/kg), and neither picrotoxin nor bicuculline altered the locomotor response to the dopamine agonist apomorphine (AP) (0.1 mg/kg). By contrast, repeated doses of PTZ increased the locomotor response to AP, and also increased circling responses to both AP (0.5 mg/kg) and methamphetamine (2.0 mg/kg) in unilateral nigrostriatal-lesioned rats.

Animals↗
PubMed1982

Hypophysectomy does not prevent the enhanced monoamine-mediated behavioural responses following repeated electroconvulsive shocks.

Groups of hypophysectomised rats were given either an electroconvulsive shock (ECS; 125V, 1 sec) once daily for 10 days or a sham-shock. Twenty-four hours after the final treatment both groups were tested for their responses to the dopamine agonist, apomorphine, the 5-hydroxytryptamine agonist, quipazine, and the alpha 2-adrenoceptor agonist, clonidine. Repeated electroconvulsive shock enhanced the locomotor activity produced by either quipazine (25 mg/kg i.p.) or apomorphine (0.2 mg/kg s.c.) compared to sham-shocked controls. This treatment also attenuated the hypoactivity produced by clonidine (0.5 mg/kg i.p.). These changes are identical to those produced in normal rats by repeated electroconvulsive shock. Hypophysectomy, therefore, did not abolish the increased 5-hydroxytryptaminergic and dopaminergic behavioural responses neither did it prevent the decreased functional activity of central alpha 2-adrenoceptors, which may be presynaptic. These data suggest that although electroconvulsive shock has been reported to stimulate the secretion of various pituitary hormones, this process is not essential for the development of the enhanced monoamine-mediated behavioural responses studied.

Animals↗
PubMed1982

Repeated administration of triiodothyronine (T3) to rats enhances nigrostriatal and mesolimbic dopaminergic behavioural responses.

A once daily injection to rats of triiodothyronine (T3; 100 micrograms/kg s.c.) for 10 days enhanced the locomotor responses of rats pretreated with tranylcypromine (5 mg/kg) to an injection into the nucleus accumbens of dopamine (5 micrograms bilaterally), when tested 24 hr after the last T3 administration. This treatment did not, however, alter the control responses of tranylcypromine-pretreated rats to injection of saline (1 microliter bilaterally). Injection of T3 for 10 days enhanced the circling responses of unilateral nigrostriatal-lesioned rats to apomorphine (0.5 mg/kg) but not to methamphetamine (0.5 mg/kg). The probable explanation for the latter result was the finding that repeated T3 administration lowered basal striatal dopamine concentrations. The treatment also produced a trend towards reduced dopamine concentrations in the n. accumbens, although the difference did not reach statistical significance. These data suggest that repeated T3 injection causes an increased post-synaptic function of both the nigrostriatal and mesolimbic dopamine systems in rat brain.

Animals↗
PubMed1982

beta-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses.

The beta-adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5-hydroxytryptamine-mediated (5-HT) hyperactivity. 2 The lipophilic beta-adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind-limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5-HT agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg) and the combination of tranylcypromine (10 mg/kg) and L-tryptophan (50 mg/kg). Salbutamol and terbutaline potentiated quipazine-induced hyperactivity only when given at the higher dose of 20 mg/kg. 3 The effect of clenbuterol in enhancing quipazine hyperactivity was blocked by the centrally acting beta 1-adrenoceptor antagonist, metoprolol (5 mg/kg), but not by the beta 2-adrenoceptor antagonist, butoxamine (5 mg/kg) or the peripherally acting beta 1-adrenoceptor antagonist, atenolol (5 mg/kg). 4 Clenbuterol (5 mg/kg) did not enhance the circling responses produced by methamphetamine (0.5 mg/kg) in unilateral nigrostriatal-lesioned rats. 5 The results suggest that beta-adrenoceptor agonists in common with some established antidepressant treatments produce enhancement of 5-HT-mediated behavioural responses.

Adrenergic beta-Agonists↗
PubMed1981

Repeated electroconvulsive shock attenuates clonidine-induced hypoactivity in rodents.

Clonidine administration at low dose produces hypoactivity in both rats and mice, probably by stimulation of presynaptic alpha 2-adrenoceptors in the brain. This behaviour is antagonised by yohimbine pretreatment but is unaffected by pretreatment with prazosin. An electroconvulsive shock (ECS) given once daily for 10 days markedly attenuated the hypoactivity in both species when tested 24 h after the final shock. The attenuation in mice was not found after either a single ECS or 10 subconvulsive shocks. Ten ECS did not alter the hypoactivity response produced by (+/-)-propranolol in mice. Clonidine administration decreased rat brain MOPEG-SO4 concentrations. A single ECS given daily for 10 days abolished this decrease. These results suggest that repeated ECS causes a subsensitivity of alpha 2-adrenoceptors in the brain and that these receptors may be located presynaptically.

Animals↗
PubMed1978

Neuroleptic drugs block both the hyperactivity and the increase in caudate nucleus cyclic AMP concentration produced by the administration of tranylcypromine and L-dopa to rats.

Injection of rats with tranylcypromine and L-dopa increased brain dopamine concentrations and produced a behavioural syndrome that includes hyperactivity. It also elevated caudate nucleus cyclic AMP concentrations by approximately 50% in vivo, probably by stimulating dopamine receptors. Pretreatment with chlorpromazine inhibited both the tranylcypromine/L-dopa-induced behaviour and elevated cyclic AMP concentrations in a dose-dependent manner. Haloperidol and alpha-flupenthixol also inhibited both effects, while beta-flupenthixol and pimozide were without effect. Since none of these drugs altered the tranylcypromine/L-dopa-induced rise of brain dopamine, it is likely that they produced their effect by inhibiting dopamine-sensitive adenylate cyclase. A good correlation was found to exist between the neuroleptic inhibition of both the increased behavioural activity and the increased caudate nucleus cyclic AMP concentrations produced by tranylcypromine and L-dopa.

Animals↗