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Biomedical subjects

C J Pycock

Publications and source records attributed to C J Pycock.

At least 37 records · Page 2Linked to original sources
PubMed1980

Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat.

The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increase in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telencephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.

Animals↗
PubMed1980

Acute motor effects of N-methyl-D-aspartic acid and kainic acid applied focally to mesencephalic dopamine cell body regions in the rat.

Bilateral application of N-methyl-D-aspartate (NMDA) and kainic acid to the substantia nigra, pars compacta (SNc) and the ventral tegmental area (VTA) induced enhanced motor responses in the rat. A greater locomotor response was elicited from the VTA; sniffing was also observed following SNc injections. Both motor activities were blocked by systemic fluphenazine. Application of NMDA and kainate to the substantia nigra pars reticulata caused sedation and catalepsy. The experiments illustrate a dual motor response for excitatory amino acids when applied to either pars compacta or pars reticulata of the rat SN.

Animals↗
PubMed1980

5,7-Dihydroxytryptamine lesions of the amygdala reduce amphetamine- and apomorphine-induced stereotyped behaviour in the rat.

5,7-Dihydroxytryptamine lesions directed towards the central nucleus of the amygdala produced an apparently selective and localised destruction of 5HT terminals within the amygdaloid complex, without damage to dopamine neurons. Such lesions attenuated the biting responses produced by both amphetamine and apomorphine, suggesting that 5HT within this area may play an important role in the mediation of these behavioural effects.

5,7-Dihydroxytryptamine↗
PubMed1980

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.

The effect of lesions of the catecholamine nerve terminals in the medial prefrontal cortex of the rat on neurotransmitter mechanisms within the basal ganglia has been investigated. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the dopamine-rich (DA) area of th frontal cortex. Animals were pretreated with desmethylimipramine to block the uptake of neurotoxin into noradrenergic (NA) terminals and to make it more selective for DA terminals. The lesion produced a selective reduction of both NA and DA from the medial prefrontal cortex, a result related to falls in tyrosine hydroxylase activity at this site. Lesioned animals showed enhanced DA turnover and utilisation in striatal and limbic regions. There was no change in subcortical tyrosine hydroxylase activity. In addition there were significant falls in other putative neurotransmitters within basal sites, including 5-hydroxytryptamine and GABA. Decreased activity of the neurotransmitter-synthesizing enzyme glutamate decarboxylase and choline acetyltransferase was also recorded in certain regions of the basal ganglia. The results suggest that frontal cortical catecholamine systems may serve to regulate various neurotransmitter mechanisms in the basal ganglia.

Animals↗
PubMed1980

Vasoactive intestinal polypeptide (VIP)-sensitive adenylate cyclase in rat brain: regional distribution and localization on hypothalamic neurons.

The regional distribution of the vasoactive intestinal polypeptide (VIP)-sensitive stimulation of adenylate cyclase activity was studied in homogenates or rat brain. The order of sensitivity of this peptide on enzyme activity was: olfactory bulb > hippocampus > thalamus > occipital cortex congruent to frontal cortex congruent to midbrain congruent to hypothalamus > striatum > cerebellum congruent to brain stem > spinal cord. With neurotoxin-induced lesions the possible location of VIP-sensitive adenylate cyclase within the anterior hypothalamus was investigated. Intrahypothalamic 6-hydroxydopamine blocked the stimulatory effect of VIP on hypothalmic adenylate cyclase, but neither kainic acid nor 5,7-dihydroxytryptamine lesions had any effect. Similarly, there was a 71% reduction in the sensitivity of VIP-sensitive adenylate cyclase activity in animals whose hypothalamic noradrenergic innervation had been interrupted by transection of the ascending dorsal and ventral bundles. Biochemical analyses of the lesions suggested that loss of VIP action on adenylate cyclase was associated with loss of hypothalamic noradrenaline-containing neurons. These results may give insight into those regions of rat brain where VIP may have a neurotransmitter role, and point to a possible noradrenergic localization of the VIP-sensitive adenylate cyclase within the hypothalamus.

5,7-Dihydroxytryptamine↗
PubMed1980

A dopamine-5-hydroxytryptamine link in the hypothalamic pathways which mediate heat loss in the rat.

1. Intrahypothalamic injection of either dopamine or 5-hydroxytryptamine (5-HT) in a dose volume of 1 microliters caused a fall in core temperature in lightly restrained rats maintained at an ambient temperature of 17 +/- 1 degree C. 2. Haloperidol (6.5 n-mole), a dopamine antagonist, prevented the hypothermic effect of dopamine (65 n-mole), but was ineffective against the response to either intrahypothalamic 5-HT (114 n-mole) or oxotremorine (6.0 n-mole). 3. Methysergide (14 n-mole) and cryproheptadine (17 n-mole) blocked the effect of both 5-HT and dopamine. However, these same doses failed to antagonise the effect of oxotremorine. 4. Rats placed on 0.65 m below a 250 W infra-red lamp responded to the imposed heat load vasodilation of tail skin blood vessels, as indicated by an increased tail skin temperature. 5. Rats tested 2 weeks after bilateral intrahypothalamic injection of 5,6-dihydroxytryptamine (42 n-mole in 2 microliters) showed a significant reduction in their tail skin temperature response and were less able to withstand the imposed heat load. 6. Three serial sections (0.8 mm thick) were prepared from the preoptic area of the rat brain, one anterior, one posterior and one corresponding to the previously defined dopamine-sensitive site. 7. Pretreatment with 5,6-dihydroxytryptamine significantly reduced the 5-HT concentration in the dopamine sensitive site, but had no effect on the concentration of dopamine. This pretreatment blocked dopamine but not 5-HT-induced hypothermia. 8. The 5-hydroxyindoleacetic acid (5HIAA) concentration in the hypothalamus of the normal rat exposed to a heat load was found to be significantly elevated, whereas there was no change in the 5HIAA concentration in the cortex. 9. Slices of rat preoptic hypothalamus and hippocampus were incubated with [3H]5-HT (0.2-2 microM). These slices accumulated 5-HT with properties characteristic of a neuronal uptake process. 10. Perfusion with either dopamine (greater than 50 microM) or apomorphine (greater than 200 microM) enhanced the release of [3H]5-HT from the prelabelled hypothalamic slices, but failed to stimulate release from hippocampal slices. 11. The release of [3H]5-HT from preoptic slices by dopamine and apomorphine was antagonised by the dopamine antagonists haloperidol (2 microM) and (+) isomer of butaclamol (1 microM), the (-) isomer of butaclamol was inactive. 12. These results support the hypothesis of a dopamine-5HT link in the hypothalamic thermoregulatory pathways of the rat.

Animals↗
PubMed1979

Specific stimulating effect of glycine on 3H-dopamine efflux from substantia nigra slices of the rat.

The effect of glycine was studied on the efflux of tritium-labelled dopamine, 5-HT and GABA from small slices of rat substantia nigra in vitro. A depolarising stimulus (50 mM KCl) stimulated the efflux of 3H-5HT, 3H-dopamine and 3H-GABA in a calcium-dependent fashion. Glycine (50 and 100 micromoles) stimulated the spontaneous efflux of 3H-dopamine but not that of 3H-5HT or 3H-GABA. Taurine, GABA and beta-alanine, all at 100 micromoles, had no effect on release of radioactivity after prelabelling nigral slices with 3H-dopamine. In keeping with a transmitter role for glycine at this site, 3H-glycine was taken up by small slices of rat substantia nigra by both high affinity (Km = 2.4 micromoles) and low affinity systems (Km = 5.96 mM). However 50 mM KCl was without effect on the efflux of radioactivity from nigral slices prelabelled with 3H-glycine.

Alanine↗
PubMed1979

The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour, and amphetamine-induced stereotypy.

5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The sterotyped responses to all doses of amphetamine tested (2.5--10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.

5,7-Dihydroxytryptamine↗
PubMed1979

Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.

The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.

Amino Acids↗
PubMed1979

Potentiation of haloperidol-induced catalepsy by dopamine agonists: possible involvement of central 5-hydroxytryptamine.

Apomorphine (0.12--2 mg/kg, SC) and d-amphetamine (1--8 mg/kg, IP) were each able, at certain doses, to potentiate the cataleptic state produced by the neuroleptic agent, haloperidol (1 mg/kg, IP). In subsequent biochemical experiments, in which the effects of combinations of apomorphine or d-amphetamine and haloperidol on brain monoamine levels were studied, this behavioural observation was seen to be related to an enhanced utilisation of 5-hydroxytryptamine (5-HT) in certain brain regions. The results suggest not only the possible involvement of 5-HT in the production of catalepsy, but also that the effects of these 'classical' dopamine agonists on other central transmitter systems should be considered when interpreting their various behavioural responses.

Animals↗
PubMed1979

Thyrotrophin releasing hormone stimulates release of [3H]-dopamine from slices of rat nucleus accumbens in vitro.

Thyrotrophin releasing hormone (TRH) (25 to 100 microM) was found to stimulate the efflux of [3Hu-dopamine from small slices of rat nucleus accumbens, but not from similar slices of rat caudate nucleus. Uptake inhibition was not responsible for this action, since at 10 and 50 microM TRH had no effect on the ability of small slices of nucleus accumbens to accumulate radioactivity when incubated with 10(-7) M [3H]-dopamine. In addition the hormone had no effect on basal or dopamine-stimulated adenylate cyclase, nor did it displace [3H]-spiperone binding, in membrane preparations from nucleus accumbens.

Adenylyl Cyclases↗