Biomedical subjects

P Winn

Publications and source records attributed to P Winn.

At least 55 records · Page 3Linked to original sources

PubMed1992

N-methyl-D-aspartate lesions of the lateral hypothalamus do not reduce amphetamine or fenfluramine anorexia but enhance the acquisition of eating in response to tail pinch in the rat.

These experiments examine the acquisition of tail pinch-induced eating and responses to the anorectic agents d-amphetamine and d,l-fenfluramine by rats bearing N-methyl-D-aspartate (NMDA) lesions of the lateral hypothalamus. Lesioned rats lost weight following surgery but had no significant eating or drinking difficulties in the home cage (Clark et al. 1990). The acquisition of eating in response to tail pinch was enhanced in lateral hypothalamic-lesioned rats: they ate on earlier test sessions than controls and less pressure was required to elicit eating. Home cage food intake over the period when tail pinch was being examined was not affected by the lateral hypothalamic lesions. There were no significant differences between lateral hypothalamic-lesioned and control rats in terms of their anorectic responses to either d-amphetamine or d,l-fenfluramine, though the lesioned rats had a lower baseline intake. These data suggest that the lateral hypothalamus is not an important site for the mediation of amphetamine or fenfluramine anorexia but is involved in the acquisition of tail pinch-induced eating. The disinhibition of responding to tail pinch by lateral hypothalamic lesions is discussed in terms of the possible role the lateral hypothalamus plays in regulating cortical activity. The role of the medial hypothalamus and non-hypothalamic systems in the response to anorectic drugs and tail pinch is discussed.

Amphetamine↗

PubMed1992

NMDA lesions of lateral hypothalamus enhance the acquisition of schedule-induced polydipsia.

Schedule-induced polydipsia (SIP) is affected by damage to various limbic structures that have connections with the lateral hypothalamus. The present experiment sought to determine whether or not SIP could be induced in rats bearing NMDA-induced lesions of the lateral hypothalamus. Following surgery, lesioned rats lost weight and were hypophagic and hypodipsic. Drinking, in response to systemic injection of hypertonic saline, was impaired in lesioned rats. Prior to testing for SIP, all rats were placed on a food-restriction regime to maintain body weight at 85% of normal. There was no statistically significant difference in mean body weight between lesioned and control groups before deprivation began, though lesioned rats were hypodipsic in their home cages. The lateral hypothalamic-lesioned rats acquired SIP significantly more rapidly than controls over the first six sessions, but over four following sessions no differences were present. The enhanced acquisition of SIP by lateral hypothalamic-lesioned rats cannot be accounted for by postoperative recovery of body weight or by hypodipsia in the home cage, neither of which correlated with SIP. It is suggested that the lateral hypothalamus has a role in cueing appropriate and inhibiting inappropriate behavior in conditions of motivational excitement. SIP is suggested to have two CNS components--one excitatory and one inhibitory.

Animals↗

PubMed1992

Additivity of nicotinic and muscarinic cholinergic stimulation of substantia nigra.

Microinjection of cholinergic agonists into the anterior substantia nigra increases behaviours for which there is a pre-existing tendency and a low current rate. Rats received microinjections of carbachol, nicotine or a combination of both into the anterior substantia nigra. Carbachol and nicotine both stimulated consumption of palatable food in a dose-dependent manner (F(3,24) = 3.99, p < 0.02 and F(3,33) = 7.07, p < 0.01 respectively). Addition of carbachol to each dose of nicotine caused a significant increase in feeding compared with nicotine alone (F(1,23) = 7.01, p < 0.015). This suggests muscarinic or nicotinic cholinergic stimulation of the anterior substantia nigra can have behaviourally similar effects and, at the doses used here, the effects of nicotinic and muscarinic stimulation are additive.

Animals↗

PubMed1991

Cholinergic stimulation of substantia nigra: abolition of carbachol-induced eating by unilateral 6-hydroxydopamine lesion of nigrostriatal dopamine neurones.

Microinjection of cholinergic agonists into the substantia nigra is known to elicit increases in eating, drinking and sexual behaviour under appropriate circumstances. It has been suggested that these effects are dependent on stimulation of nigrostriatal dopamine-containing neurones in the substantia nigra pars compacta, but no direct evidence has confirmed this. The present experiment was therefore undertaken to determine whether unilateral lesions of nigrostriatal dopamine neurones made by 6-hydroxydopamine would attenuate or abolish eating in satiated rats elicited by intranigral microinjection of the muscarinic agonist carbachol. Two groups of rats were tested: a 6-hydroxydopamine- and a sham-lesion group. Before lesions were made intranigral microinjection of 0.5 microgram/0.5 microliter carbachol stimulated significantly more eating than control microinjections in both groups. After 6-hydroxydopamine lesions, microinjection of carbachol elicited no more eating than vehicle alone. Rats given sham lesions (ascorbate-saline vehicle only) showed increased feeding to intra-nigral carbachol before and after sham-lesioning. Post-mortem analysis by HPLC was used to determine the concentration of dopamine, DOPAC, HVA, serotonin and 5-HIAA in the lesioned and non-lesioned hemispheres of both 6-hydroxydopamine- and sham-lesioned rats. In caudate-putamen there were significant reductions in the concentration of DA (to 50.03% of the level in control sides), DOPAC (to 49.34%) and HVA (to 63.98%) in the 6-hydroxydopamine-lesioned but not sham-lesioned rats. The concentration of dopamine, DOPAC and HVA were not affected in the nucleus accumbens. The turnover of dopamine (assessed by calculating the ratio of dopamine to DOPAC) in the caudate-putamen but not nucleus accumbens was also altered by the 6-hydroxydopamine lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Cholinergic stimulation of substantia nigra: effects on feeding, drinking and sexual behaviour in the male rat.

Previous studies have shown that cholinergic stimulation of the substantia nigra increases food intake but not other activities. The present experiments were undertaken to determine whether or not activities other than feeding could be stimulated if conditions were appropriate. Microinjections of the cholinergic agonist carbachol (0.5 micrograms/0.5 microliters each side) bilaterally into substantia nigra increased the consumption of dry spaghetti, and, in subsequent tests, changed sexual behaviour in male rats. Ejaculation, mount and intromission latencies were unaffected but intromission frequency (though not mount frequency) was reduced following cholinergic stimulation (experiment 1). In a second experiment, an increase in the consumption of 2.0% saccharin solution and lab chow was stimulated by intranigral carbachol while the intake of tap water, and locomotion, gnawing, grooming, rearing and sniffing were all unaffected. These data indicate that cholinergic stimulation of substantia nigra can affect activity for which there is a pre-existing tendency, regardless of its form. A possible role for nigral acetylcholine in the control of pars compacta dopamine containing neurones is discussed.

Animals↗

PubMed1991

Evidence for functional separation of alpha-1 and alpha-2 noradrenaline receptors by pre-synaptic terminal re-uptake mechanisms.

Information transfer within the central nervous system is predominantly chemical in nature, and occurs both through synaptic specialisations and non-specific diffuse release. The localisation and description of receptors for these two types of neurotransmission is currently a contentious issue. In the present study, the noradrenaline reuptake inhibitor cocaine has been shown to overcome the inhibitory effects of idazoxan, a selective alpha-2 receptor antagonist, but not phentolamine, a non-selective alpha receptor antagonist, on eating following injection of noradrenaline into the rat hypothalamic paraventricular nucleus. Similarly, lesion by 6-hydroxydopamine of noradrenaline terminals in the paraventricular nucleus also reduced the efficacy of idazoxan in blocking eating induced by noradrenaline. These data confirm that postsynaptic alpha-2 receptors are involved in the feeding response to exogenous noradrenaline, but in addition, when taken in conjunction with previously published data, are used to suggest a differential distribution of NA receptors within the hypothalamic paraventricular nucleus. It is proposed that the alpha-2 subtype may be extrasynaptic, the alpha-1 subtype intrasynaptic.

Adrenergic alpha-Antagonists↗

PubMed1991

Neuroendocrine and behavioural responses to hyperosmolality in rats with lesions of the lateral hypothalamus made by N-methyl-D-aspartate.

Excitotoxic lesions of rat lateral hypothalamus produce impairments in eating and drinking, but not motor deficits. However, it has not been established what causes these eating and drinking impairments. In the present experiments, drinking, plasma osmolality and arginine-vasopressin concentration were measured in lateral hypothalamic-lesioned and control rats following systemic injection of hypertonic saline. In response to hyperosmolality, N-methyl-D-aspartate-lesioned rats drank significantly less than controls but showed normal increases in plasma osmolality and arginine-vasopressin concentration. This dissociation of neuroendocrine and behavioural responses suggests that the impairment of rats with excitotoxic lesions of the lateral hypothalamus is unrelated to physiological (as opposed to behavioural) mechanisms of homeostasis.

Animals↗

PubMed1991

The regulation of feeding and drinking in rats with lesions of the lateral hypothalamus made by N-methyl-D-aspartate.

Rats bearing excitotoxic lesions of the lateral hypothalamus are hypodipsic and hypophagic, but responses to 24 h food or water deprivation are normal, as are responses to different taste stimuli. The most striking deficit present in lateral hypothalamic-lesioned rats is an inability to respond as controls to dehydrating, dipsogenic or glucoprivic challenges. The present experiments examined the ability of rats bearing bilateral N-methyl-D-aspartate-induced lesions of the lateral hypothalamus to recognize and respond to changes in their internal environments. All of the lesioned rats tested showed mild to moderate hypophagia and hypodipsia, and none responded properly by drinking over 1 h after i.p. injection of hypertonic saline. However, the addition of glucose to the water supply promoted an increase in drinking and a decrease in lab chow consumption to maintain a constant energy intake; the addition of salt to the diet promoted an increase in drinking and no change in eating; 24 h water deprivation induced the same amount of drinking in lateral hypothalamic-lesioned rats as in controls; and injection i.p. of water (but not physiological saline) before drinking water was returned to rats which were 24 h water deprived suppressed drinking. These data suggest that lateral hypothalamic-lesioned rats are in receipt of normal information from their peripheries, and that they can adjust their behaviour over a period of days or minutes to changes in the internal milieu. The most consistent deficit is in responding actively and rapidly to challenging stimuli; the nature of this and the mechanisms which might produce it are discussed. We suggest that the consequences of excitotoxic lesion are better explained by disruption of input to the cortex from the lateral hypothalamus rather than by interference with metabolic processes.

Adaptation, Physiological↗

PubMed1991

A comparison of excitotoxic lesions of the basal forebrain by kainate, quinolinate, ibotenate, N-methyl-D-aspartate or quisqualate, and the effects on toxicity of 2-amino-5-phosphonovaleric acid and kynurenic acid in the rat.

1. It has been suggested that an NMDA1 receptor subtype might be activated by N-methyl-D-aspartate (NMDA) and ibotenate and an NMDA2 subtype by NMDA or quinolinate, and that the NMDA2 site might be more susceptible to blockade by kynurenic acid. 2. Experiments were carried out to examine the ability of 2-amino-5-phosphonovaleric acid (AP5) and kynurenic acid to antagonize the neurotoxic properties of kainate, ibotenate, NMDA, quinolinate and quisqualate injected into the rat basal forebrain. 3. Following histological analysis of the injection sites, lesion volume was assessed parametrically. Each of the toxins except quisqualate was found to make lesions of parvocellular neurones within the basal forebrain with a relative order of potency: kainate much greater than quinolinate greater than ibotenate = NMDA. 4. Equimolar doses of AP5 abolished the toxicity produced by quinolinate and NMDA; toxicity to kainate and ibotenate was attenuated to approximately 40% of the toxin-alone condition. 5. The antagonistic properties of kynurenate were dose-dependent: equimolar kynurenate had no effect on quinolinate but attenuated the actions of ibotenate, kainate and NMDA; 2 x equimolar kynurenate had no effect on quinolinate or ibotenate but attenuated the toxicity of kainate and NMDA; and 3 x equimolar kynurenate had no effect on the toxicity of kainate or ibotenate, attenuated the actions of NMDA and abolished the toxic action of quinolinate. 6. The results are discussed in terms of the actions of the various toxins at different receptors, differentially sensitive to AP5 and kynurenate.

2-Amino-5-phosphonovalerate↗

PubMed1990

Excitotoxic lesions of the lateral hypothalamus made by N-methyl-d-aspartate in the rat: behavioural, histological and biochemical analyses.

The purpose of this study was to determine whether the excitotoxin N-methyl-d-aspartate (NMDA) could be used to make lesions within the lateral hypothalamus and what effect they had on regulatory behaviour. Larger doses of NMDA were effective in the lateral hypothalamus but tended to spread into adjacent structures; smaller doses made lesions which were contained within the lateral hypothalamus and zona incerta. Lesions which damaged the lateral hypothalamus and surrounding tissue had no effect on the concentration of dopamine (or its metabolites) in the dorsal or ventral striatum. The large lesions, including extrahypothalamic damage, were associated with long-term deficits in lab chow and water intake, but rats with lesions restricted to the lateral hypothalamus made good recoveries, eating and drinking normally from around the tenth day post-operation. Body weight gain was normal in these rats, though there was a long-term loss of body weight compared to controls. Unoperated rats with food intake yoked to lesioned rats showed identical long-term changes in body weight, suggesting that the changes in body weight of lesioned rats may be a reflection of changes in eating and drinking rather than a disruption of a body weight set-point mechanism. Motor deficits were not found; all rats were able to consume without difficulty saccharin solutions. All lateral hypothalamic lesioned rats failed to respond to dehydrating, dipsogenic or glucoprivic challenges. It is concluded that NMDA is an effective toxin in the rat lateral hypothalamus, sparing ascending dopamine fibres, and that the main effect of such lesions is an impairment in responding to physiological challenges.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Endogenous excitotoxic agents.

Although glutamate and aspartate are among the most likely compounds to function as central neurotransmitters, and both can produce cell death in neonatal animals, the efficient uptake systems for these amino acids mean that exceptionally high concentrations are required for toxicity in adults. A better candidate for an endogenous neurotoxin is quinolinic acid, which produces cell death via activation of the N-methyl-aspartate receptors. Several differences of detail between the activity of quinolinate and N-methyl-aspartate may indicate the existence of subpopulations of the N-methyl-aspartate receptor. Another compound in the same 'kynurenine' pathway as quinolinate, kynurenic acid, is an antagonist of the excitatory and neurotoxic actions of quinolinate, and the overall excitability of the central nervous system and the occurrence of cell death may therefore result from a balance between the concentrations of quinolinate and kynurenate.

Animals↗

PubMed1985

Neurotoxic amino acid lesions of the lateral hypothalamus: a parametric comparison of the effects of ibotenate, N-methyl-D,L-aspartate and quisqualate in the rat.

Separate groups of rats received unilateral lesions of the lateral hypothalamus by one of the 3 amino-acid neurotoxins, ibotenic acid (IBO), N-methyl-D,L-aspartic acid (NMA) or quisqualic acid (QA). A parametric comparison was made between the toxins on the extent of neuronal cell loss and the specificity of damage, by a systematic variation of both the volume (0.25-1.0 mm3) and concentration (0.03-0.12 M) injected. Neurotoxic potency on hypothalamic neurones varied in the order IBO greater than NMA greater than QA. All 3 toxins spared magnocellular supraoptic and accessory nuclei as well as medial hypothalamic neurones. Extrahypothalamic damage differed between the toxins: ventral thalamic neurones were susceptible to NMA and QA but only slightly to IBO, whereas the medial amygdala was sensitive to IBO but not NMA or QA. All 3 toxins spared ascending monoamine systems passing through the lateral hypothalamus, as assessed by biochemical assays of forebrain dopamine and serotonin. However, IBO induced a bilateral increase in dopamine levels, which was interpreted as an indirect consequence of the loss of lateral hypothalamic efferents projecting to the midbrain.

Animals↗

PubMed1985

Comparative effects of infusions of 6-hydroxydopamine into nucleus accumbens and anterolateral hypothalamus induced by 6-hydroxydopamine on the response to dopamine agonists, body weight, locomotor activity and measures of exploration in the rat.

Groups of rats received infusions of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens or anterolateral hypothalamus with 6-hydroxydopamine (6-OHDA), or sham operations. Body weight was monitored for 28 days after the infusion, after which rats were first tested in an exploration choice-box and then underwent a series of pharmacological challenges. At this time after the operation, rats which had received 6-OHDA in the nucleus accumbens showed neither loss of body weight, deficit in exploration, nor hypokinesia, but sustained an 80% reduction in dopamine levels in the nucleus accumbens. Locomotion was decreased in response to 1.5 mg/kg (i.p.) of d-amphetamine but increased following 0.1 mg/kg (s.c.) of apomorphine; stereotyped responses to larger doses were unaltered. By contrast, rats which had received 6-OHDA in the anterolateral hypothalamus lesions lost substantial amounts of body weight and were hypoactive. Although both locomotor and stereotypy responses to d-amphetamine were abolished, these responses were enhanced in response to apomorphine. Consistent with this, regional assay using high pressure liquid chromatography (HPLC) showed profound loss of dopamine in the caudate-putamen as well as in the nucleus accumbens and frontal cortex. It seems unlikely that the reductions in exploration previously reported after lesions of the mesolimbicocortical dopamine system at the level of anterolateral hypothalamus induced by 6-OHDA are either behaviourally specific or result solely from depletion of dopamine with the nucleus accumbens and frontal cortex.

Animals↗

PubMed1985

Changes in actual versus defended body weight elicited by a varied, palatable ("supermarket") diet in rats.

Male rats fed on a varied, palatable supermarket diet for 11 weeks gained more weight than chow-fed controls. When palatable food was discontinued, their body weights became static, but remained significantly higher than control weights for a further 5 weeks. Hoarding of food was readily elicited by food deprivation in the dietarily obese as well as in the chow-fed rats. Previous studies have shown that the critical body weight at which hoarding appears does not covary with body weight, but appears to reflect a defended level of body weight. In the present study, critical weights were not significantly different between groups before supermarket diet, but were significantly higher in the supermarket rats after obesity had developed. Thus, the increase in body weight brought about by a supermarket diet (unlike that in ventromedial hypothalamic obesity) can be accompanied by an increase in the defended level of body weight as inferred from the critical weight for the onset of hoarding behaviour.

Animals↗

PubMed1985

Ibotenic acid lesions of the lateral hypothalamus: comparison with 6-hydroxydopamine-induced sensorimotor deficits.

Three groups of rats received unilateral injections of ibotenic acid, 6-hydroxydopamine or vehicle control into the lateral hypothalamic area, and were given a range of tests of sensorimotor capacity. As expected from previous reports, the 6-hydroxydopamine injections induced a marked sensorimotor impairment to the contralateral side of the body. By contrast, the ibotenic acid injections produced no detectable sensorimotor changes, although the parameters and histological extent of the lesion were identical to those which produce aphagia, adipsia and sustained regulatory impairments when administered bilaterally. These results dissociate the classic electrolytic lesion of the lateral hypothalamus into homeostatic impairments following damage to intrinsic hypothalamic neurones, and sensorimotor impairments dependent only on damage to passing catecholamine fibre systems.

Animals↗

PubMed1984

Ibotenic acid lesions of the lateral hypothalamus: comparison with the electrolytic lesion syndrome.

Rats received either ibotenic acid, electrolytic or sham lesions of the lateral hypothalamic area. Compared to sham operated rats, both lesion groups showed aphagia and adipsia following the lesion; this was less severe in the ibotenic acid lesioned rats. Once recovered, the ibotenic acid lesioned rats showed residual regulatory impairments in their compensatory responses to glucoprivation and to extracellular and intracellular dehydration. However, unlike the electrolytic lesioned rats, those with ibotenic acid lesions did not show akinesia and exhibited normal responses to both d-amphetamine and apomorphine. Ibotenic acid lesions resulted in extensive loss of cell bodies within the lateral hypothalamic area while sparing ascending dopamine neurones. The results are interpreted as suggesting that the lateral hypothalamic area and ascending dopamine neurones are components of a single system involved in the regulation of food and water intake.

Animals↗

PubMed1983

Increased weight gain and reduced activity in brown adipose tissue produced by depletion of hypothalamic noradrenaline.

The effects of hypothalamic noradrenaline depletion produced by injection of 6-hydroxydopamine (6-OHDA) into the vicinity of cell bodies of the ventral noradrenergic bundle (VNAB) on weight gain, food intake and brown adipose tissue (BAT) activity (as measured by GDP binding in BAT mitochondria), were examined in rats at two different ages and under two different dietary conditions (chow and chow plus palatable cheese). VNAB lesions enhanced weight gain in the chow plus cheese diet conditions and produced small increases in feeding. These effects were parallelled by reductions in BAT activity in the VNAB group, suggesting a reduced capacity for dietary thermogenesis which may contribute to the significant overweight.

Adipose Tissue, Brown↗

PubMed1983

Changes in body weight and food-related behaviour induced by destruction of the ventral or dorsal noradrenergic bundle in the rat.

Three experiments contrasted the effects of 6-hydroxydopamine-induced lesions of the ventral noradrenergic and dorsal noradrenergic projections, predominantly to hypothalamus and cortex, respectively, upon body weight changes and food-related behaviour in the rat. In general, ventral noradrenergic bundle lesions enhanced weight gain and these effects were exaggerated by the provision of palatable cheese to the standard chow diet. In contrast, lesions of the dorsal noradrenergic bundle produced minor changes in body weight. Associated with the effects of ventral noradrenergic bundle lesions were hyperphagia, enhanced suppression of intake of food adulterated with quinine, (at high concentration), a small attenuation of food neophobia, and enhanced acquisition, but not performance, of the eating response to tail-pinch stimulation. These ventral noradrenergic bundle lesions failed to alter basal activity levels, amphetamine anorexia or the diurnal pattern of eating or activity. In contrast, lesions of the dorsal noradrenergic bundle did not produce either hyperphagia or enhanced rejection of food adulterated with quinine. However, there was a strong attenuation of food neophobia and a retarded acquisition (but unimpaired performance) of eating in response to tail-pinch stimulation. The results are discussed in connection with previous studies of ventral and dorsal noradrenergic bundle lesions, with the effects of ventromedial hypothalamic lesions and with the underlying behavioural and physiological processes that mediate these contrasting effects of different neuroanatomical patterns of central noradrenaline depletion.

Animals↗