Biomedical subjects

B J Everitt

Publications and source records attributed to B J Everitt.

At least 163 records · Page 9Linked to original sources

PubMed1987

Comparative functions of the central noradrenergic, dopaminergic and cholinergic systems.

The effects of lesions of the major catecholamine projections and terminal fields induced by 6-hydroxydopamine (6-OHDA), and of lesions of the cholinergic cells in the ventral pallidum/substantia innominata induced by ibotenic acid were compared within a single behavioural paradigm, the acquisition and performance of an appetitive conditional discrimination. Lesions of the coeruleo-cortical noradrenergic pathway induced by 6-OHDA produced over 90% depletion of noradrenaline in the neocortex and hippocampus and led to impairments in the acquisition, but not performance of the discrimination. Depletion of noradrenaline (NA) in the hypothalamus, produced by lesions of the rostral medullary noradrenergic cells, had no effect. Lesions of the caudate-putamen induced by 6-OHDA produced about an 80% depletion of dopamine and led to profound deficits in both the acquisition and performance of the discrimination, also retarding the latency to collect earned food pellets. Lesions of the nucleus accumbens, producing 80% depletion of dopamine from this structure had no significant effect on the acquisition or performance of the task. Lesions of the cholinergic cells in the ventral pallidum/substantia innominata induced by ibotenic acid, depending upon their size, had significant effects on the acquisition and performance of the discrimination, without affecting the latency to collect the pellets. Various problems of interpretation are discussed and the utility of a comparison of the different patterns of the effects of these lesions of catecholaminergic and cholinergic projections is made clear.

Acetylcholine↗

PubMed1987

Selective effects of beta-endorphin infused into the hypothalamus, preoptic area and bed nucleus of the stria terminalis on the sexual and ingestive behaviour of male rats.

beta-Endorphin was infused bilaterally into the medial preoptic area-anterior hypothalamic continuum at doses of 5, 10 and 40 pmol each side. The highest dose selectively abolished mounting, intromitting and ejaculating in sexually experienced male rats paired with an oestrous female. Males infused with 40 pmol beta-endorphin still followed the female, investigated her anogenital region and other parts of her body, but made abortive attempts to mount. A dose of 5 pmol beta-endorphin had no effect, but 10 pmol proved partially effective. The same males, in other tests, were allowed to ingest a highly preferred, sweet, non-calorific solution (acesulfame-K) in the absence of a female. beta-Endorphin infusions (up to 40 pmol) into the same area of the hypothalamus had no effect on this behaviour. Control males allowed simultaneous access both to an oestrous female and to the sweet solution copulated normally but reduced their ingestive behaviour, despite there being sufficient time during tests for both to occur. beta-Endorphin (40 pmol) infused into the preoptic area-anterior hypothalamic continuum under these conditions suppressed sexual interaction, but ingestion of acesulfame-K increased to values observed when the female was absent. beta-Endorphin infused into neighbouring areas of the brain had different behavioural effects. Sexual behaviour was not inhibited, and ingestion of acesulfame-K was unaltered, when beta-endorphin was infused either into the bed nucleus of the stria terminalis or the rostral ventromedial hypothalamus. However, infusions of cholecystokinin-8 into the ventromedial hypothalamus suppressed acesulfame-K ingestion in most animals, showing that the cannulae were placed in an area regulating ingestive behaviour. The inhibition of sexual behaviour after preoptic area-anterior hypothalamic continuum infusions of beta-endorphin was prevented by either pretreating rats with 1 mg/kg naloxone intraperitoneally, or by infusing a putative delta opiate receptor blocker (0.5 pmols ICI 174864) into the preoptic area-anterior hypothalamic continuum 5 min prior to beta-endorphin treatment. ICI 174864 administered alone significantly increased mount rate and reduced the post-ejaculatory refractory period in copulating males. These experiments suggest that there is both neurochemical and neuroanatomical specificity relating beta-endorphin to sexual behaviour in the male rat.

Animals↗

PubMed1987

The effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on the acquisition and retention of a conditional visual discrimination: implications for cholinergic hypotheses of learning and memory.

The effects of ibotenic acid-induced lesions of the ventral pallidum/substantia innominata region, the dorsal pallidum or both on the acquisition and retention of a conditional visual discrimination have been studied in the rat. Lesions of the ventral pallidum and large lesions of the dorsal and ventral pallidum severely impaired both the acquisition and retention of the conditional discrimination. Dorsal pallidal lesions had similar, but less marked effects. The same lesions also impaired the retention of a passive avoidance task, but had no effect on a conditioned taste aversion. Neurobiological investigations revealed that the lesions destroyed cholinergic neurons in the magnocellular nucleus basalis and caused reductions in cortical choline acetyltransferase activity of about 30-40%. Tract-tracing experiments indicated that the lesions destroyed, in particular, cholinergic neurons projecting to the frontal dorsolateral cortex and also those projecting to more posterior cortex, but not the occipital lobes. Contingency analysis of the behavioural, neurochemical and neuroanatomical data indicated that those animals with the largest decreases in choline acetyltransferase activity, or the largest areas of neuronal loss in the ventral and dorsal globus pallidus, were most impaired in the retention of the conditional discrimination. The results do not, therefore, indicate a simple relationship between cholinergic neuronal loss and the retention of response rules essential for performance of the task ("reference memory"). The relevance of the results to cholinergic hypotheses of learning and memory is discussed.

Animals↗

PubMed1987

The effects of lesions to noradrenergic projections from the locus coeruleus and lateral tegmental cell groups on conditioned taste aversion in the rat.

Lesions of the coeruleo-cortical noradrenergic projections caused marked cortical noradrenaline depletions but were not associated with deficits in the acquisition or extinction of a conditioned taste aversion (CTA). Lesions of lateral tegmental noradrenergic projections resulted in marked hypothalamic noradrenaline depletions, enhanced neophobia to the novel taste of saccharin, unimpaired acquisition but prolonged extinction of the CTA. However, when animals with lateral tegmental noradrenergic lesions received extensive preconditioning exposure to saccharin, acquisition of the CTA was attenuated and extinction was more rapid than in controls. Alterations in CTA learning and extinction following lesions of the lateral tegmental noradrenergic system appear to reflect alterations in the way that animals with lesions react toward the hedonic aspects of taste-related stimuli rather than alterations in associational or attentional mechanisms.

Animals↗

PubMed1987

Relation between aggressive behaviour and circadian rhythms in cortisol and testosterone in social groups of talapoin monkeys.

Circadian rhythms in cortisol and testosterone in both blood and cerebrospinal fluid (CSF) were studied in four groups of male and female talapoin monkeys. Samples were taken 4 h apart under two conditions: whilst the sexes were kept separate (isosexual) and again after 24 h of interaction (heterosexual). There were similar rhythms in cortisol in males and females during the isosexual condition, though in blood (but not in CSF) mean levels were higher in females. Heterosexual interaction increased cortisol levels in both sexes (though more so in males), and also altered the shape of the rhythm, acrophase being delayed by 4 h in males and by 2 h in females. The amplitude of the rhythm was not altered. Cortisol levels were positively correlated in both males and females with the amount of aggression received from other males, but not from females nor with the animal's social rank. Circadian rhythms in serum testosterone in males were also altered by heterosexual interaction. Access to females delayed acrophase by 2 h, but had no effect on mean levels (unlike the effect on cortisol). As for cortisol, the amplitude of the testosterone rhythm remained unchanged. Serum testosterone was negatively correlated with aggression from males, but not from females nor with sexual interaction. This was associated with a pronounced decrease in the levels of testosterone during the night, not observed in males receiving no aggression from others. There was a non-significant trend towards a positive correlation between social rank and serum testosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗

PubMed1987

Preclinical biochemical pharmacology and toxicology of piritrexim, a lipophilic inhibitor of dihydrofolate reductase.

Piritrexim (PTX), 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e, formerly called BW 301U, is a potent small-molecule inhibitor of dihydrofolate reductase (DHFR) that enters cells rapidly by passive diffusion and thus does not depend upon the transport-mediated uptake that can limit cell entry of methotrexate (MTX). PTX is as active as MTX in inhibiting DHFR and mammalian cell growth. In vivo, PTX is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors. After iv administration of [14C]PTX to rats, the elimination profile of intact drug from plasma was first order with a half-life (t1/2) of 38 minutes. PTX penetrates extensively into tissues and its tissue:plasma concentration ratios are generally 10-fold higher than those reported for MTX. When administered systemically, PTX inhibits the DHFR-dependent conversion of sepiapterin or 7,8-dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), demonstrating that PTX enters brain at pharmacologically relevant concentrations. Pharmacokinetic studies in the dog indicated a mean plasma t1/2 (after iv dose) of 2.15 hours, total body clearance of 0.625 liters/hr/kg and steady-state volume of distribution of 1.82 liters/kg; the absolute bioavailability was 0.64. Toxicologic studies were conducted in rats and dogs that received daily doses for 1, 5, or 90 days. In dogs, oral doses of 480 (single dose), 25 (5 daily doses), and 2.5 mg/kg (90 daily doses) were lethal, whereas 240 (single dose), 2.5 (5 daily doses), and 0.5 mg/kg (90 daily doses) produced reversible alterations in clinical toxicity and histopathologic parameters. The lethal toxicity of PTX in dogs given 25 mg/kg/day for 5 days is prevented by oral calcium leucovorin rescue with either 0.75 or 3.0 mg/kg every hour for 4 hours on any of the 5 treatment days. The general pharmacologic profile indicates that PTX should be free of CNS, cardiovascular, and respiratory side effects at clinically useful doses.

Animals↗

PubMed1987

Studies of instrumental behavior with sexual reinforcement in male rats (Rattus norvegicus): I. Control by brief visual stimuli paired with a receptive female.

We describe a novel procedure for measuring instrumental sexual behavior in the male rat by using a second-order schedule of presentation of sexual reinforcement, an estrous female. Experimental assessment and validation of the paradigm have been achieved by examining (a) the importance of the conditioned stimulus in maintaining instrumental responding by measuring the effects of its omission during a test session, (b) the effects and motivational specificity on instrumental behavior of the postejaculatory refractory period (a period of sexual unarousability) and of satiety for food by measuring the impact of each manipulation on animals working for food and for a female, (c) the effects of replacing an estrous female with an anestrous one as the earned reward, and (d) the correlations between conditioned and unconditioned measures of sexual behavior. We conclude that the second-order paradigm provides a means of distinguishing between the effects of neuroendocrine manipulations on incentive motivational and performance variables underlying the expression of sexual behavior.

Animals↗

PubMed1987

Studies of instrumental behavior with sexual reinforcement in male rats (Rattus norvegicus): II. Effects of preoptic area lesions, castration, and testosterone.

We studied effects of lesions to the medial preoptic area (POA), castration, and testosterone replacement on instrumental and unconditioned sexual behavior in male rats. We achieved instrumental measures of sexual motivation by training males to work for an estrous female, presented in an operant chamber under a second-order schedule of reinforcement. POA lesions abolished mounts, intromissions, and ejaculation but did not disrupt instrumental responses, investigation of the female, or abortive mounting attempts. Castration abolished attempts to copulate and also caused a marked decrease in instrumental responses. Testosterone resulted in the prompt reinstatement of instrumental responses and more gradual recovery of unconditioned sexual behavior. We discuss these results in terms of the motivational and performance effects of these neuroendocrine manipulations.

Animals↗

PubMed1986

The hypothalamic arcuate nucleus-median eminence complex: immunohistochemistry of transmitters, peptides and DARPP-32 with special reference to coexistence in dopamine neurons.

In this paper, we describe the results of a series of experiments which have examined the distribution within the arcuate nucleus of the hypothalamus of neurons containing the following immunoreactivities: TH-LI, GAD-LI, NT-LI, GAL-LI, GRF-LI, Met-ENK-LI, Leu-ENK-LI, Met-ENK-7-LI, Met-ENK-8-LI, metorphamide-LI, DYN-LI, NPY-LI, SOM-LI, FMRFamide-LI, and CLIP-LI and ependymal tanycytes containing DARPP-32-LI. Using elution-restaining and double antibody staining techniques we have established numerous patterns of coexistence of these various neurotransmitters and neuropeptides. Thus, neurons containing TH-LI were, in some instances, also found to contain GAD-LI, NT-LI, GAL-LI, GRF-LI, Met-ENK-8-LI, Leu-ENK-LI, or DYN-LI or combinations of these compounds. For example, some TH-IR neurons also contained GAL-LI and GRF-LI, while other TH-IR. neurons were also seen to contain GRF- and NT-LI. These neurons may, in fact, contain even more compounds. NPY-IR neurons and those containing SOM-LI and CLIP-LI were distinct and separate from those containing TH-LI. The distribution of these different neurochemical types of neurons and their patterns of coexistence are summarized in Fig. 34, while the relative distribution patterns of immunoreactive fibres in the median eminence are summarized in Fig. 35.

Animals↗

PubMed1986

Behavioral effects and general pharmacology of 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1, an antidepressant inhibiting both monoamine oxidase A and 5-hydroxytryptamine uptake.

In psychopharmacological tests in rats and mice, 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1 (CGP 4718 A) was found to exert behavioral effects typical of both monoamine oxidase (MAO)-A and 5-hydroxytryptamine (5-HT) uptake inhibitors (reserpine antagonism, L-5-HTP potentiation, antiaggressive activity in isolated mice). The potential antidepressant activity of the drug was indicated in rats by antagonism of reserpine and its effect in the social-conflict test. CGP 4718 A did not impair motor coordination and had no influence on locomotor activity up to high doses in mice and rats. In monkeys, it increased directed individual activities, including sex-related behaviors and diminished locomotor activity and passivity. Electroencephalographic studies in cats revealed a significant decrease in paradoxical sleep after treatment with CGP 4718 A. In isolated organs, no significant antagonism of norepinephrine, 5-HT, acetylcholine or histamine was found. Cardiovascular studies in cats showed only transient effects on blood pressure and no effect on heart rate. In conscious dogs no cardiovascular effects were found. No potentiation of the pressor effect of tyramine in rats was detectable after repeated doses of up to 300 mg/kg p.o. A weak cardiodepressant effect was seen in isolated guinea pig atria. In conclusion, in animal experiments CGP 4718 A combines an interesting spectrum of antidepressant, activating and antiaggressive properties with a lack of cardiovascular and tyramine-potentiating effects.

Animals↗

PubMed1985

Oxytocin and sexual behaviour in the male rat and rabbit.

In male New Zealand white rabbits, it was shown that oxytocin but not vasopressin concentrations in plasma were markedly raised after ejaculation. In male Wistar rats, oxytocin infused into the internal carotid artery reduced the number of intromissions made before ejaculation but had no other significant effect. Infusion of oxytocin into the third ventricle increased the latencies to the first mount and intromission and lengthened post-ejaculatory refractory periods. It is suggested that oxytocin released into the periphery during coitus, while not essentially involved in ejaculation, may exert effects on the genital periphery. Behavioural effects of centrally administered oxytocin suggest that it may play a role in the neural mechanisms underlying post-ejaculatory refractoriness.

Animals↗

PubMed1984

Occurrence of neurotensinlike immunoreactivity in subpopulations of hypothalamic, mesencephalic, and medullary catecholamine neurons.

By using indirect immunofluorescence histochemistry combined with the elution-restaining technique, the presence of a neurotensinlike peptide in some catecholamine neurons in the rat brain has been demonstrated. At the level of the medulla oblongata neurotensinlike immunoreactivity was observed in most of the small-sized catecholamine (adrenaline) cell bodies in the dorsolateral part of the nucleus of the solitary tract and in some catecholamine (noradrenaline) cells in the medial part. Neurotensin-positive fibers were found throughout the solitary tract nucleus with increasing concentrations in the rostral direction. Very few neurotensin fibers were seen in the vagal dorsal motor nucleus, which contained a dense network of adrenaline fibers. In the ventral mesencephalon, neurotensinlike immunoreactivity was seen mainly in dopamine cell bodies in the ventral tegmental area, including midline structures, with only single examples of coexistence in the substantia nigra. The dopamine cell bodies of both the A9 and A10 cell groups were surrounded by dense to medium-dense networks of neurotensin fibers. In the hypothalamus numerous dopamine neurons in the arcuate nucleus exhibited neurotensinlike immunoreactivity. Neurotensin-positive nerve terminals, partially overlapping catecholamine (mainly dopamine) fibers, were seen in the external layer of the median eminence. The present results demonstrate coexistence of neurotensinlike immunoreactivity and catecholamines in populations of neurons in some of the central catecholamine cell groups and provide a morphological basis for interactions between the peptide and amines.

Animals↗

PubMed1984

Ascending noradrenergic projections from the brainstem: evidence for a major role in the regulation of blood pressure and vasopressin secretion.

The role of projections from the lateral tegmental (A1, A2) and coeruleal (A6) noradrenergic cell groups in the control of arginine vasopressin (AVP) secretion was studied following lesions to the ventral (VNAB) and dorsal (DNAB) noradrenergic bundles by 6-hydroxydopamine. These lesions were associated with the expected, large reductions in cortical (DNAB) and hypothalamic (VNAB) noradrenaline concentrations. Vehicle injected, control animals and VNAB lesioned animals showed a similar AVP secretory response to haemorrhage, whilst the DNAB group showed a markedly diminished release of AVP in response to this challenge. Following Clonidine injection, both controls and VNAB animals showed major reductions in plasma AVP concentrations, but again the DNAB group behaved in a different manner, with a marked attenuation of the inhibitory effect of Clonidine on AVP secretion. In addition, the DNAB group had a significantly lower basal blood pressure, a greater initial agonist response to Clonidine and a loss of the hypotensive response to Clonidine in comparison to sham and VNAB lesioned groups. All three groups showed a similar AVP response to intravenous nicotine. These data suggest that noradrenergic projections originating in the locus coeruleus, or in the lateral tegmental NA groups but which ascend together with coeruleal axons in the DNAB, modulate the vasopressin response to visceral stimuli and to Clonidine, and that they also play an important role in mediating the hypotensive effect of Clonidine.

Afferent Pathways↗

PubMed1984

Differential co-existence of neuropeptide Y (NPY)-like immunoreactivity with catecholamines in the central nervous system of the rat.

The distribution of neuropeptide Y immunoreactive cell bodies in relation to various types of catecholamine-containing cell bodies in the rat brain was analyzed immunohistochemically using antisera to tyrosine hydroxylase, dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase. Coexistence of the peptide in catecholamine cell bodies was established by using an elution-restaining procedure. Neuropeptide Y-like immunoreactivity was observed in most noradrenergic cell bodies of the Al/Cl cell groups in the ventro lateral medulla oblongata. Similarly this peptide immunoreactivity was also observed in the majority of the adrenergic cell bodies of the C2 group. In the dorsal and dorsal-lateral part of the nucleus of the solitary tract, where a group of small adrenergic cells is present, several small neuropeptide Y immunoreactive cells were also observed. The possibility of coexistence of adrenaline and neuropeptide Y in these cells remains to be established. The majority of the noradrenergic cell bodies of the A2 group, as well as the presumptive dopaminergic cells within its ventromedial part, seemed to lack neuropeptide Y-like immunoreactivity. Many noradrenergic cell bodies of the A6 group in the locus coeruleus proper were neuropeptide Y-immunoreactive, whereas the peptide could not be observed in the subcoeruleus group. Neither the A5 and A7 noradrenergic cells in the pons, nor any of the dopaminergic cell groups in the mesencephalon and forebrain (A8-A15) seemed to contain a neuropeptide Y-like peptide. The findings indicate that central catecholamine neurons can be subdivided into distinct sub-groups based upon the coexistence of a specific peptide.

Animals↗

PubMed1984

Ascending brain-stem noradrenergic pathways modulate the renin response to haemorrhage.

Ventral noradrenergic projections (VNAB) from lateral tegmental (A1, A2) and dorsal noradrenergic projections (DNAB) from the coeruleal (A6) as well as A1 cell groups in the brain-stem of the rat were lesioned by intracerebral injection of 6-hydroxydopamine. A marked increase in plasma renin activity and adrenaline concentrations followed haemorrhage (0.5 ml/100 g body weight) in the sham-operated rats. VNAB-lesioned rats showed a similar response to the sham-operated controls, but in DNAB-lesioned animals the rise of plasma renin was markedly attenuated.

Animals↗

PubMed1984

Coexistence of tyrosine hydroxylase-like and gamma-aminobutyric acid-like immunoreactivities in neurons of the arcuate nucleus.

The distribution of glutamic acid decarboxylase(GAD)- and tyrosine hydroxylase(TH)-like immunoreactivities in the hypothalamic arcuate nucleus of the rat was investigated using an indirect immunofluorescence technique. GAD-positive cell bodies were found in the arcuate nucleus, mainly clustered in its dorsomedial parts. A dense terminal plexus was observed in the lateral palisade zone of the median eminence. The apparent overlap of this distribution pattern with that for TH immunoreactivity was studied directly using an elution-restaining procedure. This revealed apparent coexistence of GAD- and TH-like immunoreactivities in a subpopulation of arcuate neurons. The relevance of this finding to the control of anterior pituitary secretion is discussed.

Animals↗

PubMed1984

Transmitter and peptide systems in areas involved in the control of blood pressure.

The distribution of catecholamine neurons in the dorsal vagal complex is described on the basis of indirect immunofluorescence histochemistry using antisera to three enzymes in the catecholamine synthesis, tyrosine hydroxylase, dopamine-beta-hydroxylase and phenylethanolamine-N-methyltransferase, allowing differentiation between dopamine, noradrenaline and adrenaline cells. In addition attention was focused on the occurrence of two peptides, neuropeptide Y (NPY) and neurotensin in this region. It could be established that they partly were present in subpopulations of the A2/C2 catecholamine neurons. The significance of this coexistence of a peptide and a catecholamine is discussed.

Animals↗

PubMed1983

5-Hydroxytryptamine-thyrotropin releasing hormone interactions in the spinal cord: effects on parameters of sexual behaviour in the male rat.

In the studies of sexual behaviour in male rats reported here, intrathecal administration of 5-hydroxytryptamine (5-HT) together with thyrotropin releasing hormone (TRH) caused a marked and specific increase in mount and intromission latencies. In contrast, injection of either of the two compounds alone elicited only minor effects. These findings are discussed in relation to the co-existence of 5-HT and TRH in nerve endings in the ventral horn of the spinal cord originating in supraspinal, medullary nuclei.

Animals↗