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Biomedical subjects

J K McQueen

Publications and source records attributed to J K McQueen.

At least 19 recordsLinked to original sources
PubMed1999

Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids.

Estrogen increases serotonin transporter (SERT) mRNA and binding sites in female rat brain. In order to determine whether changes in SERT are gender- and steroid-specific we have now carried out studies on adult male Wistar rats which were either intact or castrated (under halothane anesthesia) and injected with arachis oil, estradiol benzoate (EB), testosterone propionate (TP) or the non-aromatizable androgen, 5alpha-dihydrotestosterone (5alpha-DHT). The number of SERT mRNA-expressing cells in the dorsal raphe (DR) nucleus was decreased by castration and increased by treatment (for approximately 32 h) with EB or TP, but not 5alpha-DHT. Sex steroids had no effect on the number of SERT mRNA-expressing cells in the median raphe nucleus. The density of SERT sites, assessed by autoradiography of [3H]paroxetine binding, was significantly reduced in arcuate nucleus and median raphe after castration, and increased in arcuate, basolateral amygdala and ventromedial hypothalamic nucleus by treatment with EB or TP, but not 5alpha-DHT. Estradiol, but not testosterone or 5alpha-DHT reduced the density of SERT sites in midbrain central grey. These data show that testosterone as well as estrogen affects SERT expression in male brain, and that the action of testosterone probably depends upon its enzymatic conversion, by aromatase, to estradiol. Our findings may have implications for sex steroid control of mood and behavior, and the action of neurotoxic derivatives of amphetamine, such as 3, 4-methylenedioxymethamphetamine, in the human.

Animals↗
PubMed1999

Serotonergic 5-HT2A receptors important for the oestradiol-induced surge of luteinising hormone-releasing hormone in the rat.

Serotonin (5-HT) plays a role in mediating the oestradiol-induced surge of luteinising hormone (LH), but so far the 5-HT receptor subtype involved has not been identified. Our previous in-situ hybridization and pharmacological studies suggest that the action of 5-HT involves the 5-HT2A receptor. The aim of the present study was to investigate this possibility by the direct approach of determining whether 5-HT2A receptor antagonists block the oestradiol-induced surge of luteinising hormone releasing hormone (LHRH). Adult female Wistar rats, which had shown at least two consecutive 4-day oestrous cycles, were ovariectomised under halothane anaesthesia in the morning of dioestrus and injected with vehicle (arachis oil) alone or oestradiol benzoate (OB). At 12.00 h of the next day, presumptive pro-oestrus, the animals were injected intraperitoneally with one of three 5-HT2A antagonists, a selective 5-HT reuptake inhibitor (fluoxetine), or the appropriate vehicles; hypophysial portal blood was then collected under alphaxalone anaesthesia between 15.00 and 19.00 h. The amount of LHRH released into hypophysial portal blood during consecutive 30-min periods was determined by radioimmunoassay. As expected, oestradiol, but not oil, triggered a surge of LHRH in hypophysial portal blood with a peak at about 16.00 h of presumptive pro-oestrus. This oestradiol-induced surge of LHRH was blocked by ketanserin, ritanserin and the highly selective 5-HT2A receptor antagonist, RP62203, but not by fluoxetine. These results provide the first direct evidence that the 5-HT2A receptor plays an important role in the oestradiol-induced surge of LHRH.

Anesthesia↗
PubMed1998

Sex steroid control of mood, mental state and memory.

1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.

Affect↗
PubMed1997

Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain.

The aim of the present study was to determine the effect of estradiol-17 beta (E2), in its positive feedback mode for gonadotropin release, on the serotonin transporter (SERT) in female rat brain. Levels of SERT mRNA were determined by in situ hybridization and SERT-binding sites were measured by quantitative [3H]paroxetine receptor autoradiography. The injection of estradiol benzoate (EB) in acutely ovariectomized rats increased significantly (approximately 50%) the numbers of cells that expressed SERT mRNA in the dorsal raphe nucleus and the density of SERT-binding sites in lateral septum (90%), basolateral amygdala (20%), ventral nucleus of thalamus (250%) and ventromedial hypothalamic nucleus (250%). SERT-binding sites in EB-treated rats were significantly lower in periaqueductal central grey (15%). These findings indicate that effects on SERT gene expression may be involved in the E2-induction of the gonadotropin surge. Together with our previous findings, they also suggest that the sex differences in depression and the apparent psychotropic effect of E2 may be due to the action of E2 on the serotonin transporter as well as 5-HT2A receptors.

Animals↗
PubMed1994

The development of astrocytes immunoreactive for glial fibrillary acidic protein in the mediobasal hypothalamus of hypogonadal mice.

Numbers of astrocytes immunoreactive for glial fibrillary acidic protein (GFAP) are markedly increased in the mediobasal hypothalamus (MBH) of adult hypogonadal (hpg) mice. The astrocytosis cannot be reversed by administration of gonadal steroids. To investigate whether the glial changes are established in the perinatal period, when crucial developments occur in rodent brain, we determined the distribution of GFAP-IR astrocytes in normal and hpg mouse brain from birth to adulthood. The period up to 3 weeks of age was characterized by the gradual disappearance of radial glia and the increase in mature astrocytes in some brain regions, for example hippocampus. However, there were no apparent differences in GFAP-IR elements between normal and hpg brains and very few astrocytes in the MBH. From age 1 month, increased numbers of GFAP-IR astrocytes were apparent in the hypothalamus in hpg mice and this difference was more obvious at 2 months. By 4 months of age the characteristic astrocytosis in the MBH had been attained and this did not change in older hpg mice. These observations provide no evidence for upregulation of the GFAP gene during the first 2 postnatal weeks when its transcription is highest and astrocytes are proliferating most rapidly. It is more likely that the astrocyte response in the MBH in hpg mice reflects permanent differences in steroid-induced neuronal connectivity, caused by the hypogonadism.

Animals↗
PubMed1991

Magnetic resonance imaging in schizophrenia: altered brain morphology associated with P300 abnormalities and eye tracking dysfunction.

This study was designed to investigate whether auditory P300 event-related potential and smooth pursuit eye-movement abnormalities in schizophrenia are associated with brain structural changes measured using magnetic resonance imaging (MRI). Serial coronal MRI scans obtained from 31 schizophrenic subjects and 33 volunteer controls were analysed by a rater who had no knowledge of the subjects' diagnoses. The brain areas measured bilaterally were the temporal lobe, hippocampus, amygdala, parahippocampal gyrus, head of caudate, cingulate cortex, frontal cortex, and the lateral ventricles. The area of the third ventricle, the thickness of the corpus callosum, and the intracranial area were also measured. Auditory P300 and eye tracking performance were recorded on all subjects. There was a significant increase in the latency and a reduction in amplitude of the P300 in the schizophrenic group. Only in the schizophrenic group was P300 latency correlated negatively with the area of the right and left cingulate cortex and positively with the difference in size between the right and left amygdala. In the subgroup of schizophrenic subjects whose P300 latency was greater than 2 standard deviations above the control mean, the area of the left cingulate cortex was significantly smaller than in controls, and the absolute right-left difference in the area of the amygdala was significantly increased. Eye tracking dysfunction in schizophrenia was not related to changes in the amygdala or cingulate cortex but was significantly correlated with enlargement of the lateral ventricles. Schizophrenic subjects with poor eye tracking had significantly larger lateral ventricles than controls. Eye tracking dysfunction, but not P300 abnormality, was correlated with the severity of both positive and negative symptom of schizophrenia. These findings demonstrate that psychophysiological abnormalities are associated with altered brain structure in schizophrenia.

Arousal↗
PubMed1991

A magnetic resonance imaging study of schizophrenia: brain structure and clinical symptoms.

Thirty-one patients with schizophrenia and 33 normal control subjects underwent MRI. The BPRS was used to rate clinical symptoms and the NART to estimate pre-morbid IQ. All were right handed. The temporal lobe was significantly smaller on the left than the right in both the control and schizophrenic groups. The amygdala was smaller on the left than the right in controls but not in schizophrenics. The parahippocampal gyrus was smaller on the left side in the schizophrenic group but not in controls. In the schizophrenic group, ventricular enlargement and cerebral atrophy were significantly related to severity of symptoms. Patients with marked negative symptoms had a bilateral reduction in the size of the head of caudate and the two measures were significantly correlated. Patients with marked positive symptoms had larger VBRs and again the clinical and morphometric changes were significantly correlated. There were no morphometric differences between patients with short duration (two years or less) and chronic symptoms.

Adult↗
PubMed1990

Glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes are increased in the hypothalamus of androgen-insensitive testicular feminized (Tfm) mice.

In the hypothalamus of androgen-insensitive testicular feminized (Tfm) mice the normal pattern of immunohistochemical staining for glial fibrillary acidic protein (GFAP) is markedly different from normal. Along the borders of the third ventricle and in the dorsomedial and arcuate nuclei, the numbers of stained astrocytes are increased. The usual ordered array of tanycytic processes is obscured by a tangle of GFAP-stained stellate glial cells. GFAP immunostaining in other regions of the Tfm forebrain is similar to that in normal mice. These results suggest that the distribution of reactive glia in the hypothalamus may have been changed as a consequence of the genetic defect in Tfm mice.

Androgen-Insensitivity Syndrome↗
PubMed1988

Gonadal steroids influence neurophysin II distribution in the forebrain of normal and mutant mice.

The distribution of arginine vasopressin-associated neurophysin (neurophysin II) immunoreactivity was investigated in normal and mutant house mice during development and after various gonadal steroid manipulations. During postnatal development of normal mice dense networks of neurophysin II immunoreactivity in the lateral septal nucleus and lateral habenular nucleus appeared earlier in male than in female mice, with an adult pattern of immunoreactivity being attained by 8 weeks and 12 weeks of age, respectively. The neurophysin II immunoreactivity in the male was denser than that in female mice. After gonadectomy of adult normal mice there was a gradual loss of neurophysin II immunoreactivity in the lateral septum and lateral habenula over a period of 15 weeks. In hypogonadal mice, a mutant in which gonadal development is arrested postnatally due to a deficiency in hypothalamic gonadotrophin releasing hormone, no immunoreactive neurophysin II could be detected in the lateral septum or lateral habenula. A pattern of neurophysin II immunoreactivity similar to that in normal control mice was observed in hypogonadal mice which had been implanted for 4 weeks with silicone elastomer capsules containing testosterone or oestradiol-17 beta, but not 5 alpha-dihydrotestosterone or progesterone. Stimulation of gonadal development and endogenous steroid production in hypogonadal mice by third ventricular grafts of preoptic area tissue from normal neonatal animals also produced a normal pattern of neurophysin II immunoreactivity in the lateral septum and lateral habenula. In the androgen-insensitive testicular feminized mouse immunoreactive neurophysin II was undetectable in the lateral septum and lateral habenula. Treatment of testicular feminized mice with oestradiol-17 beta, but not progesterone, produced a normal pattern of neurophysin II immunoreactivity. The main immunohistological findings were confirmed by radioimmunoassay of tissue extracts which showed that the concentration of arginine vasopressin in lateral septum was far greater in normal males than females and was undetectable in hypogonadal mice; no oxytocin could be detected in the septum of normal or hypogonadal mice. These results show that the expression of neurophysin II immunoreactivity in the lateral septum and lateral habenula of the mouse brain is dependent on the presence of aromatizeable androgens or oestrogens.

Aging↗
PubMed1988

Metabolic mapping of functional activity in the olfactory system of normal and hypogonadal (hpg) mice.

The hypogonadal mouse, which lacks gonadotropin-releasing hormone, has been suggested as an animal model of Kallmann's syndrome, one symptom of which is hyposmia. We have determined the metabolic activity of the olfactory system, in normal and hypogonadal mice, using [14C]-2-deoxyglucose quantitative autoradiography. In the olfactory lobes, deoxyglucose uptake was greatest in the glomerular and granule cell layers and low in the olfactory nerve layer and bulb core. The pattern of uptake was similar in both hypogonadal and normal mice breathing filtered air. Exposure of normal mice to ethyl acetoacetate significantly increased deoxyglucose uptake in the olfactory nerve layer and glomerular layer, but not in the granule cell layer. Several foci of intense metabolic activity were produced, apparently corresponding to small groups of activated glomeruli. There were no changes in the secondary or tertiary projections of the olfactory system. In hypogonadal mice, ethyl acetoacetate failed to increase the number of foci and the density of labelling in the olfactory nerve layer and glomerular layer. These data show that the functional activity of the olfactory system in hypogonadal mice breathing air is apparently normal. However, the olfactory response to ethyl acetoacetate is significantly less in hypogonadal mice. Whether this is due to their lack of gonadotropin-releasing hormone requires further experimentation.

Acetoacetates↗
PubMed1988

Changes in local cerebral glucose utilization associated with the spontaneous ovulatory surge of luteinizing hormone in the rat.

Brain activity during the spontaneous ovulatory surge of luteinizing hormone (LH) has been studied by measuring local cerebral glucose utilization (LCGU) by the [14C]-2-deoxyglucose method. The LCGU was determined in 37 brain areas and the pituitary gland in conscious, freely moving female rats in the morning and the late afternoon of proestrus. No increases in LCGU were detected, but, unexpectedly, there was a significant decrease in the LCGU measured in the afternoon compared with the morning of proestrus in the medial preoptic and anterior hypothalamic areas, the arcuate nucleus, median eminence and amygdala. Significant reductions in LCGU also occurred in the midbrain central grey and reticular formation. These results suggest that the LH and/or the prolactin surge is associated with a significant reduction in the activity of brain areas known to be essential components of the central control of gonadotropin and prolactin secretion. In the case of the arcuate nucleus and median eminence, for example, the results could be explained by a decreased activity of the opioid and dopaminergic neurons which are known to inhibit the release of luteinizing hormone releasing hormone (LHRH). Disinhibition of LHRH neurons would result in the increased release of LHRH into the hypophysial portal vessels. Reduction in the activity of the arcuate dopamine neurons could also play a major role in the prolactin surge. The decreased LCGU of the midbrain central grey may be related to the onset of lordosis behavior which appears to be time-locked to the LH surge.

Animals↗
PubMed1984

Local changes in cerebral 2-deoxyglucose uptake during alphaxalone anaesthesia with special reference to the habenulo-interpeduncular system.

The effects of the steroid anaesthetic Althesin (alphaxalone plus alphadolone acetate) on regional cerebral metabolism was studied in female rats. [14C]2-Deoxyglucose (2-DG) uptake was measured in 19 discrete anatomical areas by quantitative autoradiography. Under Althesin anaesthesia metabolic activity, relative to the corpus callosum ( rma ), was significantly (24-46%) increased in the locus coeruleus, medial (but not lateral) habenula (Hb) and interpeduncular nucleus (IPN). The Hb-IPN tract, not discernible in autoradiograms from conscious rats, became readily apparent in films from anaesthetized rats. However, the increased metabolic activity of this pathway was not associated with a significant change in the tissue concentrations of substance P in either the Hb or IPN. In sensorimotor and visual cortex, caudate nucleus, thalamic nuclei and the medial geniculate body rma was significantly (26-38%) depressed. Metabolic activity in the other 8 areas measured was unaffected by Althesin. Destruction of the stria medullaris input to the habenulae prevented the Althesin-induced increase in 2-DG uptake by the MHb and LHb.

Alfaxalone Alfadolone Mixture↗
PubMed1984

Comparison of the effects of Althesin and sodium pentobarbitone on the regional uptake of 2-deoxyglucose by the brain and pituitary gland of the rat: selective effects on pars intermedia.

The uptake of radiolabelled 2-deoxyglucose (2DG) was used to compare the effects of the steroid anaesthetic, Althesin (alphaxalone plus alphadolone acetate) with those of sodium pentobarbitone on the regional metabolism of the brain and pituitary gland. Experiments were carried out on adult female Wistar rats. Studies on conscious animals were carried out with the aid of an indwelling intra-atrial catheter. The uptake of 2DG was measured both by liquid scintillation spectroscopy of 3H-2DG in tissue blocks and by quantitative autoradiography with 14C-2DG. Both anaesthetics significantly reduced uptake of 3H-2DG in the frontal, parietal and occipital cortex, and striatum and thalamus, but 3H-2DG uptake was significantly increased in the pituitary gland. Similar effects were found by measuring 14C-2DG uptake, and this technique showed further that Althesin, but not sodium pentobarbitone, selectively increased (2-fold) the uptake of 14C-2DG by the pars intermedia. The increase in 14C-2DG uptake by the pars intermedia in animals anaesthetized with Althesin was significantly reduced by a lesion placed in the arcuate nucleus. The most likely explanation for the effects of Althesin on the pars intermedia is that this anaesthetic increases the activity of arcuate neurons that innervate the pars intermedia.

Alfaxalone Alfadolone Mixture↗
PubMed1983

Water deprivation results in increased 2-deoxyglucose uptake by paraventricular neurones as well as pars nervosa in Wistar and Brattleboro rats.

The [14C]2-deoxyglucose (2-DG) technique has been used in conjunction with quantitative autoradiography to determine the metabolic activity of the neurones of the hypothalamo-neurohypophysial system. Water deprivation (4 days) in Wistar rats led to a more than two-fold increase in the metabolic activity of the pars nervosa (PN), and a significant increase in the metabolic activity of paraventricular (PVN) but not supraoptic (SON) neurones. The PN in homozygous Brattleboro rats was significantly more active than that in hydrated Wistar and Piebald Virol Glaxo (PVG) rats; as in Wistar rats, activity of the PN and PVN was significantly increased by 12-15 h water deprivation. The administration of desamino-D-arginine vasopressin (dDAVP) to Brattleboro rats significantly reduced the activity of the PN to that seen in hydrated Wistar and PVG rats. This reduction in activity was accompanied by a significant reduction in plasma osmolality. These results show that (1) in contrast to studies in which the osmotic stimulus was a salt load, water deprivation leads to a significant increase in 2-DG uptake by the perikarya as well as the terminals of neurohypophysial neurones; (2) increased activity of the neurohypophysial neurones occurs even when there is a genetic deficiency of vasopressin and the activity can be increased further by an osmotic stimulus, and (3) the activity of the neurohypophysial neurones can be significantly reduced by the administration of dDAVP.

Animals↗
PubMed1983

Low risk of late post-traumatic seizures following severe head injury: implications for clinical trials of prophylaxis.

A randomised, controlled, double-blind clinical trial designed to determine the effectiveness of phenytoin in preventing epilepsy in patients who had suffered a serious head injury is reported. One hundred and sixty-four patients were randomly assigned to treatment with phenytoin or placebo capsules for one year. Patients who had a fit within one week of injury were excluded. Drug levels were monitored throughout with appropriate dosage adjustment; however only 48% of the phenytoin group had plasma levels greater than 40 mumol/l. There were seven deaths during the study. Only 11 patients (six in the phenytoin group and five in the placebo group) developed post-traumatic epilepsy within one year; a further four patients developed seizures between 1 and 2 years after injury. This low incidence of post-traumatic epilepsy (7% (SE 2%) at one year and 10 (SE 2%) at two years) means that future clinical trials of prophylaxis will have to be much larger (at least six fold).

Adolescent↗