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Biomedical subjects

R H McAllister-Williams

Publications and source records attributed to R H McAllister-Williams.

At least 19 recordsLinked to original sources
PubMed2004

Lack of effect of tryptophan depletion on the loudness dependency of auditory event related potentials in healthy volunteers.

It has previously been suggested that auditory event related potentials (AEPs) are a potential marker of central serotonergic (5-HT) activity in man, with the slope of the AEP amplitude stimulus intensity function (ASF-slope) inversely correlating with 5-HT activity. However, two recent studies investigating this hypothesis in healthy subjects by rapidly lowering central 5-HT concentrations using the acute tryptophan depletion paradigm have found no effect on ASF-slope [Biological Psychology, 59 (2002) 121; Psychopharmacology (Berl), 146 (1999) 101]. These studies employed a 50g tryptophan depletion drink, which has been argued may not lower central 5-HT concentrations sufficiently. We here report the effect of tryptophan depletion on the AEP ASF-slope using 100g amino acid drinks with and without tryptophan in 14 healthy male subjects, employing a within subject, double blind, random, balanced order, cross-over design. No significant effect of tryptophan depletion was found on ASF-slope. These negative findings cast further doubt on the hypothesis that the ASF-slope is an indicator of central 5-HT function.

Acoustics↗
PubMed2003

Effects of a single dose of cortisol on the neural correlates of episodic memory and error processing in healthy volunteers.

RATIONALE: Neuropsychological impairments seen in depression may be secondary to hypercortisolaemia. Repeated cortisol administration impairs episodic memory with an alteration in event-related potentials (ERPs) recorded during information retrieval. It is unclear whether such ERP effects are specific to episodic memory, or whether repeated cortisol administration is required. OBJECTIVE: To investigate the effect of a single dose of hydrocortisone on the neural correlates of episodic memory and error detection. METHODS: Twenty healthy subjects were treated with hydrocortisone (100 mg) or placebo orally, in a double-blind, two-way crossover study. ERPs were recorded during an episodic memory and a Stroop task, 1-3 h following the medication. RESULTS: Cortisol increased error rates during the Stroop task but had no effect on episodic memory. The magnitude of ERPs associated with incorrect response in the Stroop task between -250 ms and +500 ms post-response was increased by cortisol, with no effect on correct-response ERPs. There was no effect of cortisol on episodic memory-retrieval-dependent ERPs. CONCLUSIONS: Cortisol can impair not only episodic memory but also processes involved in error detection. In contrast to repeated cortisol administration, a single dose of cortisol does not alter the behavioural performance or the electrophysiological correlates of episodic memory. However, it increases error rates in a choice response task with associated quantitative changes in incorrect-response ERPs. This probably reflects an alteration in anterior cingulate cortex activity. Such changes may contribute to the neuropsychological impairment seen in depression. This study also demonstrates the utility of ERPs for investigating the effect of neuroendocrine manipulations on the neural correlates of neuropsychological function.

Adolescent↗
PubMed2003

EEG effects of buspirone and pindolol: a method of examining 5-HT1A receptor function in humans.

RATIONALE: An involvement of 5-HT(1A) receptors is postulated in the pathophysiology of affective disorders and mechanism of action of antidepressants. Methods for studying their functional integrity in humans are, however, limited. Preliminary data suggests that activation of somatodendritic 5-HT(1A) receptors cause a negative shift in the EEG frequency spectrum. Animal research suggests that pindolol is an agonist at these receptors but an antagonist at postsynaptic 5-HT(1A) receptors. OBJECTIVE: We postulated that while pindolol would antagonise known postsynaptic mediated neuroendocrine responses to the 5-HT(1A) agonist buspirone, both drugs would have a similar effect on the EEG frequency spectrum. METHODS: Fourteen healthy men were administered placebo or pindolol (20 mg orally) 90 min before placebo or buspirone (30 mg orally) in a double blind cross-over study. Plasma prolactin and growth hormone were assayed and EEGs recorded before and after drug administration. RESULTS: A significant negative shift in the EEG frequency spectrum was found for both buspirone and pindolol, with the combination producing a similar effect to each drug alone. In contrast, the neuroendocrine response to buspirone was significantly attenuated by pindolol. CONCLUSIONS: The data obtained are consistent with the EEG effects of buspirone and pindolol being mediated by somatodendritic 5-HT(1A) receptors, in contrast to the neuroendocrine response, which is known to be mediated by postsynaptic receptors. The development of this novel method of assessing somatodendritic 5-HT(1A) receptors in humans is a potentially important advance which may allow the testing of hypotheses of its involvement in depression and response to antidepressants.

Adolescent↗
PubMed2003

Bipolar disorder ignored by the Mental Health National Service framework but not forgotten by the British Association for Psychopharmacology.

Bipolar disorder (BD) is a severe mental illness that has been largely ignored by the National Service Framework (NSF) for Mental Health. This is particularly notable because it is associated with a higher suicide rate than schizophrenia and has a greater burden of disability. The NSF offers little guidance on service models that specifically consider BD. This is of concern because of the complexities that are inherent in the management of BD. These deficiencies in the NSF may have far-reaching implications for resource allocation, service organization, and patient management and well-being. Moreover, the standards and performance targets laid out in the NSF will be difficult to meet if this important and common mental illness is not specifically catered for in mental health services. Local Implementation Teams would be well advised to take note of the recently published British Association for Psychopharmacology guidelines for the management of BD.

Antidepressive Agents↗
PubMed2002

Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval.

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to proposed serotonergic abnormalities. Acute tryptophan depletion (ATD) in healthy subjects impairs episodic memory, but the mechanism of this is unclear. OBJECTIVES: To examine the effects of ATD on the neural correlates of episodic memory retrieval in healthy subjects. METHODS: Fourteen healthy men were given an amino acid cocktail drink with or without tryptophan, in a double blind, crossover design. Event related potentials (ERPs) were recorded during a well-validated episodic memory task performed 5 h after drink ingestion. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: ATD led to an 84+/-5% reduction in plasma free tryptophan concentrations, and significantly impaired episodic memory recall. ERP recordings demonstrated previously reported left parietal and right frontal "old/new" differences for ERPs to items associated with accurate episodic memory retrieval versus correctly rejected new items. ATD increased ERP voltage between 500 and 1400 ms post-stimulus particularly over posterior regions of the scalp, but there was no interaction with item type. Topographical analysis of the old/new difference revealed no significant treatment by site interaction. CONCLUSIONS: ATD impairs episodic memory recall with no effect on the magnitude or topography of the neural correlates of retrieval in healthy subjects. This suggests that the effects of ATD on recall may reflect an impairment of memory encoding and/or consolidation.

Adolescent↗
PubMed2001

Effects of repeated cortisol administration on brain potential correlates of episodic memory retrieval.

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to hypercortisolaemia. Cortisol administration to healthy subjects impairs episodic memory, though how this is mediated is unknown. OBJECTIVES: To examine the effects of 1 week's administration of cortisol on the neural correlates of episodic memory in healthy subjects. METHODS: Fourteen healthy men were treated with oral cortisol (hydrocortisone 20 mg) or placebo twice daily for 1 week, in a double blind, crossover fashion. Event related potentials (ERPs) were recorded during a well-validated source memory task. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: Response times were significantly speeded by cortisol. A significant reduction in recognition accuracy with cortisol was found for the second study occasion. ERP recordings with placebo showed greater positivity over left parietal and right frontal scalp areas for ERPs to items given correct source judgements versus correctly rejected new items. In comparison, cortisol increased ERP voltage between 500 and 1400 ms post-stimulus and this effect interacted with item type and electrode site, being diffusely distributed for correct rejections but of a lesser magnitude frontally for old items accorded a correct source judgement. CONCLUSIONS: Repeated cortisol administration leads to a qualitative change in the neural correlates of episodic memory retrieval in healthy subjects. This change may contribute to cognitive impairments seen in illnesses characterised by hypercortisolaemia.

Adolescent↗
PubMed2001

Corticosterone selectively attenuates 8-OH-DPAT-mediated hypothermia in mice.

The 5-HT1A agonist 8-OH-DPAT produces a hypothermia in mice mediated by somatodendritic 5-HT1A receptors, that is attenuated by antidepressants and corticosterone. The present study investigated if the effect of corticosterone is specific to the serotonergic system or a non-specific effect on thermoregulation. Administration of corticosterone for 3 d had no effect on dopaminergic (apomorphine) or adrenergic (clonidine) hypothermic challenges. However in addition to 8-OH-DPAT, nicotine-induced hypothermia was attenuated by corticosterone. Administration of the selective nicotinic antagonist mecamylamine had no effect on 8-OH-DPAT-induced hypothermia, although nicotine-induced hypothermia was attenuated by the selective 5-HT1A antagonist WAY-100635. This demonstrates a serotonergic-nicotinic interaction in the generation of hypothermia in mice and is consistent with corticosterone selectively attenuating somatodendritic 5-HT1A receptor function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Effects of adrenalectomy on 8-OH-DPAT induced hypothermia in mice.

Complex interactions exist between the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system, and it has been suggested that these interactions may be fundamental to the pathophysiology and treatment of depressive illnesses. It has previously been found that chronic administration of corticosterone leads to adrenal suppression and an attenuation of somatodendritic 5-HT1A receptor function. Adrenalectomy (ADX) has been shown to cause an increase in postsynaptic 5-HT1A receptor numbers and possibly function. However, other reports have suggested that ADX does not alter somatodendritic 5-HT1A receptor mRNA or binding, though little is known of the effect of ADX on the function of somatodendritic 5-HT1A receptors. This study investigated the effect of markedly reducing corticosterone levels by ADX on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced hypothermia in mice, an in vivo model of somatodendritic 5-HT1A receptor function. The degree of 8-OH-DPAT-induced hypothermia did not differ between control, sham, and ADX animals 14 days post operatively. Although repeated administration of corticosterone attenuates somatodendritic 5-HT1A receptor function, these data demonstrate that lowering of corticosteroid levels by ADX have no effect. This suggests that the effects of repeated corticosterone administration is not mediated by a secondary adrenal suppression. The difference in the effects of ADX on somatodendritic as opposed to postsynaptic 5-HT1A receptors may reflect the differential expression of corticosteroid receptor subtypes at postsynaptic and somatodendritic sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Effects of dexamethasone on neuroendocrine and psychological responses to L-tryptophan infusion.

UNLABELLED: 5-Hydroxytryptamine1A (5-HT1A) receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal experimental paradigms. This effect may be central to the pathophysiology of severe clinical depressive illness, a condition in which 5-HT1A receptor function is reduced and corticosteroid hormones are elevated. Evidence suggests that the growth hormone (GH) response to L-tryptophan (L-TRP) is mediated by 5-HT1A receptors. This response has been shown to be reduced following acute administration of hydrocortisone. The purpose of this study was to examine the effects of acute administration of dexamethasone, in normal volunteers, on hormonal and psychological responses to L-TRP infusion. METHODS: Sixteen healthy male volunteers took part in a random order, double blind study, in which 5 mg dexamethasone or placebo was administered 11 h before infusion of L-TRP. RESULTS: Pretreatment with dexamethasone had no effect on the GH response to the infusion. However, baseline prolactin (PRL) was significantly reduced, as was the prolactin response to the infusion. CONCLUSIONS: These data contrast with a previous study using hydrocortisone in the same paradigm and demonstrate important functional differences between dexamethasone and hydrocortisone.

Adolescent↗
PubMed1999

Acute effects of venlafaxine and paroxetine on serotonergic transmission in human volunteers.

RATIONALE: Antidepressant drugs are thought to enhance serotonergic neurotransmission through postsynaptic 5-HT(1A) receptors. This effect is delayed in animals and may be paralleled by a delay in the onset of a clinical response in humans. In humans, the growth hormone (GH) response to intravenous l-tryptophan (IV l-TRP) is blocked by the 5-HT(1A) antagonist pindolol and the prolactin response is blunted. Both are therefore thought to be a useful measure of 5-HT(1A) receptor function. Clomipramine has previously been found to enhance the GH and prolactin responses to IV l-TRP after only 2 h. OBJECTIVE: The purpose of this study was to use this method to investigate the effects of newer antidepressants on 5-HT(1A) receptor-mediated function. METHODS: Twelve healthy male volunteers took part in a random order, double blind study, in which 18.75 mg venlafaxine, 5 mg paroxetine or placebo was administered 3 h before infusion of l-TRP. RESULTS: Pretreatment with venlafaxine significantly enhanced the growth hormone (GH) response to the infusion compared with pretreatment with placebo. There was no significant difference between the GH response following paroxetine compared with placebo or with venlafaxine. CONCLUSIONS: The data suggest enhancement of transmission through postsynaptic 5-HT(1A) receptors by venlafaxine but not paroxetine, after only 3 h.

Adolescent↗
PubMed1998

5-Hydroxytryptamine receptor function in humans is reduced by acute administration of hydrocortisone.

5-Hydroxytryptamine1A (5-HT1A) receptors have been shown to be suppressed by corticosteroid hormones in a variety of animal experimental paradigms. It has been suggested that this effect may be central to the pathophysiology of severe clinical depressive illness, a condition in which 5-HT1A receptor function is reduced and corticosteroid hormones are elevated. We report the effects of acute administration of hydrocortisone in normal volunteers on a neuroendocrine model of 5-HT1A receptor function. Fifteen healthy male volunteers took part in a random order, double blind, placebo controlled study, in which 100 mg hydrocortisone or placebo was administered 11 h before infusion of L-tryptophan (L-TRP). Pre-treatment with hydrocortisone significantly reduced the growth hormone (GH), but not the prolactin (PRL) response to the infusion. These data are consistent with the view that acute administration of corticosteroid hormones significantly impairs 5-HT1A receptor mediated function in healthy human volunteers and are in line with animal studies of the effects of corticosteroid hormones on 5-HT1A receptors. We propose that this finding is relevant to the pathophysiological processes which cause severe depressive illness.

Adolescent↗
PubMed1998

Mood and neuropsychological function in depression: the role of corticosteroids and serotonin.

BACKGROUND: Depressed patients show deficits on neuropsychological tests. However, the basis of these impairments and their relationship with mood disturbance remains unclear. METHODS: This paper reviews the literature regarding the relationship between mood disturbance and neuropsychological impairment in depression and the evidence for serotonergic and hypothalamic-pituitary-adrenal (HPA) axis involvement in these two domains. RESULTS: Mood disturbance and neuropsychological impairment both occur in depression, but have no clear relationship in time or degree. Impairment of post-synaptic 5-HT1A receptor function may result in the symptom of low mood in depression. Depressed patients demonstrate abnormalities in the functional control of the HPA axis with a resultant hypercortisolaemia, which may impair neuropsychological function. These processes may be related given the extensive interactions between the serotonergic system and the HPA axis. CONCLUSIONS: We argue that there is a neurobiological cause of impaired neuropsychological function in depression. The complex relationship between neuropsychological function and mood may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement of serotonergic 5-HT1A and glucocorticoid receptors. A primary dysfunction in these receptors will produce a lowering of mood and neuropsychological impairment respectively. Either dysfunction will result in a secondary impairment of the alternate system. Thus, the effective and psychological changes of depressive illness are likely to have complex relationships in time and severity to one another and the illness as a whole may result from a range of primary aetio-pathologies.

Adrenal Cortex Hormones↗
PubMed1995

The temperature dependence of high-threshold calcium channel currents recorded from adult rat dorsal raphe neurones.

The temperature dependence of HVA calcium channel currents, using barium as the charge carrier, was studied in acutely isolated adult rat dorsal raphe neurones. Current amplitude was found to be highly sensitive with a Q10 of between 1.7 and 2.5. The most sensitive component of current is that that is activated from hyperpolarized holding potentials, and inactivates during a 200 msec test pulse. The least sensitive is the more sustained current elicited from depolarized potentials. Increases in temperature were also found to cause an irreversible shift in the current-voltage relationship in the hyperpolarizing direction. By far the most temperature-sensitive property was the activation time constant with an extraordinary Q10 of between 10 and 12. This was not significantly affected by holding potential, though the time constant itself is dependent on the test potential. Increases in temperature to 25 degrees C or above revealed a fast inactivating component, not seen at lower temperatures. These findings suggest that there are at least three components of HVA current in dorsal raphe neurones. In addition, the remarkably high Q10 for activation kinetics suggests that the processes underlying calcium channel current activation are multifaceted and complex. The following paper puts forward a new hypothesis which attempts to explain the way in which neurotransmitters modulate the activation kinetics of HVA calcium channel currents.

Animals↗