R.H. McAllister-Williams

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.

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.

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.

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

Abstract Rationale: Antidepressant drugs are thought to enhance serotonergic neurotransmission through postsynaptic 5-HT1A 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-HT1A antagonist pindolol and the prolactin response is blunted. Both are therefore thought to be a useful measure of 5-HT1A 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-HT1A 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-HT1A receptors by venlafaxine but not paroxetine, after only 3 h.

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

Abstract 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: Pre-treatment 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.

The modulation of calcium channel currents recorded from adult rat dorsal raphe neurones by 5-HT1A receptor or direct G-protein activation

The effect 5-HT1A receptor activation on the temperature dependence of HVA calcium channel currents has been studied in acutely isolated DR neurones, using barium as the charge carrier. 8-OH-DPAT caused a reduction in the temperature dependence of the peak current amplitude. However the most dramatic effect of 8-OH-DPAT was a large reduction in Q10 for the current activation rate. This also occurred with direct G-protein activation using GTP gamma S. In the presence of GTP gamma S, current activation became bi-exponential, rather than mono-exponential as in the control situation. The time constants of both components were significantly slower than the controls, and the Q10 for both components was significantly lower. GDP beta S had no effect on the temperature dependence or kinetics of activation of HVA current. Depolarizing prepulses applied prior to test pulses were able to reverse the action of 8-OH-DPAT on the Q10 of the activation rate. When prepulses were applied to cells containing GTP gamma S, the activation rate Q10 was similar to control values. We postulate that the highly significant reduction in activation rate Q10, seen with both 8-OH-DPAT and GTP gamma S, is as a result of a change in the mechanism underlying activation of HVA channels on depolarization. Contrary to previous models of calcium current modulation our results show that the mechanisms responsible for slowed activation by transmitters and facilitation of the residual current by depolarizing prepulses have little in common. We present a new model of transmitter modulation of HVA current, consistent with a mechanistic approach to channel subunit structure.

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

Abstract 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.