Peter H. Silverstone

Effect of naloxone-precipitated morphine withdrawal on noradrenaline release in rat hippocampus in vivo

Here we investigated the effect of naloxone-precipitated morphine withdrawal on the release of noradrenaline in hippocampus of the anaesthetised rat. Naloxone (1 mg/kg i.p.) injected 3 and 24 h, but not 3 weeks, after eight daily injections of morphine, induced an immediate increase in hippocampal noradrenaline release. This striking effect of naloxone was markedly attenuated by pretreatment with clonidine (0.1 mg/kg s.c.). These findings provide direct evidence for a marked release of noradrenaline in hippocampus during opiate withdrawal in vivo.

A review of acute treatments for bipolar depression.

Bipolar patients generally spend much more time in the depressed phase of their illness than the manic phase, and there are many more bipolar type II and bipolar spectrum disorder patients than there are bipolar type I. Additionally, there is a significant risk of suicide in bipolar patients when depressed. The treatment of the depressed phase of bipolar disorder is therefore a matter of some priority. Here, we review current evidence supporting the use of five groups of treatments: anti-depressants; lithium; anti-convulsants (valproate, and carbamazepine, lamotrigine, gabapentin); anti-psychotics; and other treatments (electroconvulsive therapy, benzodiazepines, sleep-deprivation, and dopamine agonists). From this review, it is apparent that the literature regarding the treatment of bipolar depression is significantly limited in several key areas. Nonetheless, from the evidence currently available, the treatments with the best evidence for efficacy are selective serotonin reuptake inhibitors (SSRIs) and lamotrigine. There is also some evidence in favour of bupropion and moclobemide. Although lithium and olanzapine monotherapies can also be beneficial, they appear less efficacious than antidepressants. One of the major concerns about treatment with antidepressants has been the risk of precipitating a switch into mania. However, recent studies suggest that, if a mood stabilizer and antidepressant are given concurrently, then the risk of switching is minimized. There is also recent evidence for an independent antidepressant action for at least one atypical antipsychotic. Therefore, the conclusion from this review, in contrast to previous suggestions, is that a combination of an atypical antipsychotic and either an SSRI or lamotrigine may provide a useful first-line treatment for depressed bipolar disorder patients. Further research is clearly required to examine this approach and compare it with other possible treatment options.

Ondansetron, a 5-HT3 receptor antagonist, partially attenuates the effects of amphetamine: a pilot study in healthy volunteers.

&NA; Preclinical studies suggest that 5‐HT, antagonists modulate dopamine‐mediated responses in the limbic system and may therefore have a therapeutic role in psychiatry. We have examined the effect of ondansetron, a specific 5‐HT3 antagonist, on the psychological and psychomotor changes induced by amphetamine in human volunteers. Nine healthy males took part in this double‐blind placebo‐controlled balanced‐crossover study. Each subject received one of three treatments in a randomised manner: (a) placebo/placebo; (b) placebo/amphetamine (15 mg); (c) ondansetron (4 mg)/amphetamine (15 mg). Subjects were assessed for self‐ratings of hunger, mood, energy, alertness, restlessness, irritability, and asked to rate the abnormality of their overall subjective state. In addition, systolic blood pressure, and performance on psychomotor tests were repeatedly assessed. Although amphetamine did not cause any significant changes in self‐rating of mood, energy, alertness, restlessness or irritability, it induced a significant increase in self‐ratings for overall subjective state, and a significant decrease in self‐ratings of hunger. Amphetamine also caused an increase in systolic blood pressure and a decrease in the mean time taken to complete the psychomotor tests. Pretreatment with ondansetron attenuated the effects of amphetamine on hunger and subjective state, but not on blood pressure or psychomotor performance tests. These findings suggest that in humans 5‐HT3 receptor antagonists may partially modify the subjective effects of amphetamine, and are in keeping with results from animal studies that 5‐HT3 receptor antagonists might affect neurotransmission within mesolimbic brain regions. However, it was not possible to exclude a pharmacokinetic interaction to explain the effects of ondansetron.

The 5-HT3 antagonist, BRL 46470 does not attenuate m-chlorophenylpiperazine (mCPP)-induced changes in human volunteers.

Results from animal studies have suggested that serotonin (5-HT) antagonists acting on the 5-HT3 receptor may have anxiolytic properties. We have assessed whether pretreatment with the 5-HT3 receptor antagonist BRL 46470 (1 mg orally) attenuates the increase in anxiety induced in healthy volunteers by intravenous infusion of m-chlorophenylpiperazine (mCPP: 0.08 mg/kg over 2 min). In this double-blind placebo-controlled crossover study in 12 healthy men who were volunteers, infusion of mCPP caused significant increases in self-ratings for the psychological and physical symptoms of anxiety, for the symptoms of panic attack, and in the plasma levels of cortisol and prolactin, with four subjects (33%) experiencing an mCPP-induced panic attack. Pretreatment with BRL 46470 did not attenuate any of these mCPP-induced changes. These results do not support suggestions from animal studies that 5-HT3 receptor antagonists can attenuate mCPP-induced anxiety, although it is conceivable that a different dose of BRL 46470 may have been effective.

Neurobiological findings in bipolar II disorder compared with findings in bipolar I disorder.

Objective: To determine there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II). Method: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed, examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C. Results: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent. Conclusions: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.

Clonidine but not nifedipine prevents the release of noradrenaline during naloxone-precipitated opiate withdrawal : an in vivo microdialysis study in the rat

In this study we have examined whether the α2-adrenoceptor agonist clonidine and the calcium channel antagonist nifedipine firstly inhibit the naloxone-precipitated withdrawal syndrome in morphine-dependent rats and secondly reduce central noradrenaline release during withdrawal. We demonstrate that both clonidine (0.1 mg/kg) and nifedipine (10 mg/kg) attenuate the naloxone-precipitated withdrwal syndrome. Using in vivo microdialysis, we demonstrate that following naloxone the release of noradrenaline, as measured by perfusates from hippocampus, increases 300% in morphine-dependent rats. However, whilst pretreatment with clonidine inhibited this increased noradrenaline release, nifedipine did not. These findings suggest that whilst the action of clonidine in attenuating the morphine withdrawal syndrome may be mediated by decreasing central noradrenline release, this is not the mechanism by which nifedipine acts.

Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS

BACKGROUNDnThe clinical effectiveness of lithium may be due to its decreasing the intracellular concentration of myo-inositol and increasing that of its inositol monophosphate precursors, which is known as the inositol depletion hypothesis.nnnMETHODSnMagnetic resonance spectroscopy (MRS) was used to measure the concentration of both myo-inositol (1H MRS) and phosphomonoesters (PME) [31P MRS], in healthy volunteers in a double-blind placebo-controlled study. MRS measurements were made at baseline, again on the 7th day of lithium (1200 mg, n = 10) or placebo (n = 6) administration, and again on day 8, 2 hours following oral administration of 20 mg dextroamphetamine to stimulate the phosphoinositol (PI) cycle.nnnRESULTSnSubjects who received lithium showed a greater increase in PME ratios in response to amphetamine administration than did placebo-treated subjects.nnnCONCLUSIONSnThe present results support the hypothesis that lithium administration blocks the conversion of inositol monophosphates to myo-inositol, and that this effect is especially apparent following PI cycle stimulation. The effects of lithium treatment on myo-inositol in healthy volunteers in vivo are uncertain, and may have to await improvements in the ability to measure myo-inositol in the brain.

Does ondansetron attenuate amphetamine-induced behaviour in human volunteers?

The effect of the 5-HT3 receptor antagonist, ondansetron, on the decrease in hunger produced by amphetamine was assessed in nine male volunteers using a double-blind cross-over design. Amphetamine (15 mg orally) produced a significant decrease in self-ratings of hunger 2.5 h after administration. This effect was significantly attenuated by pre-treatment with ondansetron (12 mg orally over 24 h). These findings in humans are consistent with data from animal studies suggesting that ondansetron can attenuate certain catecholamins-mediated behaviours produced by amphetamine. However, explanations founded on pharmacokinetic factors cannot be presently excluded.

Current Pathophysiological Findings in Bipolar Disorder and in its Subtypes

There have been many studies that have examined various aspects of the pathophysiology of bipolar disorder, with many positive findings in several areas of neuroimaging and metabolic abnormality. These studies might allow some conclusions to be drawn about the underlying pathophysiology. Additionally, it is of significant interest to determine if there are pathophysiological differences between patients with bipolar disorder type I (BPD-I) and those with bipolar disorder type II (BPD-II). The present review examines imaging studies in bipolar patients of possible structural changes (magnetic resonance imaging (MRI)) functional changes (focusing on functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT)), and those examining brain chemistry (utilizing magnetic resonance spectroscopy (MRS)). Metabolic studies reviewed were those that examined 3-methoxy-4- hydroxyphenylglycol (MHPG), cellular calcium, and protein kinase C (PKC). The results clearly suggest that BPD patients differ from controls on many of these measures. However, while there is evidence from genetic studies suggesting possible differences between BPD-II patients and BPD-I patients, the neuroimaging and metabolic studies to date do not support this, and there appear to be no consistent pathophysiologica differences between these subtypes from evidence available at present.

In vivo monoamine release during naloxone-precipitated morphine withdrawal.

There is much evidence from animal work suggesting that the release of noradrenaline (NA) in the brain increases during naloxone-precipitated morphine withdrawal, but the evidence in favour of changes in release of 5-hydroxytryptamine (5-HT) and dopamine (DA) is contradictory. Here we demonstrate, using in vivo microdialysis, that whilst there is a considerable increase (300%) in release of NA in hippocampus precipitated by naloxone in morphine-dependent rats, there is no change in the release of either 5-HT (in hippocampus) or DA (in nucleus accumbens). These results are consistent with suggestions that the symptoms of morphine withdrawal in rats are due primarily to an increase in central NA release.