Showing papers in "Journal of Psychopharmacology in 1997"

Catecholamine regulation of the prefrontal cortex

Abstract: The catecholamines dopamine (DA) and norepinephrine provide an essential modulatory influence on the working memory and attentional functions of the prefrontal cortex (PFC). The following critique reviews evidence that (1) either insufficient or excessive DA D1 receptor stimulation is detrimental to PFC function, while DA stimulation of the D2 family of receptors may contribute to detrimental actions in PFC and (2) that norepinephrine has an important beneficial influence on PFC function through its actions at post-synaptic, alpha 2A adrenergic receptors, but impairs PFC function through actions at alpha 1 adrenergic receptors. Critical levels of catecholamine stimulation may be needed to optimize PFC cognitive function; high levels of catecholamine release during stress may serve to take the PFC 'off-line' to allow faster, more habitual responses mediated by the posterior and/or subcortical structures to regulate behavior. These studies have relevance to our understanding and treatment of disorders with prominent symptoms of PFC dysfunction.

Dopamine, the prefrontal cortex and schizophrenia:

Abstract: Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been suspected based on observations from clinical, neuropsychological and neuroimaging studies. Since the PFC receives a dense dopaminergic innervation, abnormalities of the mesocortical dopamine system have been proposed to contribute to the pathophysiology of schizophrenia. In this review, aspects of the anatomy, physiology and pharmacology of the mesencephalic-frontal cortical dopamine system as they may relate to schizophrenia are described, and evidence for altered dopaminergic neurotransmission in the frontal cortex of schizophrenic patients is presented.

The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia

Abstract: This paper briefly discusses the anatomical criteria that have been used to delineate the prefrontal cortex (PFC) from the (pre)motor cortical areas in the frontal lobe. Single anatomical criteria,...

Frontal-subcortical circuits: the anatomic basis of executive, social and motivated behaviors

Abstract: A series of discrete, parallel frontal-subcortical circuits have been demonstrated to link specific areas of the frontal lobe to areas within the basal ganglia and thalamus. A variety of circuit-specific behaviors can be described involving the dorsolateral prefrontal, orbitofrontal and anterior cingulate circuits. Interruptions or imbalance occurring at various levels within these closed looped circuits is felt to underlie the characteristic behavioral patterns seen. The intricate neurochemical arrangement of the striatum and the complex neurotransmitter interactions that occur within these key subcortical structures form the basis for modulatory influences that can affect these circuits.

Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression

Abstract: The onset and reversibility of major depression is likely to be explained by diffuse neuromodulatory mechanisms rather than permanent abnormalities of connectivity and neurotransmission. However, the expression of mood state appears to involve fronto-striatal mechanisms. Lesions of the ventral frontal cortex give rise to profound modification of affect and behaviour not explained by effects on current intellectual function. These may represent the most extreme possible disturbances of emotional experience. Neuropsychological testing in major depression shows evidence of slowing in motor and cognitive domains with additional prominent effects on mnemonic function most marked in the elderly. Structural imaging with X-ray computed tomography or magnetic resonance imaging in older patients with major depression shows evidence of structural abnormality compared with controls. These findings are not highly localizing but they tend to confirm the role of cognitive impairment as an important age-related risk factor for major depression. Perfusion or metabolic imaging reflects both reversible changes in function and permanent loss of active neurones. The usual finding has been reductions in anterior brain structures in major depression. Hypoperfusion tends to be greatest in frontal, temporal and parietal areas and most extensive in older (male) patients; high Hamilton scores tend to be associated with reduced uptake. There have also been correlations in the cingulate cortex between increased perfusion and other aspects of the mental state. In general, reductions in frontal areas may be more likely in patients with impoverished mental states. The more prominent impairments of memory are likely to be associated with the finding of impaired temporal function or with a more diffuse failure of neuromodulation.

Rapid depletion of plasma tryptophan: a review of studies and experimental methodology.

Abstract: Evidence that the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a role in the pathophysiology of mood disorders has been accumulating over the past three decades. Recent studies on this neurotransmitter have extended across the spectrum of psychiatric disorder, suggesting a role for 5-HT in psychosis, aggression, eating disorders and addiction. However, much of the evidence has come from post-mortem examination of the brain or measures of peripheral rather than central 5-HT function. The technique of tryptophan depletion allows investigation of brain 5-HT function in living subjects by examining the behavioural responses to this pharmacological challenge. This review considers the current status of tryptophan depletion as an experimental technique and discusses the implications of findings both in affective disorders and in a range of other psychiatric syndromes. MEDLINE and PSYCHLIT searches were completed for the years 1966 to November 1996 using the key words 'serotonin', '5-hydroxytryptamine', 'tryptophan' and 'depletion'. In addition relevant journals were hand-searched for the period from 1980 to December 1996. Forty-four double-blind studies in humans and three clinical case reports were identified; these cover a range of psychiatric disorders including mood disorders and psychoses, anxiety and eating disorders and specific behaviours such as appetite, aggression and craving. The studies reviewed utilized a variety of differing methodologies reducing the extent to which results can be generalized. A series of studies in depressed patients (before and after treatment with antidepressants) and their first-degree relatives have shown the importance of an intact 5-HT system in the action of antidepressants and offer new insights into the biology of affective disorder. The mood change induced by tryptophan depletion may predict those patients likely to respond to 5-HT-specific drugs. Rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals. Effects in other disorders are conflicting and further research is needed to clarify these findings.

Anxiogenic action of caffeine: an experimental study in rats.

Abstract: The anxiogenic action of caffeine (10, 25 and 50 mg/kg, i.p.) was investigated in rats and compared with that of yohimbine (2 mg/kg, i.p.). The experimental methods used were the open-field, elevated plus-maze, social interaction and novelty-suppressed feeding latency tests. Caffeine produced a dose-related profile of behavioural changes, which were qualitatively similar to those induced by yohimbine and which indicate an anxiogenic activity in rodents. Thus, both the drugs reduced ambulation and rears, and increased immobility and defaecation in the open-field test. They decreased the number of entries and time spent on the open arms of the elevated-plus maze, reduced social interaction in paired rats and increased the feeding latency in an unfamiliar environment in 48-h food-deprived rats. Lorazepam, a well known benzodiazepine anxiolytic agent, attenuated the anxiogenic effects of caffeine and yohimbine. Subchronic administration of caffeine (50 mg/kg, i.p.) for 21 days, in different groups of animals,...

The role of noradrenaline in depression: a review.

Abstract: This review summarizes some of the evidence implicating a dysfunction in the noradrenergic system in depression. Whereas the results of studies reporting changes in the concentration of the main noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol, are equivocal, changes in adrenoceptor density and function and changes in adrenoceptors associated with the pituitary-adrenal axis function strongly implicate a disorder in central noradrenergic transmission in depression. This dysfunction may be caused by changes in the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The effect of corticotrophin releasing factor in modulating the activity of noradrenergic neurons in the locus coeruleus may provide the link between environmental trigger factors and central noradrenergic dysfunction. At the cellular level, evidence is presented of a link between noradrenaline and glutamate (via the N-methyl-aspartate receptor) and receptors. Such a link may provide a basis for the future development of novel antidepressants.

A critical review of selective serotonin reuptake inhibitor-related sexual dysfunction; incidence, possible aetiology and implications for management

Abstract: There is a high incidence of sexual dysfunction in the general population and sexual dysfunction is often an integral symptom of a depressive disorder. In addition, all antidepressants have effects...

Noradrenaline-selective versus serotonin-selective antidepressant therapy: differential effects on social functioning

Abstract: The outcome of antidepressant therapy in terms of social functioning was evaluated in a randomized, placebo-controlled, double-blind study comparing the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Of the 381 patients with major depression participating in the study, 302 patients were assessed using the new self-rating Social Adaptation Self-evaluation Scale (SASS). Mean SASS total score at last assessment was superior (p < 0.05) to placebo for both reboxetine and fluoxetine. Moreover, reboxetine was superior (p < 0.05) to fluoxetine. Evaluation of the sensitivity to change in individual items by point-biserial correlation analysis showed a significant correlation between improvement in item score and reboxetine treatment in all but one item for the reboxetine-placebo comparison. In the fluoxetine-placebo comparison, a significant correlation was evident for only 12 of the 21 items. Direct comparison of reboxetine with fluoxetine revealed a significant correlation between change in item score and treatment for nine items, in favour of reboxetine. The association was maximal for six items, mainly related to negative self-perception and to active social behaviour. In the subset of patients in remission at last assessment (n = 91), the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo (p < 0.05). Point-biserial correlation analysis revealed that most items sensitive to change under active treatment in the total population did so with reboxetine (17 items) or fluoxetine (nine items) in patients in remission. In the reboxetine-fluoxetine comparison, 14 items showed a significant association with reboxetine treatment. In conclusion, while social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment, noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action, resulting in a better quality of remission in terms of social functioning.

Reboxetine: additional benefits to the depressed patient.

Abstract: Reboxetine is a new selective noradrenaline reuptake inhibitor that has been shown to be effective in both the short-(4-8 weeks) and long-term (up to 12 months) treatment of depression. Four positive placebo-controlled studies showed reboxetine to have significant antidepressant efficacy; the response rate (> or = 50% decrease in HAM-D total score) with reboxetine ranging from 56-74%. Comparator-controlled trials showed reboxetine to be at least as efficacious as imipramine and desipramine in both adults and elderly patients. Reboxetine is also as effective as fluoxetine in the overall depressed population. However, subset analysis showed reboxetine to be significantly superior to fluoxetine in severely depressed patients. Reboxetine also showed significant advantages over fluoxetine in terms of social functioning, positively affecting patients' self perception and motivation towards action. The therapeutic effect of reboxetine is maintained for at least up to 1 year. During long-term therapy, 78% of patients receiving reboxetine were in remission at last assessment compared with only 45% of patients in the placebo group. Fewer reboxetine-treated patients relapsed (22%) compared with those receiving placebo (56%). In summary, reboxetine is effective in both the short- and long-term treatment of depression, and is at least as efficacious as traditional tricyclic antidepressant drugs and selective serotonin reuptake inhibitors. The additional benefits offered by reboxetine to the depressed patient include effective long-term treatment, efficacy in all grades of depression (including severe cases) and, importantly, specific advantages on social functioning. These additional benefits make reboxetine a favourable choice in the management of depression.

Reboxetine: a review of antidepressant tolerability.

Abstract: The tolerability of reboxetine was evaluated in 2613 adult (aged 18-65 years) or elderly (aged > 65 years) patients with depressive illness treated with reboxetine, comparator agents or placebo, who entered both short- and long-term, controlled and uncontrolled clinical trials. The reboxetine adverse-event profile in acute depression was established by comparison with placebo in 746 patients. Overall, 69% of 373 patients treated with reboxetine experienced adverse events compared with 57% of 373 patients in the placebo group. The majority of adverse events were moderate in severity, and discontinuation because of adverse events was low and comparable in both the reboxetine (8%) and the placebo (7.5%) group. When compared with imipramine, reboxetine was better tolerated. Most side-effects were less common in the reboxetine than the imipramine cohort, and fewer patients receiving reboxetine (10% in adult patients; 11% in elderly patients) discontinued treatment because of adverse events than those receiving imipramine (14% in adult patients; 16% in elderly patients). Compared with fluoxetine, the total frequency of adverse events was similar in reboxetine-treated patients (67%) and fluoxetine-treated patients (65%). In the fluoxetine group, 7% discontinued because of adverse events compared to 12% in the reboxetine group and 12% in the corresponding placebo group. In a 12-month placebo-controlled study, discontinuation because of adverse events in both groups was low (reboxetine 4%; placebo 1%), and the total frequency of adverse events was only marginally higher with reboxetine (28%) than with placebo (23%). Overall, no consistent changes were found in laboratory tests or electrocardiogram recordings and there was no indication of withdrawal symptoms upon abrupt reboxetine discontinuation. Reboxetine, a novel selective noradrenaline reuptake inhibitor, is well tolerated by adults and the elderly during short- and long-term treatment for depression.

Perspectives on the role of serotonergic mechanisms in the pharmacology of schizophrenia

Abstract: In recent years, a number of research findings has renewed interest in the possible role of serotonin (5-HT) in the pharmacology of schizophrenia. Atypical antipsychotics that potently block 5-HT receptors have been shown to be at least as effective as classical antipsychotics as well as producing fewer extrapyramidal side-effects. In addition, molecular biological studies have suggested that allelic variations of 5-HT receptor genes may affect both susceptibility to schizophrenia and clinical response to atypical antipsychotics. Building on these findings, this article proposes that 5-HT receptors are critical sites of antipsychotic action, and examines the implications of this to the treatment and pathophysiology of schizophrenia. Possible pharmacological mechanisms underlying the clinical efficacy of 5-HT blocking antipsychotics are discussed, and the potential of functional neuroimaging techniques to further elucidate these mechanisms is emphasized.

Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials:

Abstract: This study evaluates the relative effectiveness and side-effects of risperidone as compared with conventional neuroleptics in the treatment of schizophrenia, by meta-analysis of 11 double-blind, randomized controlled trials. The proportion of patients showing clinical improvement; use of medications for extrapyramidal side-effects (EPS); the treatment drop-out rates; and the changes in negative PANSS scores were measured. Compared with conventional neuroleptics, slightly more patients in the risperidone group showed clinical improvement [57 vs 52%; odds ratio 1.27, 95% confidence interval (CI): 1.04, 1.56]. The use of concomitant medications for EPS was significantly less in the risperidone group than in the conventional neuroleptic group (22.8 vs 38.4%; odds ratio 0.51, 95% CI: 0.41, 0.63). The overall drop-out rate was lower in the risperidone group than in other neuroleptic group (29.1 vs 33.9%; odds ratio 0.75, 95% CI: 0.61, 0.94). The difference in changes in negative PANSS score between the risperidone and the haloperidol group was -0.74 (95% CI: -1.50, 0.02). Weight gain and tachycardia are more common in patients treated with risperidone. Sensitivity analysis of different analytic approaches did not materially change the main estimates. It was concluded that the short-term efficacy of risperidone is comparable to other neuroleptics in the treatment of schizophrenia. It is associated with significantly fewer EPS than conventional neuroleptics (mainly haloperidol).

Changes in plasma prolactin during SSRI treatment: evidence for a delayed increase in 5-HT neurotransmission

Abstract: We studied the effect of the selective serotonin reuptake inhibitor (SSRI), paroxetine, on basal plasma prolactin concentrations in 11 healthy subjects. Subjects were tested before paroxetine, and after 1 and 3 weeks of treatment (20 mg daily). On each test occasion prolactin levels were sampled before and following administration of a placebo capsule, for a total of 4 h. After 3 weeks paroxetine treatment plasma prolactin levels were significantly higher than those seen either pre-treatment or after 1 week of treatment. In contrast, 1 week of paroxetine treatment did not significantly increase prolactin concentrations over pre-treatment values. Plasma concentrations of paroxetine did not differ between 1 and 3 weeks of treatment. The secretion of plasma prolactin is, in part, under the tonic regulation of serotonergic pathways and the present results therefore support animal experimental data suggesting that SSRIs produce a delayed increase in some aspects of brain serotonin neurotransmission.

Effects of clonidine and diazepam on the acoustic startle response and on its inhibition by 'prepulses' in man:

Abstract: This experiment examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on the eyeblink component of the acoustic startle response in healthy volunteers. Twelve males (18-30 years), screened for normal hearing thresholds, participated in three sessions in which they received oral doses of placebo, diazepam 10mg and clonidine 200 microg according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was significantly reduced both by diazepam (mean+/-SEM: -43.9+/-7.4%) and by clonidine (-75.7+/-4.7%). Under the placebo condition, the 75 and 85dB prepulses inhibited the startle response by 38.6+/-6.5 and 70.3+/-2.9%, respectively. Neither drug significantly altered the degree of prepulse inhibition. Both drugs reduced self-rated alertness; clonidine reduced systolic blood pressure and salivation. The results confirm the suppressant effect of clonidine on the startle response and show a qualitatively similar effect of diazepam; the results also demonstrate the insensitivity of prepulse inhibition of the startle response to doses of sedative drugs that are sufficient to attenuate the startle response itself.

The enhancement of social functioning as a therapeutic principle in the management of depression.

Abstract: It has long been considered that depression is a biochemical disorder resulting from dysfunction of monoamine systems in the brain and that antidepressants act upon these systems as 'magic bullets' to correct the lesion. An alternative hypothesis is that antidepressants act upon intact monoamine systems to produce functional changes that are not necessarily a reversal of the initial cause. If this is the case, one would expect that currently available classes of antidepressants would have overlapping spectra of therapeutic effects and that, while all may be effective in the majority of patients, some will be more useful according to individual needs. To date, the assessment of recovery from depression, using scales such as the Hamilton Rating Scale for Depression, has been physician centred. Such assessments leave open the possibility that patients may not have recovered in terms of their social adaptation and that, accordingly, the patients themselves and their relatives may not perceive them as having recovered. Findings of differences between antidepressants on the Social Adaptation Self-evaluation Scale highlight the importance of patient perception of treatment efficacy. These differences may indicate differences in efficacy not detected by conventional instruments, differences in tolerability, differences in the speed of onset of antidepressant activity, or differences in the behavioural profile produced by different classes of antidepressants.

The effect of central and systemic injection of the 5-HT1A receptor agonist 8-OHDPAT and the 5-HT1A receptor antagonist WAY100635 on periaqueductal grey-induced defence behaviour:

Abstract: The effects of the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) and the selective 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperzinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxa mide trichloride (WAY100635) on periaqueductal grey (PAG)-stimulated defence behaviour were tested in the rat. Microinjection of the excitatory amino acid, D, L-homocysteic acid (DLH) into the dorsal region of the PAG produced overt aversive behaviour characteristic of the defence response, consisting of explosive motor behaviours which were quantified in terms of their duration and the number of arena revolutions and jumps made by the animal. Intra-PAG pre-treatment with 8-OHDPAT (3, 10 and 25 nmol in 250 nl) 10 min before DLH stimulation significantly attenuated the defence behaviour. This could be reversed by peripheral application of WAY100635 (0.1 mg/kg). In contrast, peripheral 8-OHDPAT (0.03, 0.1 and 0.3 mg/kg) produced a significant potentiation of the DLH response which could also be bloc...

Noradrenergic mechanisms in the prefrontal cortex

Abstract: There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

Influence of anxiolytic drugs on the effects of specific serotonin reuptake inhibitors in the forced swimming test in mice

Abstract: This study aimed at investigating the effect of several selective serotonin reuptake inhibitors (SSRIs), given alone or in combination with anxiolytic drugs, on the time spent immobile in the force...

Effects of ibotenic acid-induced loss of neurons in the medial prefrontal cortex of rats on behavioral vigilance: Evidence for executive dysfunction

Abstract: Rats were trained in a previously validated task for the assessment of sustained attention, or vigilance. This task required the animals to discriminate between signals of variable lengths and non-signal events by making an appropriate lever press. The performance of sham-lesioned animals in this task was characterized by a signal-length dependent number of hits. Also, approximately 70 percent of the non-signals were correctly rejected. Ibotenic acid-induced lesions of the medial prefrontal cortex decreased the relative number of hits and correct rejections and, in essence, resulted in random lever selection. The lesion did not affect the number of omissions or side bias. Furthermore, the performance of lesioned animals was insensitive to the detrimental effects of distractors. The effects of the lesions do not support an interpretation in terms of sustained attention. Rather, the pattern of the lesioned animals' performance is speculated to reveal a fundamental disruption of decisional processes, reminiscent of the executive dysfunctions observed in patients with damage to ventromedial prefrontal areas or with schizophrenia.

Ritanserin facilitates anxiety in a simulated public-speaking paradigm

Abstract: The effects of ritanserin, a 5-HT2A/2C (5-hydroxytryptamine) antagonist, have been investigated in simulated public speaking with healthy volunteers. The aim was to investigate the role of 5-HT in subjective experimental anxiety. There were three experimental groups each comprising four or five males and 11 females. Subjects received placebo, ritanserin 2.5 or 10 mg, p.o. They rated themselves using the Spielberger State-Trait Anxiety Inventory and visual analogue scales factored into anxiety, sedation and discontentment scores. Autonomic measures included skin conductance and heart rate. Subjects were told, 75 min after drug or placebo ingestion, without prior warning, to prepare a 4-min speech. Measures were taken before, during and after the speech. Ritanserin prolonged the anxiety induced by the procedure on the subjective ratings but had minimal effect on autonomic responses to the procedure. The result contrasts with an anxiolytic-like effect of ritanserin on aversively conditioned autonomic respons...

What is an atypical antipsychotic

Abstract: This is an exciting time for research into the drug treatment of schizophrenia. Modern techniques in imaging and molecular biology have contributed to our understanding of the receptor mechanisms of antipsychotic drug action. Several new antipsychotics are, or will shortly be, available and each of these new drugs promise improvements over classical antipsychotics. This review will discuss the concept of atypicality in antipsychotic drugs, and will describe some of the models for identification of improved antipsychotic action. The various receptor mechanisms proposed to underlie atypical antipsychotic action, several of which have featured in recent debates in this journal, will be considered in the light of the pharmacology of some of the newly- emerging antipsychotic drugs.

The nature of interactions involving prefrontal and striatal dopamine systems

Abstract: A number of converging lines of evidence from work in rodents suggest that dopamine (DA) function in the prefrontal cortex (PFC) and striatal terminal fields may be linked, possibly in an 'inverse' manner, whereby a change in prefrontal dopamine transmission in one direction occasions an opposite change in dopamine function in striatal territories. The present article considers the possible functional importance of this concept in the light of recent neuroanatomical data and new data from our own laboratory indicating that, at the neurochemical level, the basic finding of an inverse relationship between dopamine function in prefrontal and striatal regions also holds good in the non-human primate. The main conclusion is that the simple idea of an inverse relationship between prefrontal and striatal dopamine systems emphasizing presynaptic release mechanisms is unlikely to underlie, solely, the full repertoire of functional interactions. Whilst there is evidence consistent with dynamic interactions between prefrontal and striatal dopamine release under some circumstances, specifically, during the early phases of aversive learning, a complete account of possible interactions between prefrontal and striatal dopamine systems requires consideration of additional factors. Such factors include: (1) the precise nature of the psychological function investigated, (2) the possibility of acute, localized changes in striatal postsynaptic function secondary to changes in presynaptic function and (3) the possibility of manipulations of prefrontal cortex leading to adaptive changes in striatal function, at a diffuse, neural systems level.

Chronic mild stress-induced reductions in saccharin intake depend upon feeding status.

Abstract: The consumption of a weak saccharin solution was examined in rats subjected to chronic mild stress (CMS). Intake of saccharin was reduced in stressed animals compared to isolated and group control animals but saccharin preference was not affected. Removal of water deprivation from the CMS schedule did not alter the effects of CMS upon saccharin intake. However, when food deprivation was omitted entirely from the CMS schedule the reduction in saccharin intake was eliminated. Similarly, in animals habituated to the full CMS procedure, reduction in saccharin intake was abolished by omitting food deprivation or by delaying the intake test for 24 h. Both CMS and food deprivation reduced water intake but had no effect on food consumed during the fluid-intake test. The presence of food deprivation during CMS appears to be a key factor affecting saccharin intake. Our data suggest that saccharin intake is not an appropriate measure of stress and anhedonia.

Caffeine and the common cold

Abstract: An experiment was carried out to determine whether caffeinated and decaffeinated coffee removed the malaise (reduced alertness, slower psychomotor performance) associated with having a common cold. One hundred volunteers were tested when healthy and 46 returned to the laboratory when they developed colds. Those subjects who remained healthy were then recalled as a control group. On the second visit subjects carried out two sessions, one pre-drink and another an hour after the drink. Subjects were randomly assigned to one of the following three conditions, caffeinated coffee (1.5 mg/kg caffeine/body weight), decaffeinated coffee or fruit juice. Subjects with colds reported decreased alertness and were slower at performing psychomotor tasks. Caffeine increased the alertness and performance of the colds subjects to the same level as the healthy group and decaffeinated coffee also led to an improvement. These results suggest that drugs which increase alertness can remove the malaise associated with the common cold, and that increased stimulation of the sensory afferent nerves may also be beneficial.

Antidepressant drugs and the cardiovascular system: a comparison of tricylics and selective serotonin reuptake inhibitors and their relevance for the treatment of psychiatric patients with cardiovascular problems

Abstract: 1Department of Psychiatry ,University of Alberta , Room 1E7.13 Mackenzie Centre , 8440-112 Street , Edmonton , Alberta , Canada T6G 2B7 and 2University of Bristol Psychopharmacology Unit , School of Medical Sciences University Walk , Bristol BS8 1TD UK . Journal of Psychopharmacology 11(1) (1997) 83-92 01997 British Association for Psychopharmacology (ISSN 0269-8811) SAGE Publications, London, Thousand Oaks, CA and New Delhi

Familial and developmental abnormalities of front lobe function and neurochemistry in schizophrenia.

Abstract: structural abnormalities of the cerebral cortex in schizophrenia have been revealed by magnetic resonance imaging, although it is not clear whether these abnormalities are diffuse or local. We predicted that changes in cortical structure would result in abnormalities in biochemical markers for the glutamate system in post-mortem brain, and that the pattern of neurochemical abnormalities would be a clue to the distribution and extent of pathology. A number of studies have now reported increases in biochemical and other markers of glutamatergic cell bodies and terminals in the frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be due to an arrest in the normal developmental process of synaptic elimination. In the anterior temporal cortex and hippocampus there is evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the glutamatergic deficit. Glutamate cell body markers are spared in the temporal lobe; we argue that the loss of glutamate uptake sites may reflect the loss of an extrinsic glutamatergic innervation of the polar temporal cortex which arises from the frontal cortex. These fronto-temporal projections may be vulnerable because they arise from a cytoarchitecture which has not been stabilized by remodelling during early post-natal life. There have been several therapeutic studies of drugs with actions on brain glutamate systems. Based on the glutamate deficiency theories, one approach has been to enhance glutamatergic function using agonists of the N-methyl-D-aspartate-linked glycine site. However, there are no clear therapeutic effects, and some studies report aggravation of positive symptoms. This might be expected if, as part of our post-mortem studies suggested, there is excess glutamatergic innervation in some brain regions in schizophrenia. There is neuropsychological evidence that frontal abnormalities in schizophrenia may be genetically determined. We found that first degree relatives of schizophrenic patients were selectively impaired in tests of frontal lobe function, whereas both frontal and temporal function is impaired in patients We conclude that the genetic predisposition to schizophrenia involves impaired frontal lobe function. Psychotic symptoms develop only when a second process results in a loss of fronto-temporal projections and leads to temporal lobe dysfunction.

Abuse liability of testosterone

Abstract: Anabolic-androgenic steroids (AAS) are used by athletes to enhance performance and physique. Case reports and observations propose that AAS have mood elevating properties and that chronic use leads to addiction. The aim of this study was to evaluate the subjective and physiological effects of single doses of testosterone. In a double-blind fashion, according to a balanced Latin square, 10 paid adult male volunteers received doses of i.m. testosterone (50, 100 and 200 mg), morphine (10 mg) or placebo for five consecutive days. Subjective and physiological responses were measured during each drug condition. Testosterone produced no significant changes in self-reported or observed measures, unlike morphine, which produced statistically significant changes in several measures, including 'feel the drug', 'like the drug' and 'feel high'. There were no adverse effects of administering high doses of testosterone. In conclusion, single doses of testosterone are devoid of the usual pharmacologic effects that are associated with abuse.

The 5-HT2A (serotonin2A) receptor gene in the aetiology, pathophysiology and pharmacotherapy of schizophrenia

Abstract: Finding the genetic and neurochemical basis of schizophrenia is like tracking down a politician’s mistress: we all know there is one (and probably several), but her identity is elusive. Busatto and Kerwin show why the 5-hydroxytryptamine (5HT, serotonin) system, especially the 5-HTZA receptor, has been of renewed interest in schizophrenia. The data that they review take the ’serotonin hypothesis’ of the disease well beyond its previously weak status to one which merits careful consideration and active investigation. Indeed, since submission of their Critique, important new data have appearedespecially in the columns of The Lancet-in all three areas they review: aetiology, pathophysiology and pharmacotherapy. In this Commentary we focus upon the recent data and their interpretation.