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Rationale: Ketamine has rapid antidepressant effects that represent a significant advance in treating depression, but its poor safety and tolerability limit its clinical utility. Accreting evidence suggests that serotonergic neurotransmission participates in the rapid antidepressant effects of ketamine and hallucinogens. Thus, understanding how serotonin contributes to these effects may allow identification of novel rapid antidepressant mechanisms with improved tolerability., Objective: The goal of this paper is to understand how serotonergic mechanisms participate in rapid antidepressant mechanisms., Methods: We review the relevance of serotonergic neurotransmission for rapid antidepressant effects and evaluate the role of 5-HT 1A , 5-HT 1B , 5-HT 2A , and 5-HT 4 receptors in synaptic plasticity, BDNF signaling, and GSK-3β activity. Subsequently, we develop hypotheses on the relationship of these receptor systems to rapid antidepressant effects., Results: We found that 5-HT 1A and 5-HT 1B receptors may participate in ketamine's rapid antidepressant mechanisms, while agonists at 5-HT 2A and 5-HT 4 receptors may independently behave as rapid antidepressants. 5-HT 1A , 5-HT 2A , and 5-HT 4 receptors increase synaptic plasticity in the cortex or hippocampus but do not consistently increase BDNF signaling. We found that 5-HT 1A and 5-HT 1B receptors may participate in rapid antidepressant mechanisms as a consequence of increased BDNF signaling, rather than a cause. 5-HT 2A and 5-HT 4 receptor agonists may increase BDNF signaling, but these relationships are tenuous and need more study. Finally, we found that ketamine and several serotonergic receptor systems may mechanistically converge on reduced GSK-3β activity., Conclusions: We find it plausible that serotonergic neurotransmission participates in rapid antidepressant mechanisms by increasing synaptic plasticity, perhaps through GSK-3β inhibition., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: It has been suggested that corticosteroid-serotonin interactions are central to the pathophysiology of depression. These interactions have been investigated in healthy and depressed humans, primarily using neuroendocrine techniques., Objectives: To review the evidence regarding the nature of these interactions in healthy and depressed humans., Methods: Electronic searches were performed for relevant papers, employing MEDLINE and Web of Science. To focus the review, we selected only those articles involving (i) assessment of serotonergic function following experimental manipulation of the HPA axis in healthy volunteers; and (ii) assessment of both serotonergic and HPA axis function in clinically depressed subjects., Results: Pre-treatment with hydrocortisone, both acutely and sub-acutely attenuates the GH response to GHRH in healthy subjects. This complicates the interpretation of 5-HT neuroendocrine studies employing GH output as a measure. In depression there is evidence that reduced availability of l-tryptophan impairs HPA axis feedback. There is also evidence that depressed and healthy subjects may adapt differently both to low tryptophan and hypercortisolaemic challenges. There is no consistent evidence of a simple relationship between HPA axis function and 5-HT function in depression., Conclusions: The putative reduction in central 5-HT function has not been shown to be a direct consequence of hypercortisolaemia. Rather, the 5-HT system and HPA axis have complex inter-relationships. Challenges to either system, such as stress or reduced dietary tryptophan, may perturb the other and subjects vulnerable to depression may fail to adapt to such challenges.

Rationale: Previous experiments have shown that rats whose 5-hydroxytryptaminergic (5-HTergic) pathways have been destroyed exhibit higher rates of switching between response alternatives on various temporal differentiation schedules., Objective: This paper reports two experiments investigating the effect of central 5-HT depletion on switching between concurrent schedules of reinforcement which do not entail temporal differentiation of behaviour., Methods: Rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They were trained to press levers for sucrose reinforcement. In experiment 1, the rats were exposed to concurrent pairs of variable-time (VT) schedules specifying equal inter-reinforcement intervals; responses on a single "changeover lever" alternated between the two VT schedules. In experiment 2, the rats were exposed to concurrent pairs of variable-interval (VI) schedules specifying equal inter-reinforcement intervals; responses on one lever ("VI lever") earned reinforcers, while responses on the other lever ("changeover lever") alternated between the two VI schedules., Results: In experiment 1, both groups showed longer "dwell-times" (intervals between successive changeover responses) when a reinforcer was delivered in the "dwell" than when no reinforcer was delivered ("win-stay" effect). The lesioned rats showed higher rates of changeover responding and shorter dwell-times (with and without reinforcer delivery) than the sham-lesioned group. In experiment 2, the rate of responding on the VI lever did not differ significantly between the two groups; however, the lesioned rats showed higher rates of changeover responding, shorter dwell-times (with and without reinforcer delivery) and smaller numbers of inter-changeover responses on the VI lever than the sham-lesioned group. In both experiments, the levels of 5-HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered., Conclusions: These results provide further evidence for the involvement of the ascending 5-HTergic pathways in behavioural "switching", and indicate that this is not restricted to temporal differentiation schedules.

Serotonin is a neurotransmitter that is widely distributed throughout the central nervous system. The role of serotonin in schizophrenia is still unclear. Postmortem studies of serotonin receptor subtypes in schizophrenia have been inconclusive for the most part. The most promising findings involve a reduction in 5-HT2 receptors and 5-HT reuptake sites in the prefrontal cortex of schizophrenic patients. In this paper we review the function, distribution and pharmacological characteristics of serotonin receptors. Postmortem studies are also reviewed, focusing upon the role of these receptors in schizophrenia.

This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K(+)-evoked release of [3H]5-HT and in 45Ca2+ uptake and both of these changes were reversed by the GABAB agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT1A receptor agonist/partial agonist; zacopride, a 5-HT3 receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.

In a previous experiment we found that destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways by microinjection of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei resulted in impaired acquisition of temporal differentiation under an interresponse-time-greater-than-15-s (IRT > 15 s) schedule of sucrose reinforcement. This paper reports three experiments, the results of which bear on the interpretation of that finding. In Experiment 1, 32 rats were trained for 120 sessions under the IRT > 15 s schedule; then 16 received lesions of the 5HTergic pathways and 16 received sham lesions. Comparisons of the IRT frequency distributions of the two groups showed that the lesion produced a significant reduction of the mean IRT and an increase in the dispersion of IRTs, as expressed by the coefficient of variation. Obtained reinforcement rates were significantly reduced in the lesioned group, but response rates were not significantly altered. Levels of 5HT and 5-hydroxyindoleacetic acid were markedly reduced in all forebrain areas examined, without significant change in noradrenaline and dopamine levels. The results indicate that destruction of the 5HTergic pathways disrupts performance as well as acquisition of temporal differentiation. Experiments 2 and 3 examined whether changes in deprivation level and reinforcer magnitude, which are known to affect reinforcer value, would influence temporal differentiation in a similar fashion to destruction of the 5HTergic pathways. In experiment 2, 20 rats were trained under the IRT > 15 s schedule while maintained at 80% or 90% of free-feeding body weight; the more severe deprivation condition was associated with a longer mean IRT and a lower coefficient of variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin is widely distributed throughout the central nervous system and is implicated in a variety of neural functions such as pain, feeding, sleep, sexual behavior, cardiac regulation and cognition. This paper is concerned with the last of these. Abnormalities of the serotonergic nervous system are well documented in pathologic studies of Alzheimer's disease and there is evidence suggesting that changes in this system occur in association with non-disease aging. Data on the role of serotonin in learning and memory and on the effects of aging on brain serotonin function are reviewed and discussed in relation to pharmacologic treatment strategies for the memory impairments associated with advancing age.

This paper describes the results of a postmortem study of the effects of tobacco smoking on the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) as well as the binding of [3H]-8-hydroxy-(di-n-propylamino)-tetralin ([3H]-8-OH-DPAT) and [3H]-ketanserin in six discrete regions of human brain. Smoking was associated with significant decreases in the concentrations of 5-HIAA in the hippocampal neocortex (P less than 0.001), hippocampal formation (P less than 0.05) and the median raphe nuclei (P less than 0.05). The 5-HT level of the hippocampal formation was also significantly reduced in smokers (P less than 0.05). These changes were accompanied by significant increases in the binding of [3H]-8-OH-DPAT in the hippocampal neocortex (P less than 0.01) and hippocampal formation (P less than 0.05). [3H]-Ketanserin binding in the brain regions studied was unaffected by smoking. It is concluded that smoking is associated with a regionally selective decrease in the activity of the serotonergic system of the human hippocampus.