Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.

Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors

1 Citalopram (Lu 10-171), a new bicyclic phthalane derivative, is an extremely potent inhibitor of neuronal serotonin (5-HT) uptake but has no effect on the uptake of noradrenaline (NA) and dopamine (DA) 2 Citalopram has no antagonistic activity towards DA, NA, 5-HT, histamine, gamma aminobutyric acid (GABA), acetylcholine, and morphine receptors In this way it clearly deviates from many old and new antidepressant drugs which have antagonistic effects towards some of these transmitters 3 In contrast to many tricyclic antidepressants citalopram is devoid of cardiotoxic effects, even when animals are exposed to concentrations far above the therapeutic level 4 In man citalopram is metabolized to compounds which are also potent 5-HT-uptake inhibitors without effect of NA uptake and which are found in lower concentrations than citalopram itself 5 In account of its extreme specificity as a 5-HT-uptake inhibitor citalopram should be considered as an experimental tool of the utmost importance In preliminary clinical experiments citalopram has shown a clear antidepressant effect This property together with the absence of troublesome anticholinergic adverse effects and cardiotoxic effects also make citalopram a most promising antidepressant drug

Citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity.

http://www.med.monash.edu.au/assets/docs/scs/psychiatry/psychopharmacology/alper-seizure-2007.pdf

Seizure Incidence in Psychopharmacological Clinical Trials: An Analysis of Food and Drug Administration (FDA) Summary Basis of Approval Reports

http://www.scielo.br/pdf/rbp/v37n1/1516-4446-rbp-2015-37-1-13.pdf

Neil S. Buckholtz

Papers

Monoamine oxidase inhibition in brain and liver produced by β-carbolines: structure-activity relationships and substrate specificity

Neurobiology of tetrahydro-β-carbolines

Inhibition by β-carbolines of monoamine uptake into a synaptosomal preparation: Structure-activity relationships

Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain

Effects of tetrahydro-β-carbolines on monoamine oxidase and serotonin uptake in mouse brain