Characterization of electroencephalographic and biochemical responses at 5‐HT promoting drug‐induced onset of serotonin syndrome in rats

Abstract

Many psychotropic substances used either for medications or illicit recreational purposes are able to produce an increase in extracellular serotonin (5HT) in the CNS. 5HT is well known to improve mood, however, only when the levels of its release are in an appropriate range. Excessive 5HT is harmful, and will generally result in serotonin syndrome. To date, clinical diagnosis of serotonin syndrome relies exclusively on observation of symptoms because of a lack of available laboratory tests. The goal of the present study was to characterize the onset of the syndrome using laboratory settings to determine excessive 5HT-evoked neurological abnormalities. Experiments were carried out in rats with the syndrome being elicited by three groups of 5HT-promoting drugs: 1) (±)-3,4-methylenedioxymethamphetamine (MDMA); 2) a combination of the monoamine oxidase inhibitor clorgyline with the 5HT precursor 5-hydroxytryptophan; 3) clorgyline combined with the serotonin-selective reuptake inhibitor paroxetine. The onset of the syndrome was characterized by electroencephalography (EEG), tremor and brain/plasma 5HT tests. We found that a mild syndrome was associated with reduced EEG amplitudes while a severe syndrome strongly with seizure-like EEG activity and increased tremor activity. The occurrence of the syndrome was confirmed with microdialysis, showing excessive 5HT efflux in brain dialysate and the increased concentration of unbound 5HT in the plasma. Our findings suggest that the syndrome onset can be revealed with EEG recording, measurements of tremor activity and changes of unbound 5HT concentration in the plasma.

Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

“…2) when the MDMA dosage was increased to 3 mg/kg. A similar reduction has been reported at a high dosage (Ma et al, 2013). Concerning excessive 5HT in the brain, the EEG reduction may be associated with not only vigilance and wakefulness but also changes in brain function.…”

“…We have shown in previous studies that, although 5HT was increased to such a high level caused by 5HT-promoting drugs, including MDMA, the syndrome intensity was not always severe (Krishnamoorthy et al, 2010; Ma et al, 2013). To reconcile the existing data, we have developed the hypothesis by which a discrete role of excessive 5HT in the syndrome has been defined (Tao et al, 2014).…”

“…Symptoms vary widely but include clonus, hyperthermia, seizure and agitation (collectively called serotonin syndrome). Neurochemically, the drug causes excessive serotonin (5-hydroxytryptamine; 5HT) release widespread within the brain (Baumann et al, 2008; Ma et al, 2013). As a result, all 5HT receptor subtypes are simultaneously activated to a great extent, presumably upsetting a neural balance between inhibitory and excitatory networks, and disturbing many aspects of the body and mind such as mood, autonomic function and somatic neuromuscular activities (Mason et al, 2000; Rang et al, 2008).…”

“…In animal studies, however, MDMA fails to cause the serotonin syndrome unless high dosages are used (Malberg and Seiden, 1998; Ma et al, 2013). Furthermore, there are debates over whether animals represent suitable models to study the adverse effects that MDMA has on people who attend raves and rave-like parties (Green et al, 2012; Parrott, 2012a; Doblin et al, 2014).…”

Metabolite of tryptophan promoting changes in EEG signal and the oxidative status of the brain

“…Reactive oxygen species are bioproducts of the cellular metabolism relationship with damage in cells and neurodegeneration and determine disorders such as Parkinson's, Alzheimer's and Schizophrenia but have a regulatory role in synaptic plasticity . In this regard, electroencephalography (EEG) has been a sensitive method to evaluate the temporal response of the brain in different situations and was recently used to characterize serotonin syndrome . The EEG signal can be reliably converted into band frequencies and analysed in a quantitative manner.…”