How Much Serotonin in the CNS is Too Much?

Serotonin syndrome is a neurological disorder primarily associated with inappropriate uses of serotonin (5HT)-promoting drugs such as serotonin reuptake inhibitors (SRIs), monoamine oxidase inhibitors (MAOIs) or 3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) (Boyer et al., 2005; Karunatilake et al., 2006; Parrott, 2002; Paruchuri et al., 2006). The primary cause of the syndrome is due to a global increase in brain 5HT that can potentially activate all 14 subtypes of 5HT receptors (5HTRs). However, the significance of a given subtype contributing to the syndrome is not always the same, depending on the amount of 5HT evoked by drugs, physical condition of individual patients and even surrounding environment of drug administration. As a result, signs and symptoms of the syndrome vary widely (Mills, 1995) and thus it has been a clinical challenge to get an accurate diagnosis. Regardless, it has been recognized since the early 1990’s that the symptoms of the syndrome can be generally classified into 3 categories: mental state changes (mood swings), neuromuscular hyperactivity and autonomic dysfunction (Sternbach, 1991). Among these, neuromuscular and autonomic symptoms can be replicated in laboratory animals with MAOIs combined with 5HT precursors (Shioda et al., 2004) or by MDMA at a high dose (Baumann et al., 2008a; Spanos et al., 1989). Thus, despite many difficulties in clinical research, there are some great advances in understanding serotonin syndrome thanks primarily to preclinical investigation in animals.