Serotonin and Hallucinogens

Abstract

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT 2A and other 5-HT 2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HTThe accidental discovery in 1943 of the hallucinogenic properties of the synthetic ergoline compound LSD (dlysergic acid diethylamide) by the chemist Albert Hoffman is well known. Five years later, in 1948, serotonin (later determined to be 5-hydroxytryptamine or 5-HT) was found in bovine blood serum (Rapport et al. 1948). Then, in 1953, during a routine survey of various tissues, relatively high concentrations of 5-HT were found in brain (Twarog and Page 1953). Shortly thereafter, based on the observation that LSD could antagonize 5-HT in peripheral tissues-plus the structural similarity between these two indole-containing structures (Figure 1)-it was proposed independently by Gaddum and Hammeed (1954) and Woolley and Shaw (1954) that the hallucinogenic effects of LSD might result from an antagonism of 5-HT in the central nervous system. This hypothesis was soon modified to include the possibility that LSD could mimic as well as antagonize the actions of 5-HT (Shaw and Woolley 1956). The 5-HT hypothesis was later extended to include such simple indoleamine hallucinogens as psilocin, which are close structural analogs of 5-HT (Figure 1) and the phenethylamine hallucinogens, such as mescaline. Mescaline, despite differences in chemical structure (Figure 1), displayed similar clinical effects and cross tolerance with LSD in human studies (Balestrieri and Fontanari 1959), suggesting that the indoleamine (including ergoline) and phenethylamine classes of hallucinogens may share a common mechanism of action or final common pathway. By the end of the 1950s, three classical questions about the relationship between 5-HT and the hallucinogens had been set into place. First, do the hallucinogens produce their effects through an action upon the central 5-HT system? Second, are hallucinogens agonists or antagonists at 5-HT receptors? Third, do indoleamine and phenethylamine hallucinogens share a common site of action? Received October 19, 1998; revised November 20, 1998; accepted November 30, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2S Serotonin and Hallucinogens 17S NEURONAL ACTIONS OF HALLUCINOGENIC DRUGS Effects of Hallucinogens on 5-HT Neurons of the Raphe NucleiThe identification of 5-HT as a neurotransmitter was not achieved until the mid-1960s, when monoaminergic neuronal pathways in the brain were discovered and mapped by histochemical fluorescence methods (Dähl-strom and F...

Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders

“…Schizophrenia is characterized by distortions in thinking, perception, emotions, language, sense of self and behavior, manifested by a mixture of debilitating positive (hallucinations and delusions) and negative symptoms (depression, cognitive impairment, social withdrawal) [64]. Whilst the neuropathology underlying schizophrenia is unclear, most theories center on either an excess or a deficiency of neurotransmitters, including dopamine, serotonin, and glutamate [65,66,67]. Positive symptoms such as hallucinations and delusions, which are thought to result from excessive dopamine release in the prefrontal cortex [68,69] have been treated by dopamine antagonists such as haloperidol [70,71].…”

Quantitative Phosphoproteomics Unravels Biased Phosphorylation of Serotonin 2A Receptor at Ser280 by Hallucinogenic versus Nonhallucinogenic Agonists

“…It is a primary target of widely used atypical antipsychotics such as clozapine, risperidone, and olanzapine, which act as antagonists or inverse agonists (1, 3). The activation of 5-HT 2A receptors expressed in the prefrontal cortex has also been implicated in the psycho-mimetic effects of psychedelic hallucinogens, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, which are often used to model positive symptoms of schizophrenia (4–8). However, these psychoactive effects are not reproduced by structurally-related agonists, such as ergotamine and the anti-Parkinson agent lisuride, despite the fact that they exhibit comparable affinities and efficacies at 5-HT 2A receptors (7, 9).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The involvement of 5-HT 2A receptors in the apical dendrites of cortical pyramidal neurons in producing hallucinogenic effects (Gonzalez-Maeso et al, 2007) suggests involvement of cortical circuit mechanisms. Evidence of thalamocortical glutamate pathway involvement comes from a study demonstrating hallucinogeninduced changes in glutamate release (Aghajanian and Marek, 1999). These results were supported by human imaging studies performed in subjects under acute exposure to hallucinogens (psilocybin, mescaline, and ketamine) that indicate activation of the frontal, cingulate, and insular cortices, with reduced activation in the striatum, thalamus, and parietal cortex (Geyer and Vollenweider, 2008).…”

“…With a K i of 0.7 nM, the 5-HT 2A receptor is also the primary target of the synthetic amphetamine hallucinogen DOI, although it also targets 5HT 2B and 5HT 2C receptors with slightly lower affinities (Canal and Morgan, 2012). Also other hallucinogens, such as N,N-dimethyltryptamine and the phenethylamine hallucinogen mescaline have significant affinity mainly to the G q/11 -coupled 5-HT 2A/C receptors (Aghajanian and Marek, 1999;Ray, 2010). Moreover, efavirenz [(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H,3,1-benoxazin-2-one], a nonnucleoside reverse-transcriptase inhibitor used for treatment of HIV-1 infection, shows a risk for neuropsychiatric adverse effects such as night terrors and hallucinations and is a potent 5-HT 2A agonist (Gatch et al, 2013).…”