5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

Abstract

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [ 11 C]raclopride to D 2 -dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n ϭ 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HTPsilocybin, a potent indoleamine hallucinogen and 5-HT receptor stimulating agent, has been reported to produce a psychosis-like syndrome in man resembling the first manifestation of schizophrenia in certain respects [for review see (Fischman 1983;Gouzoulis-Mayfrank et al. 1998)]. Particularly, ego-disorders (Rüm-mele and Gnirss 1961;Vollenweider et al. 1997), affective changes (Rümmele and Gnirss 1961), loosened associations (Spitzer et al. 1996) and perceptual alterations commonly seen in psilocybin-induced psychosis are also observed in incipient acute schizophrenic stages (Bowers and Freedman 1966;Heimann, 1986;Gouzoulis et al. 1994). In support of these suggested clinical similarities, we recently found that psilocybin produced a marked prefrontal and anterior cingulate activation in normal subjects comparable to the hyperfrontal pattern observed in some (Cleghorn et al. 1989;Ebmeier et al. 1993Ebmeier et al. , 1995Catafau et al. 1994 1994;Ebmeier et al. 1995;Sabri et al. 1997) but not all (Andreasen et al. 1992;Buchsbaum et al. 1992;Liddle et al. 1992;Siegel et al. 1993) acute schizophrenic patients. A number of functional animal studies have suggested that indoleamine (psilocybin, LSD) and phenylethylamine (DOI, mescaline) hallucinogens produce their psychotomimetic effects primarily through excessive stimulation of 5-HT, and 5-HT 2A receptors in particular (McKenna et al. 1989;Pierce and Peroutka 1989;Aghajanian 1994;Sipes and Geyer 1994;Padich et al. 1996). This assumption was corroborated in a recent human study demonstrating that the psychotomimetic effects of psilocybin can be blocked dose-dependently by pretreatment with the preferential 5-HT 2A receptor antagonist ketanserin (Vollenweider et al. 1998). However, pretreatment with the D 2 -antagonist haloperidol also reduces some of the positive symptoms of psilocybin psychosis. This raises the possibility that symptoms of psilocybin are secondary responses to increased dopaminergic transmission (Vollenweider et al. 1998).Hence, a contribution of the dopamine systems to the effects of psilocybin, presumably through a serotonindopamine interaction, cannot be ruled out. Functional interactions between central serotonin (5-HT) and dopamine (DA) systems have been well documented. Electrophysiological, biochemical, and behavioral evidence suggests that the ascending serotonergic pathways from the medial and dorsal raphe modulate or control the function of the mesolimbic and mesostriatal dopamine systems (Joyce 1993;Zazpe et al. 1994;Kapur and Remington 1996). The modulating effect of serotonin on striatal dopamine release...

The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval

“…The fact that psilocybin, in contrast to DOI, displays moderate agonistic activity at 5-HT 1A (K i ¼ 190 nM) receptors in addition to having strong agonistic action at 5-HT 2A receptors (K i ¼ 6 nM) (Aghajanian et al, 1972;Haigler and Aghajanian, 1974;Marek and Aghajanian, 1996;McKenna et al, 1990), raises the possibility that the dual effects of psilocybin on PPI in humans depend on some combination of 5-HT 2A or 5-HT 1A receptor stimulation, although downstream effects upon the glutamate and dopamine systems may also be implicated (Vollenweider et al, 1999b;Aghajanian and Marek, 2000). Moreover, the mechanism by which psilocybin reduces PPI at short and increases PPI at longer ISIs cannot be derived from the present study, but the currently available data on the effects of hallucinogens in animals and humans allow several possible explanations.…”

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

“…In humans, ketamine administration increases spontaneous and amphetamineinduced dopamine release (Breier et al, 1998;Kegeles et al, 2000;Vollenweider et al, 2000). Similarly, administration of psilocybin in healthy volunteers is associated with increased dopamine release (Vollenweider et al, 1999). In addition, both NMDAR antagonists and 5-HT 2A agonists induce excessive release of glutamate in rodents, an effect that can be blocked in both cases by group II metabotropic receptor agonists Aghajanian and Marek, 1999b;Moghaddam et al, 1997;Moghaddam and Adams, 1998).…”

“…In humans, administration of psilocybin is, like ketamine, associated with increased dopamine release (Vollenweider et al, 1999), a putative model of dysfunctional dynamics of the dopaminergic system in schizophrenia. Recently, 5-HT 2A agonists have also been reported to induce excessive release of glutamate that can be blocked by group II metabotropic receptor agonists (Aghajanian and Marek, 1999b).…”

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

“…Hallucinogens may activate dopaminergic pathways either directly, as with LSD, or indirectly by compounds that lack significant dopamine receptor affinity (Bortolozzi et al 2005;Ichikawa and Meltzer 1995;Pehek et al 2006;Vollenweider et al 1999). For example, it is well documented that activation of the 5-HT 2A receptor can modulate dopamine levels or physiological responses mediated by dopaminergic systems (Alex and Pehek 2007;Lucas and Spampinato 2000;Pehek et al 2001;Vollenweider et al 1999;Yan 2000).…”