Psilocybin exerts distinct effects on resting state networks 1 associated with serotonin and dopamine in mice
Joanes Grandjean, David Buehlmann, Michaela Buerge, Hannes Sigrist, Erich Seifritz, Franz X. Vollenweider, Christopher R. Pryce, Markus Rudin
Preprint · September 2019
Doi : 10.1101/751255
Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that is involved in self-reference and displays altered FC in depressive disorders. In this study we investigated the effects of psilocybin on FC in the analogue of the DMN in mouse, with a view to establishing an experimental animal model to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin-relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interaction between 5-HT- and DA-regulated neural networks contributes to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.
Keywords : Psilocybin, functional connectivity, serotonin, dopamine, resting-state, mouse
Psychiatric disorders are associated with changes in the status of specific neurotransmitter systems, including those of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA). Recently, psilocybin, a psychedelic compound derived from ”magic mushrooms” with high affinity to the 5-HTA receptor (Nichols, 2004; Halberstadt and Geyer, 2011), has gained in research interest due to its potential to alleviate depression and anxiety (Grob et al., 2011; Griffiths et al., 2016; Carhart-Harris et al., 2017a). Whilst the primary target of its active metabolite psilocin is the 5-HT2A receptor and it binds to a lesser extent to receptor 5-HT1A , psilocybin has also been shown to induce DA release in the nucleus accumbens in rats (Sakashita et al., 2015) and to reduce 11C-raclopride binding to the D2 receptor in the caudate-putamen in humans (Vollenweider et al., 1999).
The direct and indirect actions of psilocybin on specific monoamine neurotransmitter systems result in downstream metabolic and physiological effects on the brain. Thus, psilocybin increases global energy metabolism indicated by elevated glucose utilization rates in the frontomedial, frontolateral and anterior cingulate cortices as well as in basal ganglia (Vollenweider et al., 1997). Also, somewhat counter-intuitively, reduced cerebral blood flow (CBF) in several brain regions including cingulate cortex, thalamus and striatum, has been reported (Carhart-Harris et al., 2012). In blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) studies, psilocybin decreased functional connectivity (FC) within the default-mode network (DMN), and between the anterior DMN and task-positive networks (Carhart-Harris et al., 2012; Carhart-Harris et al., 2013; Roseman et al., 2014). Psilocybin therefore impacts on FC in various networks throughout the human brain, with the main effect centred on the DMN. This is consistent with the concept that psilocybin’s psychoactive effects are mediated by networks underlying self-referential processing (Carhart-Harris et al., 2014). The mechanisms, whereby psilocybin acts on functional activity within the DMN and other resting-state networks (RSNs), remain poorly understood, including how the 5-HT system is involved.
The contributions of the monoamine systems 5-HT and DA to FC are challenging to understand. The midbrain nuclei hosting 5-HT (raphe nuclei) and DA (ventral tegmental area, substantia nigra pars compacta) cell bodies are not included in canonical RSNs (Damoiseaux et al., 2006). Using BOLD fMRI correlational analysis of signal traces extracted from midbrain nuclei typically fails to capture evidence of functional coupling to distal regions. Integrating complementary information with FC analysis might overcome this limitation and reveal contributions of midbrain nuclei to FC. In mouse models, integration of whole-brain imaging with region-specific gene expression (Lein et al., 2007; Ng et al., 2009; Hawrylycz et al., 2012) and axonal projection maps (Oh et al., 2014) derived from the Allen Institute for Brain Science (AIBS) offers the opportunity to investigate the molecular neuropharmacology of psychoactive agents in spatio-temporal dimensions.