Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD), are psychoactive drugs which induce profound alterations of consciousness. They are popular drugs of abuse, but most recently also re-gained attention as possible promotors of psychotherapy. The controversy surrounding these drugs remains unresolved by modern science and politics, and demands for a strong scientific basis able to reveal how these drugs work and how their working potentially translates into benefit and/or detriment to human health and society.
Serotonergic hallucinogens interact with a variety of different monoamine receptors (proteins that govern the communication patterns across neurons), yet their psychoactive effects are thought to be primarily mediated by serotonin (5-HT) 2A receptors. 5-HT2A receptors densely populate certain neurons within the cortex of the brain (particularly influencing so called pyramidal cells), but they can also be found widely across the vascular system. How neuronal and vascular 5-HT2A receptors orchestrate to give rise to the brain dynamics characteristic for these drugs, however, is still largely unknown. That most serotonergic hallucinogens (including LSD) tend to be highly promiscuous in their receptor binding preferences, adds another layer of complexity and renders any final appraisal of the mechanistic implications of 5-HT2A receptors difficult. Here, taking advantage of a recent development in drug design, we use the highly selective 5-HT2(A) agonist 25CN-NBOH in mice. We describe the drug as to the essentials of its behavioural and autonomic properties; apply pulse oximetry to measure drug induced blood flow changes in brain-imminent arteries; and follow up on peripyramidal haemodynamics and midlayer pyramidal cell activity by means of cutting-edge techniques of optogenetic brain imaging. The overall aim is to provide insights into the (neuro-)physiology of 5-HT2A activity, delineating a possible mechanism of action of serotonergic hallucinogens.
