Bill Connelly in the maps forum provides a very nice review of recent work on hallucinogens :
There's been a lot of (well deserved) coverage of the recent renaissance in the clinical study of hallucinogens, but quietly, the physiological/pharmacological study of hallucinogens, has also been advancing.
(When I say hallucinogens, I mean, in this context, LSD/mescaline like compounds, i.e. chemicals which activate the subclass of serotonin receptors known as 5-HT2A receptors).
Three papers spring to mind, published in the some of the most influential science journals, including Science, and the Proceedings of the National Academy of Science (PNAS).
It has been known for a long time that hallucinogens increased excitation in the brain, and specifically in the cortex, that is to say, that the connections between neurons (synapses) became more active in the presence of hallucinogens, and the kind of synapses that became active were the type that made neurons more likely to fire action potentials and signal to other neurons. These synapses belong to neurons which are being activated by the hallucinogens, but where to these neurons reside? As brain cells are capable of making connections from one end of the brain to the other, it could be anywhere. The likely hypothesis was a region of the brain called the thalamus. This is the main relay in the brain for most sensory and all motor connections, and on top of that, reciprocal connections between the cortex and the thalamus are believed to underpin consciousness in the round. Modulating signalling through the thalamus could explain the powerful effects hallucinogens have on perception and thought. However, in a paper published in Science, (the best or second best Science journal in the world)a multidisciplinary team, including G. Aghajanian from Yale University,using genetic manipulation of mice, so that they only expressed 5-HT2A receptors in the cortex, and no where else, showed that these mice were received the enhanced excitation caused by stimulating the 5-HT2A receptor; showing that the hallucinogen induced excitation in the cortex by directly activating cortical neurons.
Another paper published in Neuron (the second ranked pure neuroscience journal) revealed several other interesting results. A chemical known as Lisuride activates the 5-HT2A receptor, however in humans, it does not produce hallucinations. This has been paradox in hallucinogen research for some time. This paper revealed that Lisuride, though a 5-HT2A receptor agonist, activates genes in a completely different pattern than 6 hallucinogens studied (DOI, DOM, DOB, LSD, Mescaline and psilocin), and these 6 hallucinogens produced a very similar pattern as each other . Indeed, Lisuride was unable to induce any of the changes in neuronal excitability that LSD could, and was able to block that LSD induced changes. This indicates that Lisuride activates the 5-HT2A receptor, but in a fashion completely different to hallucinogens. Also they showed that selective restoration of 5-HT2A receptor function in the cortex, allowed these mice to show the same hallucinogen-induced behaviours noted in normal mice (head twitch); further indicating that 5-HT2A receptors in the cortex mediated the behavioural manifestations of hallucinogens.
Finally a recent (May 29th) publication in PNAS showed once and for all the source of the hallucinogen-induced excitation. It was demonstrated that the increase in excitation is caused by a small population of neurons which are highly sensitive to hallucinogens. These neurons begin firing constant action potentials in the presence of 5-HT2A receptor agonists. It is these neurons which the must synapse onto a large population of cortical neurons,which these cause the increase in synaptic function recorded previously.
These papers collectively tell us that that likely mechanism of hallucinogens is by causing a small population of cortical neurons to become hyper-excited, which then increases excitation in other neurons. What it does not tell us is what special properties these neurons have that allow them to produce such marked changes in human psychology (or whether they even exist in humans).
Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice.
Weisstaub NV, Zhou M, Lira A, Lambe E, González-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA.
Science. 2006 Jul 28;313(5786):536-40.
Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex.
Béïque JC, Imad M, Mladenovic L, Gingrich JA, Andrade R.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9870-5.
Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A,
Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA.
Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling
pathways to affect behavior.
Neuron. 2007 Feb 1;53(3):439-52.
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Bill Connelly
Assistant Research Fellow
Department of Pharmacology
University of Otago
