http://www.world-science.net/othernews/070129_hallucinogen.htm
How drugs cause hallucinations
Jan. 31, 2007
Special to World Science
Scientists say they have partly explained what causes the mind-
bending effects of hallucinogens—drugs, such as LSD, mescaline, and
psilocybin, that trigger states akin to dreaming or madness.
The researchers said their discovery may illuminate more than just
the workings of these drugs, which became popular in Western culture
in the 1960s though some had been used for millennia.
The findings also offer a path to understanding the function of drugs
used to treat brain disorders, sometimes with no clear understanding
of how they work, the researchers said.
The scientists, with the Mount Sinai School of Medicine and Columbia
University in New York, detailed the findings in the Feb. 1 issue of
the research journal Neuron.
Hallucinogens—sometimes taken ritually to induce what users feel are
mystical experiences—are known to act on brain molecules called 5-
HT2A receptors. These sit on the surfaces of brain cells and act
as "keyholes" that can be "unlocked" by one of the signaling chemi
cals that naturally flow through the brain.
The receptor, normally "unlocked" by the brain chemical serotonin,
then causes chemical and electrical changes in the cell, which may
consequently relay signals to neighboring cells. This is all part of
a complex electrical circuitry that underlies mental activity.
Yet hallucinogens, also called psychedelics, present a puzzle.
They "unlock" the same receptors as serotonin, or similar non-
hallucinogenic chemicals. So why do they cause such different effects?
The researchers compared differences between the effects of LSD and a
non-hallucinogenic chemical that also activates the receptors in
mice. Since the rodents couldn't report the mind-altering experiences
that drugged people relate, the researchers gauged these effects by
measuring a head twitch the mice characteristically showed when under
hallucinogens, but not the other compounds.
The scientists focused on the cortex, an advanced part of the brain
in mammals that is responsible for much of thought, perception, memo
ry, advanced motor function, social abilities, language and problem
solving. The researchers found that LSD produced an array of electri
cal and cell signaling responses in the cortex very different from
those induced by the nonhallucinogen.
The apparent key to the difference was that LSD activated the recep
tor in a subtly different way from natural chemicals, said Mount Si
nai's Stuart C. Sealfon, a co-author of the paper. The receptor seems
to be "like a switch that can go on in more than one direction," he
explained.
When the mind-bending drug activated the receptor, it not only trig
gered the typical changes in the cell, it caused additional cell res
ponses, he said. The evidence for this, the group reported, was that
the LSD seemed to cause a characteristic chain reaction of brain chem
istry involving a class of molecules called G proteins, which are of
ten involved in normal signaling processes.
G proteins can be linked to signaling receptors, such as HT2A. When a
signal arrives, the proteins can change the cell in ways that, for ex
ample, make either it more or less prone to pass on similar signals
in the future. The alterations can last for periods ranging from a
few minutes to a lifetime; they're key to the way our mental world
changes over time, for instance with learning and memory formation.
In the experiments, one type of G protein was activated by both non-
hallucinogens and hallucinogens; but only the latter also switched on
a second type, called Gi/o, Sealfon said.
The significance of the difference is unknown. But it was particu
larly noticeable in a special layer of cells in the cortex, called
Layer 5, Sealfon said. This is often described as the "output" layer
of the cortex: it essentially gathers up decisions made in that struc
ture and relays them on to other brain regions, including centers
that execute physical movements.
Layer 5 also has extensive interconnections to other parts of the cor
tex, Sealfon said. It's also hypothesized to contribute to a certain
filtering function, in which it helps squelch unimportant information
so that this doesn't overwhelm other brain areas that don't need it.
Hallucinogens may thus disrupt this filtering, Sealfon speculat
ed. "You have a sensory overload, a less filtered experience of your
sensory input."
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