April, 1956 : The pharmaceutical company Parke & Davis first synthesize what
they believe to be the perfect anesthetic (Souza, 1995). When administered to
patients, it causes a completely dissociative state, with no significant
respiratory or cardiovascular depression. Patients appear to be awake, eyes
open, breathing normally.but are unaware of their surroundings or the procedures
being performed upon them (Souza, 1995). Indeed, this is the perfect drug.
Unfortunately, like all good things, this one has a darker side. 15% of
patients awake from their slumber with what appeared to be an acute case of
paranoid schizophrenia (Peterson; Stillman, 1978). The drug is PCP, and to this
day it is the scourge of the underground drug community, and the focal point of
intense scientific research. Parke Davis and Company did not know how terrible,
and wonderful, a discovery they made that day; but our world has been changed
forever because of it.quite possibly for the better.

The Dust of Angels

Phencyclidine, more commonly known as PCP, is a polycyclic compound belonging to
the arylcyclohexylamine class of chemicals [figure 1.0] (Souza 1993). In pure
form, it is a white powder which readily dissolves in water. The cyclohexamines
are known for their the potent neurological effects, with PCP being the most
potent. Almost every variation has been administered to, or abused by, humans at
some time (Nintey Fifth Congress, 1978). All these compounds have similar
pharmacological effects, which vary considerably according to the amount
administered. Small doses produce a `drunken' state, in which subjects report a
numbness in the extremities, while some species (like dogs and cats) become
quite excited (Halberstadt, 1995). Intermediate doses have anesthetic and
analgesic effects , with the psychic state resembling sensory isolation with one
important exception: the sensory impulses (when tested electrophysiologically)
reach the neocortex but "the neuronal signals are grossly distorted"
(Halberstadt, 1995). Large doses, especially of PCP, may produce convulsions.
Any dose produces cataleptoid muscle effects (Halberstadt, 1995). All the
chemicals in this class produce a range a physiological effects, including
tachydardia and hypertension (Halberstadt, 1995). Unlike the other
cyclohexamines, however, PCP causes severe "emergence delirium" when taken in
moderate to anesthetic quantities (Halberstadt, 1995). On the other hand,
ketamine, a close cousin of PCP, produces depressant effects which are more
amplified than PCP without the psychotic aftereffects (although hallucinations
are reported by patients during sedation, (Halberstadt, 1995)). In special cases,
ketamine is still used as an anesthetic. (C.H. Badenhorst M.D, personal
communication).

Ten years after its initial discovery, phencyclidine found a new
audience in the scientific and underground drug culture communities (Nintey
Fifth Congress, 1978). At this time, a few Freudian psychologists carried out
unauthorized experiments in which perfectly healthy patients were given PCP and
observed (Nintey Fifth Congress, 1978). Although their research did not provide
much useful data, it did begin a revolution in our knowledge of the chemical
basis for schizophrenia (Nintey Fifth Congress, 1978). In 1987, the FDA removed
Sernyl (phencyclidine's market name) from the human market and reserved it for
use only as an animal tranquilizer, for which it is still used today (Peterson,
1978). Unfortunately, some individuals were still able to obtain the drug,
either through theft or home synthesis in a garage laboratory (Nintey Fifth
Congress, 1978). It was distributed under a number of slang terms, including
PeaCe Pill, THC, and Love Boat; and rapidly spread throughout the country as a
result of its low price and availability (Peterson, 1978). There were many
casualties.not because of the drug, but because of its effects. Hospitals also
noticed a sudden increase in paranoid schizophrenic admissions (Peterson, 1978),
which naturally sparked more interest in this enigma of a drug, and raised many
questions: Why were people addicted to a drug which seldom generated "good
trips"? Why (and more importantly, how) was this drug causing episodes of
paranoid schizophrenia? A new era in drug research for schizophrenia had been
opened.

The Excitory Amino Acid Link

If one takes a moment to consider what a amazing drug PCP is, then it is easy to
see just why scientists were so excited. Here was a single chemical which could
induce schizophrenia (Restak, 1994), a bright arrow pointing to a possible cause
of this terrible disorder. Scientists hypothesized that perhaps there were
naturally occurring phencyclidine-like substances within the brain which
malfunction and caused psychotic states (Restak 1994). This "magic" compound was
jokingly referred to as "Angle Dustin" (Restak, 1994). In truth, these
scientists were much closer to the truth than they thought.but there is an
interesting twist.

In the brain, there are three prevalent amino acid neurotransmitters:
glycine, glutamate, and aspartate; collectively these are referred to as the
excitory amino acids (Restak, 1994). They are secreted at nerve terminals, and
interact with receptors on the neuron at the post synaptic membrane (Haberstadt,
1995). Without these neurotransmitters, the brain would simply cease to work.
Too much of them, however, and the brain also tends to stop working. These
neurotransmitters function by opening ion channels within a neuron, effectively
depolarizing it; through "coupling via the glutamate receptor with other
chemicals that initiate a chain reaction of interlinked chemical processes
within the neuron" (Haberstadt, 1995). In other words, they excite the neuron by
allowing charged ions to enter it. As said before, however, too much of these
neurotransmitters would kill the neuron by exciting it to death. As a matter of
fact, this is the principle damaging factor in stroke patients (Restak, 1994).
When a neuron dies, it releases copious amounts of amino acid neurotransmitters
which then kill other brain cells through the excitotoxic effect (Souza, 1993).
In order to study this effect more fully, scientists used a glutamate analog
known as NMDA (N-methyl-D-Aspartate) which was considerably more potent than
glutamate by itself (Souza, 1993). Quite accidentally, the scientists also
discovered an NMDA antagonist, which turned out to be phencyclidine. Now here is
an interesting situation: PCP is known to be a "bad" drug, causing many unwanted
effects and hardly any beneficial ones. NMDA (or more appropriately, the
excitatory amino acids), on the other hand is a good drug; being necessary for
normal brain functioning. Ironically, PCP is a N-methyl-D-Aspartate antagonist
and counteracts any damage done by excitotoxic levels of NMDA in laboratory
animals (Restak, 1994). This is where a very important question is raised: What
role do excitory amino acids play in schizophrenia? There are, of course, two
possible directions to this question. Either schizophrenic patients have too
much glutamate, or too little (Haberstadt, 1995). Unfortunately, the answer is
never quite so simple; but some important pieces in the schizophrenia puzzle had
been found (Haberstadt, 1995).

Biochemistry of an Angel

For the last decade, scientists have been hard at work trying to
decipher the complex biochemistry of PCP. The results have been extraordinary,
with the effects of phencyclidine depending on a magnificent symphony of
receptor sites and chemical concentrations on the neuron. As was stated before,
the effects of the excitory amino acids are mediated by the NMDA receptor
subtype (in addition to 4 others) (Restak, 1995). It is known that one of PCP's
major preferences lies with the NMDA receptor complex (Souza, 1993). The NMDA
receptor "mediates ion flux through a channel permeable to Na+, K+, and Ca2+"
(Souza, 1993). The ion flux is voltage dependent, which is in turn controlled by
Mg2+ and phencyclidine (Souza, 1993). On the other hand, the extent of channel
activation is controlled by glycine through the use of NMDA agonists (Souza,
1993). Some polyamines have also recently been shown to use some sites to
control glycine binding (Haberstadt, 1995). In addition, the NMDA and glycine
receptors have been shown to exist in both antagonist and agonist conformations,
depending on the relative concentrations of glutamate, glycine, and polyamine
compounds (Haberstadt, 1995). It is through this rather complex series of checks
and balances that the effects of PCP are mediated. In short, the effects depend
on the extent of channel activation; which is dependent on at least five
different receptor/binding sites.

After considerable experimentation, the actual site of the PCP receptor
was pinpointed as being within the actual channel gated by the NMDA excitory
amino acid receptor (see figure 2.0). There are several important points which
support this conclusion. Most obvious is that the "PCP and NMDA receptors are
co-localized in the central nervous system" (Souza, 1995). Second, the "PCP
receptor ligands have been shown to inhibit NMDA-receptor-mediated conductance
non-competitively in a voltage and use dependent fashion" (Souza, 1995). Lastly,
the effectiveness of the PCP receptors is decreased by competitive NMDA receptor
agonists but increased by competitive NMDA receptor antagonists (Souza, 1993),
an exciting lead when it comes to determining the chemical mechanisms of
schizophrenia, as related to a malfunction in the NMDA receptor function. Since
PCP inhibits the NMDA receptor, the schizophrenic brain's NMDA receptors may be<...