Phencyclidine The Dawn Of A New Age Term paper

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Phencyclidine: The Dawn of a New Age

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

below normal functional parameters (Haberstadt, 1995).

The Crazy Angel is Blamed

There is no doubt that PCP induces a state very similar to positive

symptom schizophrenia. There is some doubt, however, if PCP's tendency to block

the NMDA channel is to blame for the relevant clinical symptoms (Halberstadt,

1995). The ability for the PCP molecule to bond with such effectiveness to the

PCP receptor within the channel is certainly strong evidence, but some doubt the

degree of blame. Fingers have also been pointed at the "haloperidol-sensitive

sigma" receptor sites, and at monoamine reuptake sites (the core of the dopamine

hypothesis for schizophrenia) (Halberstadt, 1995). These alternative sites are

also receptive to a PCP molecule, and undoubtedly play a role in schizophrenia,

but several lines of evidence support the PCP receptor as the major force behind

the "psychotomimetic effects of PCP" (Svennson, 1995).

First, "PCP receptors have been shown to mediate the discriminative

stimulus effects of PCP in rodents" (Svennson, 1995). PCP researchers have

trained animals to discriminate between PCP and saline solutions. When these

animals are give one of a wide range of chemical substances (each from a

distinctive chemical class), the animal's response is directly proportional to

the rank order of the drug's binding power to the PCP receptor. Hence, a

stronger PCP receptor bond leads to a better NMDA channel blockade, and a

stronger drug response. On the other hand, there is no PCP-like result when the

test animals are given drugs which selectively bind to sigma...

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