NOTE: Free essay sample provided on this page should be used for references or sample purposes only. The sample essay is available to anyone, so any direct quoting without mentioning the source will be considered plagiarism by schools, colleges and universities that use plagiarism detection software. To get a completely brand-new, plagiarism-free essay, please use our essay writing service.
One click instant price quote
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's tate, 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 electro physiologically) reach the neo cortex but 'the neuronal signals are grossly distorted' (Halberstadt, 1995). Large doses, especially of PCP, may produce convulsions. Any dose produces cataleptic muscle effects (Halberstadt, 1995). All the chemicals in this class produce a range a physiological effects, including tachycardia 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 Serial (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 excitor amino acids (Restak, 1994). They are secreted at nerve terminals, and interact with receptors on the neuron at the post synaptic membrane (Halberstadt, 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' (Halberstadt, 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 excitor 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 (Halberstadt, 1995).
Unfortunately, the answer is never quite so simple; but some important pieces in the schizophrenia puzzle had been found (Halberstadt, 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 excitor 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 Ca 2 +' (Souza, 1993).
The ion flux is voltage dependent, which is in turn controlled by Mg 2 + 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 polyamides have also recently been shown to use some sites to control glycine binding (Halberstadt, 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 polyamide compounds (Halberstadt, 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 excitor 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 (Halberstadt, 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-...
Free research essays on topics related to: paranoid schizophrenia, pcp, receptor, amino acids, receptor sites
Research essay sample on Paranoid Schizophrenia Amino Acids
