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Example research essay topic: York N Y Play An Important Role - 1,781 words

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... like result when the test animals are given drugs which selectively bind to sigma and / or dopamine reuptake sites (Svennson, 1995). Second, 'psychotomimetic effects similar to those induced by PCP can be induced by ketamine, a related arylcyclohexamine derivative' (Sevvenson, 1995). This is a particulary strong point of evidence, especially when coupled with the following point: A dosage of ketamine ten times that of PCP is required in order to induce the same effect (Halberstad, 1995). This fits perfectly with ketamine's reduced effectiveness in binding to PCP receptors, which is approximately ten times less than that of PCP.

Ketamine is also 'essentially inactive' (Halberstad, 1995) at both sigma receptor and dopamine reuptake sites. At this time it is important to note that PCP does indeed also bind to sigma receptors and dopamine reuptake sites, albeit with a lower affinity (Okuyama, 1994). This may be an important functional link between schizophrenia and PCP; since ketamine binds only to PCP receptors and does not induce paranoid schizophrenia. PCP, on the other hand, has a broader receptor range and does induce schizophrenia (Halberstad, 1995). Finally, there is consistent evidence that PCP psychosis can be induced by serum concentrations of 20 nM (Souza, 1993).

Any PCP levels which are higher than 400 nM are associated with anesthetic effects. It has been shown that PCP receptors bind to PCP at concentrations of 30 - 50 nM, 'suggesting a highly significant degree of receptor occupancy by levels of PCP present during low dose PCP psychosis' (Souza, 1993). This point is hammered home, considering that sigma binding and dopamine reuptake sites only bind to PCP along the order of 600 nM and 700 nM, respectively (Souza, 1993). It is easy to see that the affinity these sites have for PCP is significantly lower than that of the PCP receptor.

Hence, it is not very likely that the small amount of PCP needed for psychosis would be acting on anything except the PCP receptors. Once again, however, it is important to remember that PCP does not bind solely to PCP receptors. Opposites Attract One of the prevailing theories of schizophrenia is the dopamine hypothesis, in which abnormal dopamine levels are implicated as its cause. This theory seems to conflict with the theory presented in this paper, in which abnormal functioning of the NMDA ion channel is seen as the cause.

There is, however, another important aspect of PCP induced psychosis which has not yet been discussed: the link to the A 10 dopamine releasing neurons (Restak, 1994). Most of the brain's dopamine is thought to be released from the A 10 - meso limbic-meso cortical system within the ventral teg mental region of the brain (Halberstad, 1995). This area is thought to play an important role in addiction to PCP since PCP seems to stimulate the release of dopamine, a behavior enforcing mechanism (Halberstad, 1995). How phencyclidine was is able to do this has remained a mystery until only recently.

It was previously unknown as to which receptor was more important in stimulating dopamine release, the PCP receptor or the sigma receptor (Halberstad, 1995). To find out, scientists gave test animals one of five PCP-receptor specific drugs; MK- 801, PCP, (+) SKF, or ketamine (Restak, 1994). The degree of A 10 excitation was then measured. With MK- 801 being the most powerful PCP ligand, a 40 % increase in A 10 neuronal firing rate is detected. Following closely behind are PCP, (+) SKF and ketamine, respectively (Restak, 1994).

This order correlates perfectly with the respective order of PCP receptor binding, strong evidence in supporting the role of the NMDA ion channel in A 10 dopamine release (Restak, 1994). On the other end of the spectrum, giving test animals the potent sigma ligand (+) pentazocine resulted in only a 14 % increase in A 10 neuron firing rate (Halberstad, 1995), with DTG having no measurable effect (Halberstad, 1995). Moreover, A 10 activation by PCP is not attenuated by haloperidol; which has the highest known sigma receptor affinity (Halberstad, 1995). In other words, 'The potency of PCP-like drugs to alter A 10 activity was found to correlate positively with their affinity for the PCP receptor and consequently with their potency as NMDA agonists'. (Halberstad, 1995) The obvious conclusion to draw from the above research is to say that stimulation of the A 10 neurons is the result of NMDA channel blockage. In a strange twist however, this does not appear to be the case.

The chemicals NPC 12626 and (~n) CPP are among the most potent NMDA channel blockers known (Souza, 1995). When animals are given NPC 12626 or (~n) CPP there is no change in A 10 firing rate, even after 45 minutes of infusion (Souza, 1995). If this treatment is then followed up by infusion with PCP, then the normal 40 % increase in dopamine firing is noted. not a higher rate as would be predicted by the current model (Souza, 1995).

Obviously, NMDA channel blockage is not behind the increased A 10 neuronal firing (Souza, 1995). The mechanism by which PCP does induce this effect is still subject to research (Halberstad, 1995). Regardless, phencyclidine does have an effect on dopaminergic activity and dopamine does play an important role in schizophrenia (Souza, 1995). From this, one can see that PCP agonists or antagonists may well be useful in treating schizophrenia. The Crazy Crazy Man When applying PCP psychosis to schizophrenia, a rather intriguing question arises: What effect would PCP have on schizophrenics. The answer, of course, raises more questions than it answers.

According to Crow, there are two types of schizophrenics, Type I and Type II (Halberstad, 1995). Surprisingly, this model fits quite nicely when these patients are treated with PCP. Type I schizophrenics have a 'super sensitive response to the normal amounts of endogenous PCP ligand' (Halberstad, 1995). Type II schizophrenics, on the other hand, show 'Dysfunction of the feedback look regulating PCP ligand activity, resulting in excess PCP ligand levels' (Halberstad, 1995). Type I's response is the result of excess A 10 dopaminergic activity which makes the PCP receptor considerably more sensitive (Halberstad, 1995). Type II's response, the dysfunction of the feedback loop, 'is analogous to hypothalamic-pituitary-adrenal (HPA) axis dysfunction in endogenous dysfunction (Halberstad, 1995).

In general terms, a small dose worsens Type I but leaves Type II untouched (Halberstad, 1995). A larger dose of PCP worsens Type I to an even greater extent, while Type II shows moderate improvement (showing the amphetamine-like activity induced by PCP) (Halberstad, 1995). From this data, it can be concluded that people who have a psychotic response to PCP have a 'biologic diathesis' (Restak, 1994) sensitivity to PCP resembling that which Type I patients exhibit; except with a diminished genotypic expression (Halberstad, 1995). Curing the Ill A number of novel drug treatment ideas have arisen from all the PCP research, the most obvious of which is a attempted treatment of schizophrenia by drugs which keep the NMDA channel open.

This is, however, more difficult than one would first expect. Direct stimulation on the channel is not possible, since neurotoxicity would result from excessive calcium ion levels within the neuron (Peterson, 1978). Instead, many of the current drugs call on glycine to stimulate the channel indirectly. Recall that glutamate is responsible for keeping the channel open, with help from certain reinforcing molecules like glycine and polyamides (PCP closes the channel, and causes psychosis). In one experiment, 11 schizophrenic patients were given 5 - 25 mg of glycine per day as 'a concomitant drug to the neuroleptic treatment' (Souza, 1993). Four of the initial eleven patients responded favorably to this, as would be expected.

In a related open study, glycine was given to six chronic schizophrenic patients. Two of the subjects benefited, one of which deteriorated when denied the drug (Souza, 1993). Two other patients actually worsened as a result of the treatment, while the remaining four showed no change (Souza, 1993). In another study, five male schizophrenic patients were given the pro- drug known as Milacemide (Souza, 1993), which is an acetylated version of glycine. Milacemide is better able to cross the blood brain barrier, as compared to pure glycine (Souza, 1993).

Milacemide was given to five male schizophrenic patients after a three day medication free period (Souza, 1993). All of the subjects worsened, three of which could not complete the study due to increases suspiciousness, hostility, or agitation. The negative results, however, could have been the result of the 3 day drug free period preceding the test period (Souza, 1993). Although no real benefit has been shown by the preceding treatments, the principle behind their action is still strong. It has been suggested that tests be run on other glutaminergic drugs, like polyamides (Souza, 1993).

The NMDA complex will probably be better stimulated by 'direct glutamate agonists' (Halberstad, 1995), which we may be able to synthesize in the future without their neuron damaging effects. Regardless, we must not be dissuaded by these disappointing results. PCP does induce schizophrenia, and there must be a preventive or curative measure. Conclusion It is ironic to think that a drug as terrible as phencyclidine could hold such incredible promise in cracking the mystery of schizophrenia. Although that day may be far in the future, PCP research has already opened many new doors in other areas of neurologic dysfunction; such as in the treatment of epilepsy and stroke damage.

PCP has already been shown to have a number of good uses, If not anything else, this amazing substance has given us a fascinating look into the elegantly complex world of neuro chemistry. Bibliography - dont forget this! Carroll, Marilyn. (1992). Encyclopedia of Psychoactive Drugs. New York, N.

Y: Chelsea House Publishers. Halberstad, A. L. (1995). The phencyclidine-glutamate model of schizophrenia.

Clinical Neuropharmacology. (Vol. 18) 237 - 249. Nine Fifth Congress. (1978). Abuse of dangerous and illicit drugs - psychotropics, phencyclidine (PCP), and talking; Hearings before the select committee on narcotics abuse and control house of representatives. Washington, DC: US Government Printing Office.

Okuyama, Shigeru. (1994). NE- 100, a novel sigma receptor ligand: Effect on phencyclidine-induced behaviors in rats, dogs, and monkeys. Life Sciences. (Vol. 55) PL 133 - 138 Peterson, R. C, & Stillman, R. C. (1978). PCP-Phencylidine Abuse: An appraisal.

New York, NY: National Institute on Drug Abuse. Restak, R. M. (1994). Receptors. New York, N. Y: Bantam Books.

Souza, Errol B. , & Clouet, D. , & London, E. D. (1993). Sigma, PCP, and NMDA Receptors. New York, NY: National Institute on Drug Abuse. Svensson, T. H. (1995).

Mode of action of atypical neuroleptic's in relation to the phencyclidine model of schizophrenia. Journal of Clinical Psychopharmacology. (Vol. 15) 11 S- 18 S


Free research essays on topics related to: play an important role, schizophrenic patients, national institute on drug abuse, york n y, test animals

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