Sex differences confirmed in schizophrenia by means of a quantitative %PPI cocaine model and implications for

treatment

Samantha Lee, Bronx High School of Science

AbstractA quantitative approach was developed to detect, diagnose, and monitor treatment efficacy for schizophrenia. Methodology is based

on %PPI, a quantitative measure, and the acoustic startle response paradigm. A quantitative cocaine model was used as a stepping stone in order to

develop a %PPI quantitative approach. The quantitative approach helped discovered sex differences in symptom severity and treatment response for

schizophrenia.

An acoustic startle response chamber was used extensively in order to determine quantitatively the effects of cocaine on %PPI. It was

observed that cocaine generally causes a noticeable decrease in %PPI for both male and female rats, with the decrease more noticeable in females than

males. At 20 mg/kg cocaine dosage, however, the %PPI of both males and females increased after the initial injection. This behavior was specific to

this dosage, indicating that at 20 mg/kg cocaine is metabolized or eliminated from the body the quickest.

The PPI-deficit caused by cocaine mirrored that in schizophrenic individuals which led to the development of this new cocaine model of

schizophrenia. The sex differences observed as the result of cocaine administration confirm that there are sex differences in schizophrenia most

importantly emphasize the need for different treatments for the mental disorder as different the negative impact of schizophrenia vary from one

individual to another. This quantitative model could be an excellent way to gauge the efficacy of future treatments based off of recorded increase

in %PPI in schizophrenic individuals.

Schizophrenia:

a disabling brain disorder that affects 1% of the United States population. Some of the symptoms include hallucinations, paranoia, apathy, and withdrawal from social activities. Pathogenesis and etiology are currently unknown.

Sensorimotor Gating:

the ability to filter out redundant stimuli

Acoustic Startle Response (ASR):

measures startle magnitude of humans and animals in terms of Prepulse Inhibition

Prepulse Inhibition (PPI):

the measure of sensorimotor gating used in ASR experiments. If a rodent, for example, hears a small startle 30 to 500 ms before hearing a larger startle (the smaller startle before the larger startle is called the prepulse), the rodent’s response to the bigger startle will not be as large as it would be if the rodent heard the bigger startle without the prepulse. The higher the number the better the ability to gate stimuli.

Cocaine:

a psychostimulant that blocks the dopamine transporters in neurons, inhibiting the reuptake of dopamine

Literature Review

• Schizophrenia was originally thought to have one indicative symptom and the presence of that symptom dictated whether or not an individual was afflicted with the mental disorder [7]

• Other methods of diagnosis were developed but all were qualitative and relied on patient complaints which were not always reliable [6, 9, 12, 14]

• Other methods even included determining whether a patient would become afflicted based on family history and current condition [6]

Problem:

Schizophrenia is hard to accurately diagnose with the current qualitative methods

Hypothesis

Cocaine will decrease PPI

Materials

• Subjects: Six male and six female Sprague-Dawley Rats

• Acoustic startle response (ASR) chamber and specialized data collecting software

• Injection: saline or cocaine solution administered proportional to rat’s body mass

Acoustic Startle Response Paradigm

• Each rat underwent four trials

• Each trial was divided into three parts: Habituation, Injection, and Post Injection

• Habituation: began with five minutes of background noise before the chamber emitted different startles

• Injection: assessed the short term effects of whatever injection the rat received (saline or cocaine)

• Post Injection: measured the lingering effects of injection on the rat

• Cocaine was given in doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg

Saline/Control Data

• Average %PPI for males never fell below 90%

• The range of %PPI for males was 92.96% to 93.56% while the range for females was 70.14% and 84.88%

• STDEV for males was 2.8, 3.9, and 2.9 while STDEV for females was 2.1, 3.3, and 6.9

10 mg/kg cocaine

• Average %PPI for females was lower than males all across the board

• Range for females was between 75.76% and 82.37%

• Range for males was between 92.91% and 93.77%

• %PPI decreased for females between Injection and Post Injection while that for males increased

• STDEV for males was 2.7, 2.4, and 6.7 while STDEV for females was 2.7, 2.4, and 3.8

20 mg/kg cocaine

• Range for males was from 85.50% to 95.21% (the largest)

• Range for females was from 80.07% to 87.08%

• Average %PPI increases between Injection and Post Injection

• STDEV for males was 1.6, 4.5, and 1.5 while STDEV for females was 5.5, 6.6, and 3.7

40 mg/kg cocaine

• Range for males from 83.62% to 92.77% (second largest for males)

• Range for females from 76.19% to 87.35%

• Average %PPI for males increased between Injection and Post Injection while that for females continued to decrease

• STDEV for males was 2.7, 9.6, and 2.0 while STDEV for females was 4.2, 6.4, and 3.5

Discussion

• Saline data: showed that female rats inherently have lower %PPI than males do, indicating that males can sensorimotor gate better than females

• 10 mg/kg cocaine data: the divergence between Injection and Post Injection showed sex differences in response to cocaine

• Females have a more “sporadic” response than males do

• 20 mg/kg cocaine data: average %PPI of both males and females increase between Injection and Post Injection meaning both respond similarly to the same dosage size

Discussion (continued)

• The increase of %PPI for males is larger than that of males between Injection and Post Injection→sex differences in responses to 20 mg/kg cocaine

• 40 mg/kg cocaine data: %PPI of females decreased between Injection and Post Injection while that of males increased→ sex differences in response to dosage size

• PPI deficit observed mirrors that in schizophrenia→ cocaine model

Conclusions and Applications

• Schizophrenia also causes drastic decreases in %PPI similar to that observed with cocaine→ cocaine can mimic schizo. in a lab setting

• Cocaine model for schizo. can be used in a lab setting to test treatments and medications as development progresses

• Treatments that increase the %PPI when affected by cocaine could increase the %PPI in schizophrenics→ possible treatment/medication

• Perhaps confirm schizophrenia diagnosis with ASR chamber

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