Assessment of Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs using Brain Microdialysis
thesisposted on 2010-12-01, 12:06 authored by Pooja Sood
In order to assess pharmacokinetics and pharmacodynamics (PK/PD) accurately, it is necessary to obtain measurements of the absolute concentrations of compounds in the brain. A major shortcoming of using microdialysis to measure PK/PD is that microdialysis measurements do not give us absolute concentrations of solutes in the brain, since the relationship between dialysate concentrations and true extracellular fluid (ecf) concentrations surrounding the probe is unknown. Several methods have been devised to circumvent this problem. The present study employed a novel method, MetaQuant (MQ) microdialysis, which achieves near 100% recovery, and so enables the measurement of absolute ecf concentrations. I examined the effect of the D4 receptor agonist, PD168077 on extracellular dopamine levels (that is PD) in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of freely moving rats, while simultaneously measuring brain concentrations (that is PK) of the drug. Thus we were able to estimate the PK/PD profile of the drug in the two brain regions. Compared with basal extracellular levels, subcutaneous administration of PD168077 caused significant increase in dopamine in mPFC. Activation of dopamine D4 receptors in the mPFC may improve cognitive function, which is highly impaired in individuals with schizophrenia. Moreover, it has been consistently shown that phencyclidine (PCP) produces robust cognitive disruption, in a novel object recognition (NOR) test. I studied the efficacy of PD168077 to attenuate sub-chronic PCP induced deficit in the NOR task. Sub-chronic PCP induced a robust cognitive disruption and PD168077 (10 mg/kg, s.c. dose) reversed this disruption. Further MQ dialysis data showed that PD168077 (10 mg/kg, s.c. dose) increased dopamine levels in mPFC that was depleted due to PCP suggesting a mechanism for the observed alleviation of PCP induced cognitive deficits.