Examining the effects of a sub-chronic exposure to phencyclidine: An analysis of functional network connectivity, behavior, and mRNA expression
Glutamate is the primary excitatory neurotransmitter in the central nervous system and plays a vital role in the pathology of various disease states. Thus, the manipulation and examination of glutamate has been and continues to be pivotal in experimental research. For example, a chronic administration of phencyclidine (PCP), a non-competitive glutamatergic N-methyl-D-Aspartate (NMDA) receptor antagonist, generates behavioral and neurobiological changes that mimic symptoms and microlevel changes found in psychiatric disease states, such as schizophrenia . Prior research has established that PCP induces cognitive deficits, impedes spatial learning and memory performance, and alters mRNA expression of γ-aminobutyric acid (GABA)ergic markers parvalbumin, GAD67, calbindin, and tyrosine kinase ErbB4 in addition to glutamate NMDA receptor subunits GluN2A and GluN2B in ways that are comparable to findings in the schizophrenia population [10, 11, 18, 48]. Recently, a growing interest in observing functional network connectivity (FNC) has lead to innovative ways of examining both normal systems and disease states. FNC imaging has successfully identified similar networks in both humans and rats  which has motivated translational research. Yet, little research has examined the effects of PCP on FNC in an animal system. In the current study, we characterized how a sub-chronic administration of PCP can manipulate FNC and how those changes relate to observed behavioral and mRNA expression outcomes. Adult male hooded Long Evan rats (N=40) were pre-trained in the hidden platform Morris water task (MWT) prior to beginning their sub-chronic treatment. Rats received 14 intraperitoneal (i.p.) injections of either PCP (2.58 mg/kg/injection) or 0.9% saline solution (1 mL/kg) over a period of 26 days. Seventy-two hours after the final injection all animals were anesthetized with isoflurane and imaged in a 4.7 T Bruker Biospin MRI Scanner. Fast spin-echo anatomical scans, resting state functional magnetic resonance imaging (fMRI) scans with echo-planar imaging (EPI) acquisition sequences, and arterial spin labeling (ASL) scans were acquired during the one-hour imaging session. On day 36, 10 days following the final injection, a subset of animals (PCP treated n=10, saline treated n=10) were rescanned to examine the effects of a one week washout period. Following the final scan all animals were retested in the MWT. The animals were initially tested in 8 retraining trials. After a break of least an hour in their home cage, the animals were given a short retraining session consisting of 4 trials followed by 8 trials of reversal where the hidden platform was shifted 180o from the trained location in order to examine behavioral flexibility. Upon completion of behavioral testing, the animals were sacrificed and tissue was collected and stored at -80 degrees C for GABA and NMDA receptor mRNA expression analysis. Group differences in the individual components were assessed through comparisons of FNC (inter-component correlations) and spectral power comparisons. Group independent component analyses (ICA) were conducted through the implementation of the Group ICA of fMRI Toolbox (GIFT). Additionally, select brain regions of interest, including the medial frontal cortex and ventral frontal cortex, were assessed for mRNA expression. Real-time polymerase chain reaction (RT-PCR) was used to assess mRNA expression of the GABAergic markers parvalbumin, calbindin, ErbB4, and GAD67, as well as NMDA receptor subunits GluN2A and GluN2B. The expression of these receptors within the frontal cortex were compared to expression levels within the parietal cortex, which was used as a control region. These analyses were used to observe the neurobiological effects of a sub-chronic exposure to PCP. MWT data was analyzed to determine the effects of the treatments and to characterize learning and memory performance changes following a low dose sub-chronic administration of PCP. Finally, these behavioral data also allowed for the examination of behavioral differences between groups based on temporal proximity to cessation of PCP treatment. The PCP exposed animals displayed persistent connectivity changes and alterations in mRNA expression of parvalbumin, calbindin, and GAD67.
Level of Degree
Hamilton, Dr. Derek A.
First Committee Member (Chair)
Perrone-Bizzozero, Dr. Nora
Second Committee Member
Calhoun, Dr. Vince D.
Third Committee Member
Bustillo, Dr. Juan
rat, phencyclidine, MRI, Morris water task, RT-PCR
Magcalas, Christy M.. "Examining the effects of a sub-chronic exposure to phencyclidine: An analysis of functional network connectivity, behavior, and mRNA expression." (2015). https://digitalrepository.unm.edu/psy_etds/88