Effect of chronic D-Amphetamine and Phencyclidine treatment on cortical Inhibitory Interneurons

Presented at: Society for Neuroscience annual conference, Chicago, 2009
Engel M a, b, Sandager-Nielsen K a, Thomsen MS a,c, Mikkelsen JD c, Mirza NR a
a Dept In Vivo Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark
b School of Biosciences, Cardiff University, Cardiff, United Kingdom
c Neurobiology Research Unit, University Hospital Copenhagen


Introduction
Working memory deficits in schizophrenia are thought to be caused by dysfunction of the prefrontal cortex (PFC). Evidence from post mortem tissue of these patients indicates that there is a decrease in presynaptic markers involved in neurotransmission in a subset of GABAergic interneurons in the dorsolateral part of the PFC (dlPFC). Attempts to model these pathological changes have entailed treating animals chronically with phencyclidine (PCP) and d-amphetamine (AMPH). The goal of the present study was to compare a chronic AMPH regimen known to result in cognitive impairments in rodents (Fletcher et al., 2003, Schiz Res, 64, 103-114), with a PCP regimen demonstrated to decrease the expression of the Ca2+ binding protein parvalbumin (PV) mRNA in the PFC (Cochran et al., 2003, Neuropsychopharm, 28(2), 265-75). We assessed the level of PV and glutamic acid decarboxylase (GAD67) in the PFC and hippocampus. In addition, we provide some preliminary prepulse inhibition (PPI) data.
Methods
Rats were administered with AMPH (3-days/week for 3-weeks) using an escalating dosing regimen (1-3mg/kg s.c. at a rate of 1mg/kg/week). PCP was administered at 2.6 mg/kg s.c. for 4 weeks, 5-days in the first week and on three days in each of the following weeks. Appropriate control groups were run alongside. The animals were perfused with 4% paraformaldehyde 72 hours after the last injection and free-floating section were immunostained using an avidin-biotin methods and diaminobenzidine as chromagen. The number of PV- and GAD67-immunoreactive neurons was counted blinded in the PFC (prelimbic & infralimbic) and hippocampus (pyramidal cell layer of CA1 and CA2/3 and the granular cell layer of the dentate gyrus, DG). Two animals from each of the four treatment groups were tested in PPI, with each animal tested on four occasions over a 2-week period beginning 2-weeks after the last dosing day.
Results
Chronic PCP treatment significantly (P<0.029; t-test) reduced the number of GAD67–immunoreactive neurons in the DG. No effects on numbers GAD67 neurons were seen in other regions of the hippocampus and the PFC. Also, the number of PV-immunoreactive neurons was unchanged after PCP in both cortical regions. Although chronic AMPH treatment did not significantly alter the number of PV- or GAD67–immunoreactive neurons in the areas sampled, there was a strong tendency (P=0.06) for a reduction of both markers in the CA1. Interestingly, in our preliminary behavioural data both chronic treatments with AMPH and PCP significantly disrupted PPI.
Conclusion
Our data suggest that chronic AMPH and PCP regimens result in differential alterations of PV- and GAD67-containing interneurons coincident with similar deficits in the PPI model.

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