Effect of chronic D-Amphetamine and Phencyclidine treatment on Parvalbumin expressing interneurons.

Presented at: British Association for Psychopharmacology annual summer conference, Oxford, 2009
Engel M a, b, Sandager-Nielsen K a, Thomsen S M a, 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

Working memory deficits in schizophrenia are thought to be caused by dysfunction of the prefrontal cortex (PFC). Recent evidence from post mortem tissue indicates that there is a deficit in the integrity of a subset of GABAergic interneurones in the dorsolateral part of the PFC (dlPFC). Attempts to model these pathological changes have entailed treating animals chronically with phencyclidine (PCP) and, to a lesser extent, d-amphetamine (AMP). These studies have met with some overall limited success, and this is likely a consequence of methodological differences between labs.
The goal of the present study was to compare a literature cited chronic AMP regimen known to result in cognitive impairments in rodents (Fletcher et al., 2003, Schizophrenia Research, 64, 103-114), with a PCP regimen demonstrated to alter the integrity of PFC GABAergic interneurons ( Cochran et al., 2003, Neuropsychopharmacology, 28(2), 265-75) as measured by reductions in the level of the Ca2+ binding protein parvalbumin (PV). In addition we provide some preliminary prepulse inhibition (PPI) data.
Rats were administered AMP 3-days/week for 3-weeks using an escalating dosing regimen (1-3mg/kg at a rate of 1mg/kg/week). PCP was administered at 2.6 mg/kg for 4 weeks, 5-days in the first week and on three days in each of the following weeks. PV immunostaining in interneurons of the PFC (prelimbic & infralimbic ) and hippocampus (CA1, CA2/3 & DG) was quantified three days after the last injection. Appropriate control groups were run alongside (N=8/group). 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.
Although chronic AMP treatment did not significantly alter the number of PV expressing cells in in the 5 areas sampled, there was a strong tendency for a reduction in the CA1. There were no strong trends in any areas for PV reductions after chronic PCP treatment. Interestingly, in our preliminary behavioural data both chronic treatment with AMP and PCP significantly disrupted PPI.
Our conclusions can only be preliminary at this point since we are: (i) looking at PV immunostaining at a more refined level of resolution (i.e., quantification in specific layers of the PFC), (ii) additionally determining immunostaining for GAD67 at the gross/finer resolution level, and (iii) are completing PV/GAD67 immunostaining in the animals subjected to PPI assessment. Nonetheless, our data suggests this chronic AMP regimen results in some alteration of PV-containing interneurons coincident with deficits in PPI.

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