Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats.
Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and γ-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction.
Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Nurith
N
Amitai
Ronald
R
Kuczenski
M Margarita
MM
Behrens
Athina
A
Markou
D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D010622:Phencyclidine
Schizophr Bull. 1999;25(2):233-55
10416729
Eur J Pharmacol. 2009 Jan 5;602(1):78-84
19026629
Pharmacol Biochem Behav. 2002 May;72(1-2):125-30
11900779
J Neurophysiol. 2008 Aug;100(2):959-65
18525022
Neuropsychopharmacology. 2001 Jul;25(1):1-27
11377916
J Neurochem. 2008 Jul;106(2):943-56
18466321
J Neurocytol. 2002 Mar-Jun;31(3-5):277-87
12815247
Nature. 2009 Jun 4;459(7247):663-7
19396156
Eur J Pharmacol. 2005 Sep 5;519(1-2):114-7
16099452
Behav Brain Res. 2006 May 15;169(2):263-73
16500717
Psychopharmacology (Berl). 2003 Sep;169(3-4):247-56
12898123
Behav Pharmacol. 2005 Feb;16(1):25-34
15706135
Psychopharmacology (Berl). 2009 Jan;202(1-3):275-86
18618099
J Neurosci. 2007 Oct 24;27(43):11496-500
17959792
J Neurosci Res. 2003 Feb 15;71(4):526-33
12548708
Biol Psychiatry. 2001 Nov 15;50(10):750-7
11720693
Psychopharmacology (Berl). 2003 Sep;169(3-4):215-33
12955285
AMA Arch Gen Psychiatry. 1959 Dec;1:651-6
14438905
J Neurosci. 2002 Apr 15;22(8):3070-80
11943810
Crit Rev Neurobiol. 1998;12(1-2):21-36
9444480
J Neurosci. 2003 Jul 16;23(15):6315-26
12867516
Behav Brain Res. 2007 Nov 22;184(1):31-8
17675172
Nat Rev Neurosci. 2007 Jan;8(1):45-56
17180162
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5341-6
9560277
Pharmacol Biochem Behav. 2009 Sep;93(3):248-57
18809428
Schizophr Res. 1997 Apr 11;24(3):349-55
9134596
Psychopharmacology (Berl). 2007 Sep;193(4):521-37
17497138
Psychopharmacology (Berl). 2007 Jun;192(2):283-90
17265073
J Neurophysiol. 1973 Jan;36(1):61-78
4196203
Arch Gen Psychiatry. 1995 Dec;52(12):998-1007
7492260
Neurosci Biobehav Rev. 1984 Winter;8(4):493-501
6514253
J Neurosci. 1996 Mar 15;16(6):2034-43
8604048
Psychopharmacology (Berl). 2005 May;179(2):336-48
15645224
Psychopharmacology (Berl). 2005 Apr;179(1):136-43
15682309
Am J Psychiatry. 1991 Oct;148(10):1301-8
1654746
Crit Rev Neurobiol. 2000;14(1):1-21
11253953
Psychopharmacologia. 1972;26(1):44-53
5051461
Mol Psychiatry. 2002;7(4):392-404
11986983
Arch Gen Psychiatry. 2000 Mar;57(3):237-45
10711910
Biol Psychiatry. 1998 Jun 1;43(11):811-6
9611670
J Neurosci. 2006 Feb 1;26(5):1604-15
16452684
Psychopharmacology (Berl). 2004 Jun;174(1):143-50
15205885
Arch Gen Psychiatry. 1995 Apr;52(4):258-66
7702443
Neurosci Lett. 1998 Dec 24;258(3):175-8
9885959
Biol Psychiatry. 2002 Oct 1;52(7):708-15
12372661
Neuropsychopharmacology. 2003 Feb;28(2):265-75
12589379
J Neurosci. 1989 Jun;9(6):2051-65
2566664
Prog Brain Res. 1998;116:421-37
9932393
J Neurosci. 1997 Apr 15;17(8):2921-7
9092613
Naunyn Schmiedebergs Arch Pharmacol. 2007 Jun;375(4):261-71
17458542
Science. 2007 Dec 7;318(5856):1645-7
18063801
Neuropsychopharmacology. 1999 Mar;20(3):201-25
10063482
Arch Gen Psychiatry. 2000 Nov;57(11):1061-9
11074872
Naunyn Schmiedebergs Arch Pharmacol. 2006 Dec;374(3):177-93
17103144
Eur J Pharmacol. 2010 Aug 10;639(1-3):67-80
20371228
Am J Psychiatry. 2001 Feb;158(2):256-65
11156808
J Neurochem. 2004 Apr;89(1):204-16
15030405
Neuropsychopharmacology. 2007 Oct;32(10):2087-97
17356574
Philos Trans R Soc Lond B Biol Sci. 1996 Oct 29;351(1346):1463-70; discussion 1470-1
8941958
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6496-9
9177246
J Neurosci Res. 1998 Mar 1;51(5):583-92
9512002
Arch Gen Psychiatry. 1994 Mar;51(3):199-214
8122957
J Neurosci. 1998 Jul 15;18(14):5545-54
9651235
Biol Psychiatry. 2010 Jul 1;68(1):5-16
20488434
Eur J Pharmacol. 1998 Jan 2;341(1):45-56
9489855
Arch Gen Psychiatry. 1986 Feb;43(2):114-24
3947207
Am J Psychiatry. 1999 Nov;156(11):1709-19
10553733
Psychopharmacology (Berl). 2007 Aug;193(2):225-33
17406859
Neuropsychopharmacology. 1996 May;14(5):301-7
8703299
Nature. 2009 Jun 4;459(7247):698-702
19396159