Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit.
Phencyclidine (PCP) is a drug of abuse that produces schizophrenia-like symptoms in humans and increases locomotor activity and stereotypic behavior in rodents. PCP-induced alteration in rat locomotor activity is thought to be mediated by an inhibition of N-methyl-D-aspartate (NMDA) receptors in the striatum and other brain regions. In this study, rats treated chronically with PCP (20 mg/kg once per day for 5 days) showed a marked increase in locomotor activity following a PCP challenge (3.2 mg/kg) administered after either 3 or 8 days of withdrawal. In biochemical assays, the release of striatal [14C]GABA by NMDA was enhanced by about 77% by chronic PCP treatment, whereas [3H]ACh release was increased by about 31% in tissue from PCP-treated rats. Even though binding experiments with 1-[1-(2-thiethyl)cyclohexyl]piperidyl-3,4 3H(N) ([3H]TCP) showed no alteration in the Kd or Bmax in whole striatum, quantitative immunocytochemical experiments found an upregulation in the NR1 subunit in the cell bodies and neuropil of cortical and striatal regions of the forebrain following chronic PCP treatment. An increase in the size of NR1-immunoreactive cells in the forebrain was also observed following chronic PCP treatment. Together, these data may help in understanding the mechanisms underlying the adaptive response to chronic reduction in glutamatergic NMDA transmission that has been postulated to be involved in the etiology of schizophrenia.
Hanania
T
T
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston 77555-1031, USA.
Hillman
G R
GR
Johnson
K M
KM
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors; D015854:Up-Regulation
D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D010622:Phencyclidine