Long-term changes in brain following continuous phencyclidine administration: An autoradiographic study using flunitrazepam, ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-H-3(N)-TCP, and AMPA receptor ligands

Phencyclidine induces a model psychosis which can persist for prolonged per iods and presents a strong drug model of schizophrenia. When given continuo usly for several days to rats, phencyclidine and other N-methyl-D-aspartate (NMDA) antagonists induce neural degeneration in a variety of limbic struc tures, including retrosplenial cortex, hippocampus, septohippocampal projec tions, and piriform cortex. In an attempt to further clarify the mechanisms underlying these degeneration patterns, autoradiographic studies using a v ariety of receptor ligands were conducted in animals 21 days after an ident ical dosage of the continuous phencyclidine administration employed in the previous degeneration studies. The results indicated enduring alterations i n a number of receptors: these included decreased piperidyl-3,4(-3)H(N)-TCP (TCP), flunitrazepam and mazindol binding in many of the limbic regions in which degeneration has been reported previously. Quinuclidinyl benzilate a nd (AMPA) binding were decreased in anterior cingulate and piriform cortex, and in accumbens and striatum. Piperidyl-3,4(-3)H(N)-TCP binding was decre ased in most hippocampal regions. Many of these long-term alterations would not have been predicted by prior studies of the neurotoxic effects of cont inuous phencyclidine, and these results do not suggest a unitary source for the neurotoxicity. Whereas retrosplenial cortex, the structure which degen erates earliest, showed minimal alterations; some of the most consistent, l ong term alterations were in structures which evidence no immediate signs o f neural degeneration, such as anterior cingulate cortex and caudate nucleu s. In these structures, some of the receptor changes appeared to develop gr adually (they were not present immediately after cessation of drug administ ration), and thus were perhaps due to changed input from regions evidencing neurotoxicity. Some of these findings, particularly in anterior cingulate, may have implications for models of schizophrenia.