Nurith Amitai1, Susan B Powell2, Jared W Young3. 1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA. 2. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System,3350 La Jolla Village Drive, San Diego, CA, 92037, USA. 3. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System,3350 La Jolla Village Drive, San Diego, CA, 92037, USA. Electronic address: jaredyoung@ucsd.edu.
Abstract
BACKGROUND: Schizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population with heterogeneous symptoms including positive, negative, and cognitive. While treatment for positive symptoms exists, none have been developed to treat negative symptoms. Animal models of schizophrenia are required to test targeted treatments and since patients exhibit reduced effort (breakpoints) for reward in a progressive ratio (PR) task, we examined the PR breakpoints of rats treated with the NMDA receptor antagonist phencyclidine or those reared in isolation - two common manipulations used to induce schizophrenia-relevant behaviors in rodents. METHODS: In two cohorts, the PR breakpoint for a palatable food reward was examined in Long Evans rats after: 1) a repeated phencyclidine regimen; 2) A subchronic phencyclidine regimen followed by drug washout; and 3) post-weaning social isolation. RESULTS: Rats treated with repeated phencyclidine and those following washout from phencyclidine exhibited higher PR breakpoints than vehicle-treated rats. The breakpoint of isolation reared rats did not differ from those socially reared, despite abnormalities of these rats in other schizophrenia-relevant behaviors. CONCLUSION: Despite their common use for modeling other schizophrenia-relevant behaviors neither phencyclidine treatment nor isolation rearing recreated the motivational deficits observed in patients with schizophrenia, as measured by PR breakpoint. Other manipulations, and negative symptom-relevant behaviors, require investigation prior to testing putative therapeutics.
BACKGROUND:Schizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population with heterogeneous symptoms including positive, negative, and cognitive. While treatment for positive symptoms exists, none have been developed to treat negative symptoms. Animal models of schizophrenia are required to test targeted treatments and since patients exhibit reduced effort (breakpoints) for reward in a progressive ratio (PR) task, we examined the PR breakpoints of rats treated with the NMDA receptor antagonist phencyclidine or those reared in isolation - two common manipulations used to induce schizophrenia-relevant behaviors in rodents. METHODS: In two cohorts, the PR breakpoint for a palatable food reward was examined in Long Evans rats after: 1) a repeated phencyclidine regimen; 2) A subchronic phencyclidine regimen followed by drug washout; and 3) post-weaning social isolation. RESULTS:Rats treated with repeated phencyclidine and those following washout from phencyclidine exhibited higher PR breakpoints than vehicle-treated rats. The breakpoint of isolation reared rats did not differ from those socially reared, despite abnormalities of these rats in other schizophrenia-relevant behaviors. CONCLUSION: Despite their common use for modeling other schizophrenia-relevant behaviors neither phencyclidine treatment nor isolation rearing recreated the motivational deficits observed in patients with schizophrenia, as measured by PR breakpoint. Other manipulations, and negative symptom-relevant behaviors, require investigation prior to testing putative therapeutics.
Authors: Andrew J Grottick; David L MacQueen; Samuel A Barnes; Chris Carroll; Erin K Sanabria; Vishal Bobba; Jared W Young Journal: Psychopharmacology (Berl) Date: 2021-01-06 Impact factor: 4.530