Strain Differences in the Gating-Disruptive Effects of Apomorphine: Relationship to Gene Expression in Nucleus Accumbens Signaling Pathways

• Published in: Biological psychiatry (1969) 2008-04, Vol.63 (8), p.748-758
• Main Authors: Shilling, Paul D, Saint Marie, Richard L, Shoemaker, Jody M, Swerdlow, Neal R
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; Apomorphine; Apomorphine - pharmacology; Attention - drug effects; Cues; DNA microarray; dopamine; Dopamine - metabolism; Dopamine Agonists - pharmacology; gene expression; Gene Expression - drug effects; Neural Inhibition - drug effects; Nucleus Accumbens - drug effects; Oligonucleotide Array Sequence Analysis; Phenotype; prepulse inhibition; Psychiatry; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Dopamine - drug effects; Receptors, Dopamine - genetics; Reflex, Startle - drug effects; RNA, Messenger - genetics; schizophrenia; Signal Transduction - drug effects; Species Specificity; Transcription, Genetic - drug effects
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2007.10.015

Background Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in certain psychiatric disorders, including schizophrenia. Sprague Dawley (SD) rats are more sensitive to PPI-disruptive effects of apomorphine (APO) at long interstimulus intervals (ISIs) (60–120 msec) and less sensitive to PPI-enhancing effects of APO at short ISIs (10–30 msec) compared with Long Evans (LE) rats. Methods Prepulse inhibition was tested in SD and LE rats after APO (.5 mg/kg) or vehicle in a within- subject design and sacrificed 14 days later. Total RNA was extracted from the nucleus accumbens (NAC). Approximately 700 dopamine-relevant transcripts on the Affymetrix 230 2.0 microarray were analyzed. Results As previously reported, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared with LE rats. One hundred four genes exhibited significantly different NAC expression levels in these two strains. Pathway analysis revealed that many of these genes contribute to dopamine receptor signaling, synaptic long-term potentiation, or inositol phosphate metabolism. The expression of some genes significantly correlated with measures of APO-induced PPI sensitivity in either SD or LE rats. The expression of select genes was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). Conclusions Differences in PPI APO sensitivity in SD versus LE rats are robust and reproducible and may be related to strain differences in the expression of genes that regulate signal transduction in the NAC. These genes could facilitate the identification of targets for ameliorating heritable gating deficits in brain disorders such as schizophrenia.