The i.c.v. injection experiments showed that ondansetron modulated naloxone-induced jumping, by acting within the CNS. Furthermore, none of the SNPs within either Htr3a-associated haplotype blocks altered its predicted amino acid sequence. Many SNPs were located within 3′ and 5′ regulatory regions, suggesting that they may alter mRNA transcription or stability. Thus, differences in CNS Htr3a mRNA expression could be responsible for interstrain differences in the severity of naloxone-precipitated withdrawal. To investigate this possibility, we evaluated Htr3a mRNA expression in several brain regions in the presence or absence of chronic morphine treatment. Measurements were made in strains with high (C57BL/6J) or low (129/SvlmJ) morphine dependence, which possess different Htr3a haplotypes. Chronic morphine treatment induced strain and brain-region-specific changes in Htr3a expression (Fig. 6); the C57BL/6J strain exhibited a more drastic decrease in Htr3a mRNA in cortical and brainstem tissue, whereas the 129/SvlmJ strain exhibited a larger decrease in the cerebellum. An approximately equal change in the spinal cord Htr3a expression was observed in both strains.
