Pharmacology and behavior genetics of heroin dependence in mice.

摘要

Exposure to opioid drugs can lead to a dependent state that is manifested by physical symptoms during naloxone-precipitated withdrawal (NPW). Because heroin pharmacology is similar to morphine, it has been assumed that they utilize common neural substrates. This dissertation reports several studies that test this assumption. The specific aim of the first study was to examine jumping frequency as a valid measure of NPW from heroin in mice. The data show a positive dose-response relationship between acute and chronic heroin doses and NPW jumping, and reveal the interval yielding maximal responding. These doses and drug intervals were used in all subsequent studies.;The second study assessed the contribution of opioid (delta1, delta 2 & kappa) and excitatory amino acid (NMDA and AMPA) receptors to NPW jumping frequency in heroin-dependent mice. We found that delta 1 & delta2-antagonists attenuated both acute and chronic heroin dependence, while the kappa antagonist increased chronic heroin, but had no effect on acute heroin, dependence. The NMDA and AMPA receptor antagonists MK-801 and LY293558 appear to impact heroin dependence as well. Acute heroin dependence was not affected by single injections of either MK-801 or LY293558, but continuous infusion or chronic injection of these antagonists was effective in reducing acute and chronic heroin dependence. The data thus indicate that the attenuation of heroin dependence in acute and chronic paradigms likely results from neuronal adaptations from long term pretreatment with this class of drugs.;In a third study, we assessed the contribution of genotype on heroin withdrawal magnitude by surveying 6 inbred mouse strains for NPW jumping after acute and chronic heroin injection. The data demonstrate that the magnitude of NPW jumping frequencies in inbred mice following acute and chronic heroin treatment is associated with genetic variability. The data also show that acute and chronic heroin dependence share common genes. The data also reveal a strong genetic correlation between acute and chronic heroin and acute and chronic morphine dependence, indicating that common physiological substrates underlie dependence to these two opioids.;The fourth study studied the ability of antisense oligonucleotides (AS ODNs) targeting various exons from the MOR-1 to alter heroin and morphine dependence. AS ODNs directed against exon-1 of the mu-receptor attenuated heroin and morphine dependence, but had no impact on heroin analgesia. These data suggest that heroin and morphine dependence are mediated by splice variants containing exon-1, but that heroin analgesia may be mediated by a separate variant of the mu-receptor. Overall, these studies characterize heroin dependence in mice, and reveal that morphine and heroin dependence are not identical processes.