Verification of a genetic locus for methamphetamine intake and the impact of morphine
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A quantitative trait locus (QTL) on proximal chromosome (Chr) 10 accounts for > 50% of the genetic variance in methamphetamine (MA) intake in mice selectively bred for high (MAHDR) and low (MALDR) voluntary MA drinking. The µ-opioid receptor (MOP-r) gene, Oprm1, resides at the proximal end of Chr 10, and buprenorphine reduces MA intake in MAHDR mice. However, this drug has only partial agonist effects at MOP-r. We investigated the impact of a full MOP-r agonist, morphine, on MA intake and saccharin intake, measured MOP-r density and affinity in several brain regions of the MA drinking lines and their C57BL/6J (B6) and DBA/2J (D2) progenitor strains, and measured MA intake in two congenic strains of mice to verify the QTL and reduce the QTL interval. Morphine reduced MA intake in the MAHDR line, but also reduced saccharin and total fluid intake. MOP-r density was lower in the medial prefrontal cortex of MAHDR, compared to MALDR, mice, but not in the nucleus accumbens or ventral midbrain; there were no MOP-r affinity differences. No significant differences in MOP-r density or affinity were found between the progenitor strains. Finally, Chr 10 congenic results were consistent with previous data suggesting that Oprm1 is not a quantitative trait gene, but is impacted by the gene network underlying MA intake. Stimulation of opioid pathways by a full agonist can reduce MA intake, but may also non-specifically affect consummatory behavior; thus, a partial agonist may be a better pharmacotherapeutic.
The research presented here was supported by Department of Veterans Affairs Grants I01BX002106 and I01BX002758, National Institutes of Health Grants T32DA07262, P50DA018165, U01DA041579, and R24AA020245, and a National Institutes of Health-Veterans Affairs interagency agreement. The views and opinions expressed are those of the authors and should not be construed to represent the views of the affiliated institutions or the funding agencies. We thank Harue Baba for her help with genotyping and data collection and Robert Johnson for his technical support with the receptor binding assays. We also thank Drs. Glenn Doyle and Thomas Ferraro for provision of the congenic mice from which we established our breeding stock for the current study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
- Aoyama N, Takahashi N, Kitaichi K, Ishihara R, Saito S, Maeno N, Ji X, Takagi K, Sekine Y, Iyo M, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iwata N, Inada T, Ozaki N (2006) Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. Alcohol Clin Exp Res 30:1644–1649CrossRefPubMedGoogle Scholar
- Ben-Shahar OM, Szumlinski KK, Lominac KD, Cohen A, Gordon E, Ploense KL, DeMartini J, Bernstein N, Rudy NM, Nabhan AN, Sacramento A, Pagano K, Carosso GA, Woodward N (2012) Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex. Addict Biol 17:746–757CrossRefPubMedPubMedCentralGoogle Scholar
- Jayaram-Lindström N, Guterstam J, Häggkvist J, Ericson M, Malmlöf T, Schilström B, Halldin C, Cervenka S, Saijo T, Nordström AL, Franck J (2017) Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study. Transl Psychiatry 7:e1104CrossRefPubMedPubMedCentralGoogle Scholar
- Kalvass JC, Olson ER, Cassidy MP, Selley DE, Pollack GM (2007) Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice: assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data. J Pharmacol Exp Ther 323:346–355CrossRefPubMedGoogle Scholar
- Lominac KD, McKenna CL, Schwartz LM, Ruiz PN, Wroten MG, Miller BW, Holloway JJ, Travis KO, Rajasekar G, Maliniak D, Thompson AB, Urman LE, Phillips TJ, Szumlinski KK (2014) Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation. Front Syst Neurosci 8:70CrossRefPubMedPubMedCentralGoogle Scholar
- Lominac KD, Quadir SG, Barrett HM, McKenna CL, Schwartz LM, Ruiz PN, Wroten MG, Campbell RR, Miller BW, Holloway JJ, Travis KO, Rajasekar G, Maliniak D, Thompson AB, Urman LE, Kippin TE, Phillips TJ, Szumlinski KK (2016) Prefrontal glutamate correlates of methamphetamine sensitization and preference. Eur J Neurosci 43:689–702CrossRefPubMedPubMedCentralGoogle Scholar
- Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W, Kieffer BL, Takeshima H, Carroll FI, Maidment NT, Evans CJ (2003) Buprenorphine-induced antinociception is mediated by µ-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci 23:10331–10337PubMedGoogle Scholar
- Szumlinski KK, Lominac KD, Campbell RR, Cohen M, Fultz EK, Brown CN, Miller BW, Quadir SG, Martin D, Thompson AB, von Jonquieres G, Klugmann M, Phillips TJ, Kippin TE (2017) Methamphetamine addiction vulnerability: the glutamate, the bad, and the ugly. Biol Psychiatry 81:959–970CrossRefPubMedGoogle Scholar
- Wheeler JM, Reed C, Burkhart-Kasch S, Li N, Cunningham CL, Janowsky A, Franken FH, Wiren KM, Hashimoto JG, Scibelli AC, Phillips TJ (2009) Genetically correlated effects of selective breeding for high and low methamphetamine consumption. Genes Brain Behav 8:758–771CrossRefPubMedPubMedCentralGoogle Scholar