Haiyang Xu1, Sasmita Das2,3, Marc Sturgill4, Colin Hodgkinson5, Qiaoping Yuan5, David Goldman5, Kenneth Grasing6,7. 1. Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA. 2. Molecular Bio-Nanotechnology, Imaging and Therapeutic Research Unit, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA. 3. Division of Hematology and Oncology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, 66160, USA. 4. Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, USA. 5. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20852, USA. 6. Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA. kgrasing@kumc.edu. 7. Division of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, 66160, USA. kgrasing@kumc.edu.
Abstract
RATIONALE: The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding. OBJECTIVE: The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats. METHODS: Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats. RESULTS: HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors. CONCLUSIONS: Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.
RATIONALE: The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding. OBJECTIVE: The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HSrats. METHODS: Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LSrats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HSrats. RESULTS:HSrats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LSrats, but not in HS animals, while high-dose cocaine augmented activity only in HSrats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HSrats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors. CONCLUSIONS: Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HSrats and an altered dose-effect relationship for cocaine-induced locomotor activity.
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