Strain differences in the effects of adrenalectomy on the midbrain dopamine system: implication for behavioral sensitization to cocaine.
Adrenalectomy (ADX) abolishes behavioral sensitization to cocaine in DBA/2, but not C57BL/6 inbred mice. The present study tests the hypothesis that this ADX effect on behavioral sensitization in the DBA/2 strain involves changes in midbrain dopamine systems that do not occur in the C57BL/6 strain. For that purpose, we have measured tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA and D1- and D2-like receptor binding in C57BL/6 and DBA/2 mice that were i) unoperated, ii) ADX or sham (SHAM) operated, or iii) ADX or SHAM operated and subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days, followed by a 7.5 mg/kg challenge after a 5-day withdrawal). ADX prevented behavioral sensitization to cocaine in the DBA/2, but not the C57BL/6 strain [de Jong IEM, Oitzl MS, de Kloet ER (2007) Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner. Behav Brain Res 177:329-339]. Mice were killed under basal conditions, in the latter case 24 h after the cocaine challenge. ADX did not affect the dopaminergic markers in drug naïve mice. By contrast, strain-dependent neuroadaptations were found in the midbrain dopamine system of mice subjected to the sensitization regimen. In the DBA/2 strain, sensitization-resistant ADX mice were characterized by reduced D2 binding in the nucleus accumbens core and rostral caudate putamen. Furthermore, ADX prevented the increase in TH and DAT mRNA expression in the substantia nigra, and the decrease in D2 binding in the dorsomedial subdivision of the caudal caudate putamen associated with sensitization in SHAM mice. In the C57BL/6 strain ADX only marginally affected dopaminergic adaptations. These data suggest that adrenal hormones modulate behavioral sensitization to cocaine in a genotype-dependent fashion possibly through adaptations in pre- and post-synaptic components of the midbrain dopamine system. During cocaine sensitization, the DBA/2, but not the C57BL/6 strain, was susceptible to ADX in the dopamine system with respect to presynaptic TH and DAT and terminal D2 receptor expression.
de Jong
I E M
IE
Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Division of Medical Pharmacology, Leiden, The Netherlands. IDJ@Lundbeck.com
Steenbergen
P J
PJ
de Kloet
E R
ER
D000222:Adaptation, Physiological; D000313:Adrenal Medulla / Q000502:physiology; D000315:Adrenalectomy; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine