ABSTRACT
Although opioid addiction has risen dramatically, the role of gender in addiction has been difficult to elucidate. We previously found sex-dependent differences in the hippocampal opioid system of Sprague-Dawley rats that may promote associative learning relevant to drug abuse. The present studies show that although female and male rats acquired conditioned place preference (CPP) to the mu-opioid receptor (MOR) agonist oxycodone (3â¯mg/kg, I.P.), hippocampal opioid circuits were differentially altered. In CA3, Leu-Enkephalin-containing mossy fibers had elevated levels in oxycodone CPP (Oxy) males comparable to those in females and sprouted in Oxy-females, suggesting different mechanisms for enhancing opioid sensitivity. Electron microscopy revealed that in Oxy-males delta opioid receptors (DORs) redistributed to mossy fiber-CA3 synapses in a manner resembling females that we previously showed is important for opioid-mediated long-term potentiation. Moreover, in Oxy-females DORs redistributed to CA3 pyramidal cell spines, suggesting the potential for enhanced plasticity processes. In Saline-injected (Sal) females, dentate hilar parvalbumin-containing basket interneuron dendrites had fewer MORs, however plasmalemmal and total MORs increased in Oxy-females. In dentate hilar GABAergic dendrites that contain neuropeptide Y, Sal-females compared to Sal-males had higher plasmalemmal DORs, and near-plasmalemmal DORs increased in Oxy-females. This redistribution of MORs and DORs within hilar interneurons in Oxy-females would potentially enhance disinhibition of granule cells via two different circuits. Together, these results indicate that oxycodone CPP induces sex-dependent redistributions of opioid receptors in hippocampal circuits in a manner facilitating opioid-associative learning processes and may help explain the increased susceptibility of females to opioid addiction acquisition and relapse.
Subject(s)
Hippocampus/drug effects , Oxycodone/pharmacology , Sex Characteristics , Animals , Hippocampus/metabolism , Interneurons/drug effects , Interneurons/metabolism , Long-Term Potentiation/drug effects , Male , Neurons/drug effects , Neurons/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/drug effects , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/drug effects , Receptors, Opioid, mu/metabolismABSTRACT
TaqMan is significantly more sensitive than other methods of mRNA quantification and makes possible the simultaneous analysis of numerous genes in small brain regions. This technique was used to quantify levels of mRNAs of 21 genes in tissue extracts from caudate putamen and nucleus accumbens from individual rats after 1 day 'binge' cocaine or saline administration. Expression of glyceraldehyde-3-phosphate-dehydrogenase, cyclophilin and actin mRNAs as well as 18S ribosomal RNA were evaluated for normalization of levels of gene expression.
Subject(s)
Brain/metabolism , Cocaine-Related Disorders/metabolism , Cocaine/pharmacology , Fluorescent Dyes , Gene Expression Regulation/genetics , Polymerase Chain Reaction/methods , RNA, Messenger/analysis , Animals , Brain/drug effects , Cocaine-Related Disorders/genetics , Gene Expression Regulation/drug effects , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , RNA, Messenger/drug effects , Rats , Rats, Inbred F344 , Reproducibility of Results , Time FactorsABSTRACT
Male Hartley guinea pigs were administered i.p. injections of cocaine or saline for 2 or 7 days in a "binge" paradigm. RNA was isolated from dissected brain regions and levels of preproenkephalin mRNA and total RNA were quantified by RNase protection assays. Following 2 days of "binge" cocaine administration, no significant alterations in preproenkephalin mRNA levels were detected in six brain regions. Following 7 days of cocaine administration, however, lower levels of preproenkephalin mRNA were observed in the nucleus accumbens and hypothalamus of cocaine-treated animals and higher levels in the frontal cortex and amygdala. These findings differed from previous studies in the rat, so an additional experiment was performed with animals treated at the 7 day time point. For increased statistical power, data from the two experiments were combined and examined by two-way ANOVAs; in this combined analysis, increases in preproenkephalin mRNA were observed in frontal cortex, amygdala, and hippocampus, decreases were found in the nucleus accumbens and hypothalamus, with no change in thalamus, caudate putamen, or cerebellum. These observed differences between guinea pigs and rats make this species an interesting model for neurobiological studies of cocaine-induced alterations in neuropeptide gene expression in the mammalian brain.
