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      Testosterone modulation of ethanol effects on the µ-opioid receptor kinetics in castrated rats

      research-article
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      Biomedical Reports
      D.A. Spandidos
      testosterone, ethanol, opioid receptor kinetics

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          Abstract

          The present investigation was conducted to evaluate the effects of testosterone on ethanol-induced alterations of µ-opioid receptor binding kinetics in specific brain regions of castrated rats. Male Sprague Dawley rats (100-124 g) adapted to a 12-h light/dark cycle were used. Animals were castrated under pentobarbital anesthesia. After a recovery period of 14 days, ethanol [3 g/kg as 22.5% solution in saline via intraperitoneal injection (i.p.)], testosterone [2.5 mg in 0.2 ml of olive oil via subcutaneous injection (s.c.) in the dorsal neck region] or the combination of ethanol and testosterone were administered to rats at 9:00 a.m. The control group was injected i.p. with 2 ml saline and s.c. with 0.2 ml olive oil for 7 days. Animals were sacrificed by decapitation at 2 h after the final injection. The brains were immediately removed, and the cortex, hippocampus, hypothalamus and midbrain were dissected. In an attempt to elucidate the mechanism involved in the hormonal modulation of the effects of ethanol and testosterone on the endogenous opioid system, the binding kinetics of the µ-opioid receptors were determined. The results obtained in the present study assisted in identifying the regulatory role of testosterone on ethanol-induced changes on µ-opioid receptor binding kinetics.

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          Most cited references71

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          Dopamine and drug addiction: the nucleus accumbens shell connection.

          Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and 'high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs.
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            How addictive drugs disrupt presynaptic dopamine neurotransmission.

            The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms that can be involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce nonexocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions about the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study.

              The mu, delta, and kappa opioid receptors are the three main types of opioid receptors found in the central nervous system (CNS) and periphery. These receptors and the peptides with which they interact are important in a number of physiological functions, including analgesia, respiration, and hormonal regulation. This study examines the expression of mu, delta, and kappa receptor mRNAs in the rat brain and spinal cord using in situ hybridization techniques. Tissue sections were hybridized with 35S-labeled cRNA probes to the rat mu (744-1,064 b), delta (304-1,287 b), and kappa (1,351-2,124 b) receptors. Each mRNA demonstrates a distinct anatomical distribution that corresponds well to known receptor binding distributions. Cells expressing mu receptor mRNA are localized in such regions as the olfactory bulb, caudate-putamen, nucleus accumbens, lateral and medial septum, diagonal band of Broca, bed nucleus of the stria terminalis, most thalamic nuclei, hippocampus, amygdala, medial preoptic area, superior and inferior colliculi, central gray, dorsal and median raphe, raphe magnus, locus coeruleus, parabrachial nucleus, pontine and medullary reticular nuclei, nucleus ambiguus, nucleus of the solitary tract, nucleus gracilis and cuneatus, dorsal motor nucleus of vagus, spinal cord, and dorsal root ganglia. Cellular localization of delta receptor mRNA varied from mu or kappa, with expression in such regions as the olfactory bulb, allo- and neocortex, caudate-putamen, nucleus accumbens, olfactory tubercle, ventromedial hypothalamus, hippocampus, amygdala, red nucleus, pontine nuclei, reticulotegmental nucleus, motor and spinal trigeminal, linear nucleus of the medulla, lateral reticular nucleus, spinal cord, and dorsal root ganglia. Cells expressing kappa receptor mRNA demonstrate a third pattern of expression, with cells localized in regions such as the claustrum, endopiriform nucleus, nucleus accumbens, olfactory tubercle, medial preoptic area, bed nucleus of the stria terminalis, amygdala, most hypothalamic nuclei, median eminence, infundibulum, substantia nigra, ventral tegmental area, raphe nuclei, paratrigeminal and spinal trigeminal, nucleus of the solitary tract, spinal cord, and dorsal root ganglia. These findings are discussed in relation to the physiological functions associated with the opioid receptors.
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                Author and article information

                Journal
                Biomed Rep
                Biomed Rep
                BR
                Biomedical Reports
                D.A. Spandidos
                2049-9434
                2049-9442
                September 2019
                18 July 2019
                18 July 2019
                : 11
                : 3
                : 103-109
                Affiliations
                Department of Biology, Florida A&M University College of Science and Technology, Tallahassee, FL 32307, USA
                Author notes
                Correspondence to: Dr Rafaat Khalil, Department of Biology, Florida A&M University College of Science and Technology, 1601 Martin Luther King Jr Blvd, Tallahassee, FL 32307, USA rafaat.khalil@ 123456famu.edu
                Article
                BR-0-0-1230
                10.3892/br.2019.1230
                6684941
                c13e62ae-1c7b-40b0-825f-b2a3e4ca23db
                Copyright: © Khalil et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 27 December 2018
                : 05 June 2019
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                testosterone,ethanol,opioid receptor kinetics
                testosterone, ethanol, opioid receptor kinetics

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