Gene Transcription Alterations Associated with Decrease of Ethanol Intake Induced by Naltrexone in the Brain of Wistar Rats

Abstract

Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (43.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mopioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB 1 receptor (CB 1 -R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the m-opioid receptor, TH, PENK, CRF, CB 1 -R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone. INTRODUCTIONAlcoholism is a serious health, social, and familiar problem of difficult solution produced by the conjunction of different complex causes that reflect the interaction of genetic, environmental, socio-cultural, and personal factors (Saatcioglu et al, 2006). In general, the main objective in the treatment of alcohol dependence is the maintenance of the abstinence and the reduction of seeking behavior to avoid relapse. The development of alcohol dependence is a slow process produced by continuous and repeated consumption of ethanol that results specially damaging to subjects presenting high impulsivity, low self-esteem, and sensation-seeking behavior. The vulnerability to develop any kind of problems related to ethanol becomes even higher in patients with certain psychiatric disorders such as phobias, attention-deficit hyperactive disorder or affective disorders (anxiety, depression, or bipolar disorder) (Hines et al, 2005). The reinforcing actions of ethanol are enhanced in these situations facilitating the progression to ethanol dependence. It has been proposed that consumption of ethanol stimulates dopamine neurons by acting directly on the nucleus accumbens and by disinhibiting GABA mesencephalic neurons projecting into the dopamine tegmental area (Spanagel and Weiss, 1999;Kienast and Heinz, 2006). Alterations in dopamine neurons ...

CB1 Receptor Blockade Decreases Ethanol Intake and Associated Neurochemical Changes in Fawn‐Hooded Rats

“…Measurement of blood ethanol levels under this experimental design would have yielded inconsistent values. A similar experimental design also was used in previous studies in our laboratory to evaluate the effects of naltrexone on gene expression and functional autoradiography in Wistar rats (Oliva and Manzanares, 2007).…”

“…Furthermore, these results point to specific key proteins closely involved in the ''normalization'' of the activity of brain regions altered by prolonged ethanol consumption. The experimental design of the ''2-bottle-choice paradigm'' was similar to a design used previously in our laboratory (Oliva and Manzanares, 2007). A 12-day acquisition period, in which solutions of progressively higher ethanol concentration were consumed, was followed by a 15-day maintenance period (10% ethanol v ⁄ v).…”

“…Ethanol intake protocol was conducted as described previously (Oliva and Manzanares, 2007). The experiment was divided into 3 phases: acquisition, maintenance, and treatment.…”

“…This is the first study that uses AM251 to reduce ethanol intake and compare the neurochemical alterations under this experimental design. This pattern of treatment was used following the same design as another study with naltrexone using Wistar rats (Oliva and Manzanares, 2007). Treatments were carried out daily 30 minutes before the dark phase started (8:00 pm).…”

“…Previous studies reveal that the decrease in ethanol consumption after treatment with naltrexone is accompanied by a full blockade or a high tendency to return to normal values several alterations previously induced by ethanol, which include the l-opioid receptor, tyrosine hydroxylase (TH), proenkephalin (PENK), corticotrophin-releasing factor (CRF), cannabinoid CB1 receptors, and serotonin transporter (5-HHT) in specific brain regions (Oliva and Manzanares, 2007). Considering these previous studies with naltrexone, it is tempting to hypothesize that the reduction of ethanol consumption by the cannabinoid CB1 antagonist SR141716A may be mediated, at least in part, by its ability to return to normal values several alterations induced by ethanol.…”