Naltrexone Dampens Ethanol-Induced Cardiovascular and Hypothalamic- Pituitary-Adrenal Axis Activation

Abstract

Alcohol ingestion activates the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. This study examined naltrexone effects on alcohol-induced increases in physiological responses and their association with alcohol liking. Using a within-subjects design, heavy drinking men (N ϭ 19) were maintained on each of three naltrexone doses (0, 50, and 100 mg, p.o.) over an 8-day inpatient stay. Within each naltrexone dose, subjects had three alcohol challenge sessions (none, moderate, high) The brain opioid system has been proposed to be part of the neurocircuitry involved in alcohol reward and heavy alcohol drinking (Froehlich and Wand 1997;Gianoulakis and deWaele 1994;Reid et al. 1991). Pharmacological studies indicate that opioid receptor antagonists, such as naloxone hydrochloride and naltrexone, decrease alcohol self-administration in animal models (Altshuler et al. 1980;Froehlich et al. 1990;Hubbell et al. 1986Hubbell et al. , 1991Marfaing-Jallat et al. 1983;Samson and Doyle 1985;Weiss et al. 1990). Clinical trials demonstrated that naltrexone reduces alcohol drinking and self-reported "high," alcohol craving, as well as relapse rates in recently abstinent outpatient alcohol-dependent patients (O'Malley et al. 1992;Volpicelli et al. 1992Volpicelli et al. , 1995 . These findings led to naltrexone's approval by the Food and Drug Administration as a pharmacotherapeutic agent for the treatment of alcohol dependence. Naltrexone is thought to reduce alcohol-induced high and relapse by binding to opioid receptors in discrete brain regions associated with reward and craving, and to prevent receptor activation by alcohol-induced release of endogenous opioid peptides.Alcohol induces a variety of acute physiological responses when consumed in moderate-to-high doses. It is well established that intoxicating doses of alcohol increase heart rate (Docter et al. 1966;Iwase et al. 1995 McCaul et al. 1989;Sellers et al. 1972;Turkkan et al. 1988;van de Borne et al. 1997). These heart rate increases are hypothesized to be positively associated with the reinforcing or appetitive motivational effects of alcohol (Peterson et al. 1996) . Alcohol has less predictable effects on blood pressure, with reports of blood pressure increases (Iwase et al. 1995;Sellers et al. 1972) and no effects following alcohol ingestion (Turkkan et al. 1988;van de Borne et al. 1997). Finally, alcoholinduced peripheral vasodilation and associated skin temperature increases have been consistently reported (Iwase et al. 1995;Turkkan et al. 1988) and is thought to be one explanation for the lack of a consistent rise in blood pressure after alcohol consumption.Acute administration of intoxicating doses of alcohol also activates the hypothalamic-pituitary-adrenal (HPA) axis thereby increasing ACTH and glucocorticoid levels (Inder et al. 1995;Rivier et al. 1984;Waltman et al. 1993). It remains unclear whether alcohol-induced activation of the HPA axis has any relationship to its reinforcing properties. Rodent studies show that alcohol increases pla...

Distinct Patterns of Neural Activation Associated with Ethanol Seeking: Effects of Naltrexone

“…Alcoholics show an impaired HPA axis function, and there is growing evidence of a link between HPA axis dysregulation and ethanol relapse (Adinoff et al 2005a(Adinoff et al , 2005b(Adinoff et al , 2005cKiefer et al 2006;O'Malley et al 2002). It has been suggested that NTX-induced HPA axis activation suppresses ethanol craving and reduces relapse risk by substituting for the HPA axis-activating effects of ethanol (Kiefer et al 2006;Kreek et al 2002;McCaul et al 2001;O'Malley et al 2002). Consistent with this hypothesis, NTX increased Fos-positive mpPVN cells and nearly doubled the number of activated Fos-positive neurons in the BST-LD and CeA, activation of which is directly linked to recruitment of the mpPVN and HPA axis activation (Buller et al 1998;Dayas et al 1999).…”

Relationship between the cardiac response to acute intoxication and alcohol‐induced subjective effects throughout the blood alcohol concentration curve

“…One human PET study reported that the cardiac response to alcohol was proportional to the level of alcohol-induced dopamine release (Boileau et al, 2003). Interestingly, cardiac as well as subjective stimulation following alcohol ingestion can be attenuated by Naltrexone, an opiate antagonist that indirectly blocks DA release (King et al, 1997;McCaul et al, 2000;McCaul et al, 2001;Peterson et al, 2006). It has also been demonstrated that only individuals who display an elevated cardiac response to alcohol consume less alcohol following a procedure that reduces dopaminergic neurotransmission (Barrett et al, 2005).…”

Pharmacogenetics of Naltrexone in Asian Americans: A Randomized Placebo-Controlled Laboratory Study

“…Human laboratory studies have examined the biobehavioral mechanisms of action of naltrexone Drobes et al, 2004;King et al, 1997;McCaul et al, 2001;Monterosso et al, 2001;Swift et al, 1994;Volpicelli et al, 1995). Results of such studies revealed that naltrexone dampens feelings of alcohol-induced stimulation Swift et al, 1994), decreases ratings of liking of the alcohol (McCaul et al, 2001), causes an increase in self-reported fatigue, tension, and confusion (King et al, 1997), reduces alcohol consumption, and slows down the progression of drinking in a delayed access laboratory paradigm .…”

“…Results of such studies revealed that naltrexone dampens feelings of alcohol-induced stimulation Swift et al, 1994), decreases ratings of liking of the alcohol (McCaul et al, 2001), causes an increase in self-reported fatigue, tension, and confusion (King et al, 1997), reduces alcohol consumption, and slows down the progression of drinking in a delayed access laboratory paradigm . More recently, pharmacogenetic studies have focused on the gene coding for m-opioid receptors (ie, OPRM1 gene), which are the primary targets of naltrexone (Goldman et al, 2005;Oslin et al, 2003).…”