An Initial, Three-Day-Long Treatment with Alcohol Induces a Long-Lasting Phenomenon of Selective Tolerance in the Activity of the Rat Hypothalamic–Pituitary–Adrenal Axis

Abstract

We determined whether an initial alcohol challenge induced long-lasting changes in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Adult male rats received intragastric injections of the vehicle or a moderately intoxicating dose of alcohol (3.0 gm/kg) daily for 3 d. When animals were acutely challenged with alcohol 3-12 d later, their ACTH and corticosterone responses were significantly blunted, compared with that of vehicle-pretreated rats. In contrast, exposure to mild electric foot shocks induced a pattern of ACTH secretion that was comparable in animals administered alcohol or the vehicle previously, indicating a lack of cross-tolerance. No significant differences were observed in pituitary responsiveness to corticotropin-releasing factor or vasopressin in rats pretreated with the vehicle or alcohol. The influence of the initial drug treatment was not mimicked by exposure to foot shocks, nor was it prevented by administering a potent corticotropinreleasing factor antagonist to block the elevations in plasma ACTH and corticosterone induced by this initial treatment. Finally, we found that rats injected initially with the vehicle and challenged subsequently with alcohol exhibited the expected increased neuronal activation (measured by the upregulation of steady-state mRNA and protein levels of immediate early genes) in the paraventricular nucleus of their hypothalamus. In contrast, this response was markedly decreased in animals exposed previously to the drug.To our knowledge, this is the first report that exposure to a stress (i.e., alcohol), although not immediately altering the response of the HPA axis to this particular signal, induces a selective tolerance that is both slow to develop and longlasting. The primary mechanism mediating the ability of an initial drug treatment to decrease subsequent responses of the HPA axis to a second drug challenge seems to be the inability of hypothalamic neurons to respond adequately to this second challenge.

Stress, Dysregulation of Drug Reward Pathways, and the Transition to Drug Dependence

“…Also, corticosterone and hypothalamic CRF mRNA are increased during acute withdrawal from long-term cocaine administration (62). Similar decreases in HPA activity have been observed with repeated alcohol administration in a binge model (63)(64)(65). Long-term daily administration of alcohol in a liquid diet showed a decrease in HPA axis activity that persisted up to 3 weeks postabstinence (66).…”

Role of hippocampus in alcohol-induced memory impairment: implications from behavioral and immediate early gene studies

“…Chang et al 1995;) Thiele et al 1996;Lee and Rivier 1997) Suppression Suppression of basal Suppression of PTZSuppression of PTZc-fos expression in induced c-fos in cerebral induced c-fos in cerebral several brain areas, cortex and hippocampus; cortex and hippocampus; no suppression of novel suppression of NMDAsuppression of NMDAenvironment-induced induced c-fos in cerebral induced c-fos in cerebral c-fos expression cortex, but not in cortex, but not in (Ryabinin et al 1997) hippocampus hippocampus (Le et al 1990(Le et al , 1992(Le et al 1990(Le et al , 1992Davidson et al 1995) Davidson et al 1995. Suppression of IL-1β-induced c-fos in the paraventricular nucleus of hypothalamus (Lee and Rivier 1994) Suppression of cocaineinduction of FOS in caudate putamen (Torres 1994) Suppression of stress-, fear conditioning-, and novel context-induced c-fos in hippocampus (Melia et al 1996;Ryabinin et al 1995Ryabinin et al , 1997Ryabinin et al ) et al 1993Hope et al 1994b;Melia et al 1994;Chang et al 1995).…”

“…These include stress-related areas such as the central nucleus of amygdala, the paraventricular nucleus and several other areas of the hypothalamus, nucleus of solitary tract, the bed nucleus of striatum, and the sensory information processing-associated areas like the Edinger-Westphal nucleus and the paraventricular nucleus of thalamus (Zoeller and Fletcher 1994;Chang et al 1995;Thiele et al 1996;Hitzemann and Hitzemann 1997;Lee and Rivier 1997;Ryabinin et al 1997). Although an increase in c-Fos expression after alcohol intoxication was also observed in the nucleus accumbens and VTA, areas traditionally associated with reward pathways, it was much less robust than in the stress-and sensory processing-associated brain areas (Hitzemann and Hitzemann 1997;Ryabinin et al 1997).…”

Modeling Relapse Situations in the Human Laboratory

“…In other evidence, it has long been known that alcohol stimulates the hypothalamic-pituitaryadrenal (HPA) axis and initially stimulates the autonomic systems by provoking sympathetic arousal followed by depressing such activation (Ehrenreich et al 1997;Lee and Rivier 1997). Dramatic adaptations of the HPA axis akin to tolerance has also been demonstrated with regular and chronic alcohol abuse in animals (Zhou et al 2000;Richardson et al 2008) and in humans (Adinoff et al 1998(Adinoff et al , 2005Wand and Dobs 1991).…”