Immediate and prolonged effects of alcohol exposure on the activity of the hypothalamic-pituitary-adrenal axis in adult and adolescent rats

Abstract

Alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Part of this influence is likely exerted directly at the level of the corticotropin-releasing factor (CRF) gene, but intermediates may also play a role. Here we review the effect of alcohol on this axis, provide new data on the effects of binge drinking during adolescence, and argue for a role of catecholaminergic circuits. Indeed, acute injection of this drug activates brain stem adrenergic and noradrenergic circuits, and their lesion, or blockade of α1 adrenergic receptors significantly blunts alcohol-induced ACTH release. As alcohol can influence the HPA axis even once discontinued, and alcohol consumption in young people is associated with increased adult drug abuse (a phenomenon possibly mediated by the HPA axis), we determined whether alcohol consumption during adolescence modified this axis. The number of CRF-immunoreactive (ir) cells/section was significantly decreased in the central nucleus of the amygdala of adolescent self-administering binge-drinking animals, compared to controls. When another group of adolescent binge-drinking rats was administered alcohol in adulthood, the number of colocalized c-fos-ir and PNMT-ir cells/brain stem section in the C3 area was significantly decreased, compared to controls. As the HPA axis response to alcohol is blunted in adult rats exposed to alcohol vapors during adolescence, a phenomenon which was not observed in our model of self-administration, it is possible that the blood alcohol levels achieved in various models play a role in the long-term consequences of exposure to alcohol early in life. Collectively, these results suggest an important role of brain catecholamines in modulating the short- and long-term consequences of alcohol administration.

Figure 1

Compared to rats without lesions, LC lesions abolish the ACTH response to alcohol (EtOH). Time = 0 indicates plasma ACTH levels (pg/mL) immediately prior to alcohol administration (4.0 g/kg, ig). Each point illustrates the means ⩲ SEM of 5–7 rats. ☆☆: P<0.01, when comparing EtOH/LC lesion vs. ACTH response in corresponding controls (EtOH only).

Figure 2

(A) Lesions caused by the anti-DBH-saporin toxin significantly decreases the number of DBH-positive cells in the A1/C1, A2/C2, and C3 cell groups, compared to rats pretreated with the vehicle. Bright-field photographs through the A1/C1, A2/C2, and C3 areas of brain stem from sham controls (top) and lesion (bottom) rats challenged with alcohol (4.0 g/kg, ig). Images show a representation of the immunohistochemical techniques, which stained DBH-ir cells in brown (scale bar = 200 μm). (B) Cell counts were obtained for DBH-ir positive cells in the A1/C1, A2/C2 and C3 areas of the brain stem. Mean ⩲ SEM number of DBH-ir cells per section in the A1/C1, A2/C2 and C3 areas of sham and lesion rats injected with alcohol. ☆: P<0.05; ☆☆: P<0.01; ☆☆☆: P<0.001.

Figure 3

Self-administered binge-like alcohol consumption during adolescence (PND 29–42) blunts the number of CRF immunoreactive (ir) cells in the CeA of adolescent rats (PND 43, Group A), but has no effect upon the number of colocalized c-fos-ir and CRF-ir cells. A: Double immunohistochemical procedure stained c-fos nuclei black and CRF cytoplasm brown. Display panels compare the two conditions and the pictures were taken with a 20X dry objective (scale bar = 10 μm) and the inset a 40X dry objective; B: Mean ± SEM number of colocalized c-fos and CRF (top) or CRF (bottom) positive cells per section, n = 6 rats/group. ☆☆: P<0.01.

Figure 4

Self-administered binge-like alcohol consumption during adolescence (PND 29-42) decreases the number of colocalized c-fos and PNMT immunoreactive (ir) cells in the C3 region of the brain stem of adult rats subjected to a stressor (4.0 g/kg alcohol challenge via intragastric catheter, Group C), in adulthood (PND 70) but has no effect upon the number of PNMT-ir cells. A: Double immunohistochemical procedure stained c-fos nuclei black and PNMT cytoplasm brown. Display panels compare the two conditions and the pictures were taken with a 40X dry objective (scale bar = 10 μm) and the inset with a 60X oil objective; B: Mean ± SEM number of colocalized c-fos and PNMT (top) or PNMT (bottom) positive cells per section, n = 6 rats/group. ☆: P<0.05.