Claudia Fahlke

Involvement of corticosterone in the modulation of ethanol consumption in the rat

Several studies report that rats exposed to stressful conditions may increase their ethanol consumption. Stress is accompanied by a rise in the secretion of adrenocortical hormones, and the possibility that these hormones exert an influence on ethanol consumption should be considered. The present investigation addressed this issue by studying the effect of adrenalectomy (ADX) and subsequent corticosterone (CORT) or aldosterone (ALDO) treatment on ethanol intake. The results showed that ADX rats decreased their ethanol intake compared to the sham-operated controls and that treatment with CORT restored the intake of ethanol to the preoperative level. In contrast, treatment with ALDO (0.25 or 0.75 mg/kg) had no effect on ethanol intake. Biochemical analyses showed increases in monoamine turnover in the brain stem and limbic forebrain after ADX. The reduction of ethanol consumption caused by ADX may thus be specifically attributed to the loss of one of the adrenal hormones, CORT. The results indicate that CORT may be a factor of importance in the modulation of alcohol consumption.

Metyrapone-induced suppression of corticosterone synthesis reduces ethanol consumption in high-preferring rats

The fluid intake of male Wistar rats with simultaneous access to water and 6% ethanol was determined between 0900 and 1500 h. In high-preferring males (normally covering > 60% of their daily fluid consumption in the form of ethanol), two injections with the corticosterone synthesis inhibitor metyrapone (50 mg/kg) at 0900 h and 1200 h for 4 consecutive days significantly reduced ethanol preference such that they preferred water over alcohol. Treatment with corticosterone (0.6 mg/kg) 2 h before each metyrapone injection partially cancelled this effect of the synthesis inhibitor. By contrast, there was no significant effect of metyrapone treatment on the drinking of ethanol in low-preferring rats (normally covering < 30% of their daily fluid consumption in the form of ethanol). These results suggest that the adrenal secretion of corticosterone directly or indirectly modulates the intake of alcohol in high-preferring rats.

Consequence of long-term exposure to corticosterone or dexamethasone on ethanol consumption in the adrenalectomized rat, and the effect of type I and type II corticosteroid receptor antagonists

The daily fluid intake of male Wistar rats with simultaneous access to 6% ethanol and water was determined during a baseline period (1 week), following adrenalectomy (1 week) and for 3 weeks following SC implantation of hormone pellets containing corticosterone (CORT) or dexamethasone (DEX). Ethanol consumption dropped during the first week of adrenalectomy (ADX) but increased again in the absence of hormone replacement to reach preoperative levels during the ensuing weeks. The CORT treatment, which produced plasma hormone levels similar to the 24-h mean concentration of adrenally intact rats, not only reversed the effect of ADX on alcohol consumption but also enhanced it to levels above those observed in intact rats. Water intake was not affected by the CORT treatment. DEX implants stimulated water intake, but did not enhance the drinking of ethanol. SC injections of RU 28318 (type I corticosterone receptor antagonist; 10 mg/kg) or mifepristone (RU 38486; type II receptor antagonist; 25 mg/kg) at the beginning and halfway through three daily, 6-h tests failed to affect ethanol drinking in adrenally intact rats or in ADX rats bearing CORT implants. Similarly, there was no effect of giving the two antagonists in combination. These results suggest that exogenous CORT can induce excessive alcohol intake in genetically unselected rats and that this facilitatory effect may be mediated by non-genomic cellular mechanisms.

Minimization of childhood maltreatment is common and consequential: results from a large, multinational sample using the childhood trauma questionnaire

Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale—originally designed to assess a positive response bias—are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ’s MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ’s discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias—as detected by the MD subscale—has a small but significant moderating effect on the CTQ’s discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables.

Anabolic androgenic steroids affects alcohol intake, defensive behaviors and brain opioid peptides in the rat

The present study investigated whether a relationship exists between nandrolone decanoate and voluntary ethanol intake in laboratory rats. Animals were subjected to daily subcutaneous injections with nandrolone decanoate (15 mg/kg) during 2 weeks. One group of animals was tested for voluntary alcohol intake 1 week after the end of the 2-week treatment period and another group received alcohol 3 weeks after the treatment. In addition, assessment of defensive behaviors and immunoreactivity (ir) levels of the brain opioid peptides dynorphin B and Met-enkephalin-Arg-Phe (MEAP) were performed. The nandrolone decanoate-treated animals were significantly more aggressive and showed lower fleeing and freeezing reaction than the oil-treated controls. Treatment with nandrolone decanoate enhanced voluntary alcohol intake, regardless if it was presented 1 or 3 weeks after end of the treatment period. These animals had a decreased activity of dynorphin B-ir in the nucleus accumbens, decreased levels of MEAP-ir in the periaqueductal gray (PAG) and higher levels of MEAP-ir in the hypothalamus compared to controls. In line with previous studies, this suggests that the altered dynorphin B-ir activity may promote the rewarding effects of ethanol and thereby increasing alcohol intake, whereas MEAP-ir may be associated with the ability to control the aggressive reaction. Abuse of nandrolone decanoate may thus constitute a risk factor for increased alcohol consumption and defensive aggression. In human, this constellation of behavioral symptoms is closely related to acts of crimes and violence and is often observed among those abusing anabolic androgenic steroids.

Facilitation of ethanol consumption by intracerebroventricular infusions of corticosterone

Male Wistar rats bearing intracerebroventricular (ICV) cannulae and with simultaneous access to 6% ethanol and water were subjected to adrenalectomy (ADX) or sham surgery. ADX decreased ethanol intake. Starting a few days later, the animals received ICV infusions with 100 μg corticosterone acetate (CORT) with 2-to 3-day intervals for 2 weeks. ICV CORT, but not SC CORT at the same dose, restored ethanol consumption in ADX rats to preoperative levels, whereas vehicle infusions (propylene, glycol) did not. Adrenally intact animals, which normally consumed moderate amounts of ethanol (≈0.5 g/kg per day), also showed a robust effect of ICV infusions of CORT, whereas this facilitatory effect was not observed in high consumers (≈3.0 g/kg per day). The suppressive effect of ADX on ethanol intake was not reproduced by concurrent and repeated ICV infusions of intracellular mineralocorticoid (RU 28318) and glucocorticoid (mifepristone) receptor blockers. It is concluded that CORT stimulates alcohol consumption by acting in the brain, probably by way of neuronal membrane mechanisms.

Effects of ventral striatal 6-OHDA lesions or amphetamine sensitization on ethanol consumption in the rat

Female rats with continuous access to water and 6% ethanol were given bilateral ventral striatal 6-OHDA infusions, which induced pronounced striatal depletions of dopamine. The postoperative ethanol consumption of these rats was not significantly affected in comparison to vehicle-infused controls. In a second experiment, female rats received escalating doses of d-amphetamine over a 5-week period (from 1 to 9 mg/kg/injection). Control females were given saline injections. Following a 3-month drug-free interval, the females were given access to ethanol, the concentration of which was gradually increased from 2% to 12% with weekly intervals. Amphetamine-sensitized rats consumed significantly more alcohol than the saline-treated controls. Taken together, these results suggest that striatal dopaminergic mechanisms, while not necessary for basal ethanol drinking, can facilitate alcohol drinking.

Do Alcohol-dependent Individuals with DRD2 A1 Allele Have an Increased Risk of Relapse? A Pilot Study

AIMS The TaqIA polymorphism of the dopamine D2 receptor (DRD2) gene has been extensively studied in relation to alcoholism, and the TaqI A1 allele appears to be over-represented in alcohol-dependent individuals. In a recent study, this allele has also been associated with a highly increased mortality rate in alcohol-dependent individuals. In the present study, we investigated whether the TaqI A1 allele of the DRD2 gene region was associated with a higher relapse rate in alcohol-dependent individuals. METHODS Adult women (n = 10) and men (n = 40) with a diagnosis of alcohol-dependence were recruited from two Swedish 12-step treatment units for alcoholism. Subjects were genotyped for the TaqIA polymorphism. On average, 1½ year after the end of the treatment program, subjects were re-interviewed by using the alcohol-related items from the Addiction Severity Index follow-up version. RESULTS Thirty-three (66%) subjects self-reported relapse and 17 (34%) abstinence during the follow-up period. Thirty-sex percent (18/50) were carriers of the A1 allele of the DRD2 gene region, and 64% (32/50) were non-carriers. Among the carriers of the A1 allele, 89% (16/18) reported relapse in contrast to 53% (17/32) in the non-carriers (P = 0.01; odds ratio = 7.1). CONCLUSION The present study is, to our knowledge, the first report of an association between the TaqI A1 allele and a substantially increased relapse rate. It should be emphasized that the number of subjects is relatively small, and this investigation should therefore be considered as a pilot study.

Psychosocial outcomes of fetal alcohol syndrome in adulthood.

BACKGROUND AND OBJECTIVE: Primary disabilities in children prenatally exposed to alcohol have a major impact on their daily life. It is suggested that these issues persist into adulthood, but few studies have addressed the outcome in adults with prenatal exposure, especially those with fetal alcohol syndrome (FAS). The aim of this follow-up study was to investigate outcome variables, such as education, employment, health, and criminal acts, in 79 adults diagnosed with FAS. METHODS: We carried out a national register–based study of 79 adults with an FAS diagnosis, at a mean age of 32. Education, social adjustment, and mental health outcomes were analyzed and compared with 3160 comparison individuals matched on age, gender, and place of birth. RESULTS: The FAS group was much more likely to have received special education (25% vs 2%), be unemployed (51% vs 15%), and receive a disability pension (31% vs 3%) than the comparisons, but the levels of criminal offenses were similar. The FAS group had higher hospital admission rates for alcohol abuse (9% vs 2%) and psychiatric disorders (33% vs 5%) and was more likely to be prescribed psychotropic drugs (57% vs 27%). CONCLUSIONS: Swedish children with FAS have quite diverse psychosocial outcomes in adulthood, considerably worse than for majority population peers. Potential risk and protective factors within the FAS group deserve study to enable development of effective interventions.

Significance of adrenal corticosteroid secretion for the food restriction-induced enhancement of alcohol drinking in the rat

Male Wistar rats with continuous access to 6% ethanol solution and water in their home cages were subjected to food restriction (FR). Reduction of body weight to 80% of normal was associated with a significant increase in ethanol drinking. It is known that the stress of FR gives rise to increased corticosterone secretion, and in line with these findings it was found that the weight of the thymus (whose size is inversely related to corticosterone levels) was reduced to 55% of normal in the present FR rats. Two subsequent experiments indicated that this adrenal activation contributed to the FR-induced enhancement of alcohol drinking. Firstly, adrenalectomized rats showed no evidence of enhanced alcohol drinking during food restriction, suggesting that adrenal corticosterone hypersecretion contributes to the enhanced ethanol consumption during FR. Secondly, treatment of FR rats with the enzyme inhibitor cyanoketone, which blocks stress-induced but not basal corticosterone secretion, at least partly prevented the FR-induced increase in ethanol drinking. These results add further evidence that sustained exposure to corticosterone facilitates ethanol consumption in the rat.