Ernest Hård

Reduced fearfulness in the lactating rat

The freezing reaction in response to a brief auditory signal was assessed in lactating and virgin rats. Freezing was markedly reduced in lactating animals, but only when their litters were present in the testing cage. Pup exposure did not shorten the duration of freezing in virgin animals. The reduced fearfulness in lactating females, as measured by the freezing response, may complement maternal aggression in the protection of the offspring.

Biochemical and behavioral evidence for an interaction between ethanol and calcium channel antagonists

In the present series of experiments we have studied the effects of the dihydropyridine calcium channel antagonist nifedipine on ethanol-induced changes in behavior and dopamine (DA) release and metabolism. The locomotor-stimulatory effect of low doses of ethanol (2.5 g/kg) was antagonized by nifedipine, whereas ethanol-induced sedation observed after higher doses (4.5 g/ kg) was potentiated. Biochemical studies indicated that ethanol enhanced the metabolism and release of DA in the striatum and the DA-rich limbic regions measured by post mortem analyses of DA-metabolites by HPLC with electrochemical detection and by in vivo voltammetry in anaesthetized rats, respectively. Pretreatment with nifedipine antagonized the stimulatory effects of ethanol on the DA-system. Nifedipine reduced the preference for ethanol, estimated by the relative intake of ethanol (6% v/v) and water in a free-choice situation, suggesting an influence of nifedipine not only on the stimulatory but also on the positive reinforcing effects of ethanol. The present results suggest that the locomotor-stimulatory and positive reinforcing effects of ethanol as well as its enhancing effect on dopaminergic activity may involve an enhancement of calcium mediated mechanisms.

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.

Involvement of the serotonergic system in ethanol intake in the rat

A two-bottle, free-choice paradigm was used to investigate the influence of the serotonergic (5-HT) system on ethanol intake in genetically heterogeneous Wistar rats. Systemic administration of the 5-HT1A agonist ipsapirone (1.25-5.0 mg/kg) caused a dose-dependent decrease in ethanol preference and intake, while the 5-HT2 antagonist ritanserin (1.25-5.0 mg/kg) and the 5-HT3 antagonists ondansetron (0.01-1.0 mg/kg) and granisetron (0.5-1.0 mg/kg) failed to alter ethanol consumption. The effect of ipsapirone treatment on ethanol intake was more pronounced in high-preferring animals than in low-preferring. A closer look at the microstructure of the rats drinking behaviour by means of a microcomputer-controlled data acquisition system showed that ipsapirone treatment caused a significant decrease in the number of licks recorded at the ethanol-containing bottle and a decrease in the time spent at this bottle. Furthermore, ipsapirone treatment caused a significant increase in the number of breaks in licking behaviour recorded at this bottle. The drinking behaviour at the water-containing bottle was not affected by the ipsapirone treatment. Neither was the rats eating behaviour altered by this treatment. These findings support the hypothesis that the 5-HT system is involved in the regulation of ethanol intake, with special emphasis on the involvement of the 5-HT1A receptor subtype, and may indicate that central reward-mediating mechanisms are influenced.

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.

Effects of the 5-HT receptor agonist, 8-OH-DPAT, on ethanol preference in the rat

Clinical and animal studies have suggested that consumption of ethanol is influenced by the central serotonergic (5-HT) transmission system. In the present study this hypothesis was tested by observing the effects of a selective 5-HT receptor agonist, 8-OH-DPAT, on ethanol preference in the rat. The rats had access to a 6% (v/v) ethanol solution and water during baseline and treatment periods. Based on the baseline recordings, 2 groups of rats were formed: A high preference group (ethanol intake greater than 50% of total fluid intake) and a low preference group (ethanol intake less than 30%). Both groups were treated SC with 0.125 mg/kg 8-OH-DPAT twice daily for 3 days. The treatment caused a significant reduction of ethanol consumption in the high preference group, but no change in the low preference group. The findings support the hypothesis that activation of the 5-HT system reduces ethanol intake. This effect was restricted to the high preferring rats, suggesting that 8-OH-DPAT interferes only with the positive reinforcing effect of ethanol.

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.

Amphetamine-induced hyperactivity : differences between rats with high or low preference for alcohol

This study determined the relationship between ethanol intake and spontaneous and amphetamine-induced locomotor activity. Locomotion was studied in high-preferring (HP; > 70% of total fluid intake consumed as alcohol) and low-preferring (LP; < 20% of total fluid intake consumed as alcohol) male Wistar rats with free access to water and a 6% (v/v) ethanol solution for 3 weeks. Following an alcohol-free 3-week period, the animals were tested for spontaneous motor activity for 1 h. One week later, locomotion was recorded in the same activity boxes following a subcutaneous injection with d-amphetamine sulfate (1 mg/kg). For determination of plasma levels of corticosterone, blood samples were taken immediately after each of the two tests for locomotor activity. There was no difference between HP and LP rats with regard to spontaneous locomotor activity. Neither were there any differences in plasma levels of corticosterone between the groups. Amphetamine stimulated locomotion in both HP and LP rats, but to a significantly greater extent in HP animals. Both groups had higher blood levels of corticosterone after the amphetamine test than after the drug-free test, but the corticosterone increase was significantly larger in the HP than in the LP rats. These data indicate that the same neural substrate (e.g., the mesocorticolimbic dopamine system) may mediate important aspects of both ethanol drinking and amphetamine responsiveness. Individual differences in the properties of this substrate may account for the finding that ethanol drinking and amphetamine responsiveness covary. A possible explanation for this association may be that prior consumption of ethanol sensitizes the neural substrate responsible for amphetamine-induced hyperactivity.(ABSTRACT TRUNCATED AT 250 WORDS)