Specific memory and sedative effects of the benzodiazepine triazolam.

Fifteen normal volunteers were administered placebo, 0.250, 0.375 and 0.500 mg of triazolam in a double- blind cross-over design. Triazolam induced robust dose-dependent impairments in explicit memory of information presented after drug administration. Subjects were unaware of their memory deficit (an impairment in meta-cognition). In contrast, memory for information presented prior to the administration of triazolam was facilitated following the administration of low doses of triazolam. Implicit memory and access to knowledge memory was unaltered by this benzodiazepine. An analysis of these results controlling for concurrent sedation as measured subjectively, through the use of self rating scales and objectively, based upon psychomotor performance, demonstrated that the amnestic effects of triazolam are largely independent of sedative effects. The pattern of memory changes induced by benzodiazepines, such as triazolam, is similar to the memory inpairment expressed in amnestic patients but unlike the pattern of impaired memory evident in dementia such as Alzheimer's disease.

Are there preexisting behavioral characteristics that predict the dominant status of male NIH Swiss mice (Mus musculus)?

The behavior of isolated Cr:NIH(S) mice (Mus musculus) was studied in a holeboard test of exploration, in a plus-maze test of anxiety, in the resident-intruder paradigm of aggression, and in the swim test. Thereafter, mice that were matched for body weight were housed together in groups of 4-5. Within a week, 1 mouse per cage (the alpha) had attacked all its subordinate cagemates but lacked any signs of attack itself. Subordinate mice had bite marks on their tails and backs. When mice were isolated, no differences were found between the behavior of those that later became alphas and those that became subordinates. In contrast, after the establishment of the social hierarchy, alpha mice spent less time immobile in the swim test and had higher locomotor activities than did the subordinate mice. The results suggest that the differences in behavior between the alpha and subordinate mice result from aggressive social interactions in the home cage.

The effects of two different inhibitors of PNMT and their interactions with ethanol.

The effects of two structurally different inhibitors of phenylethanolamine-N-methyltransferase, LY 134046 and CGS 19281A were investigated in a holeboard test of directed exploration and locomotor activity. Both compounds dose-dependently reduced exploratory head-dipping without affecting locomotor activity. The interaction of each drug with ethanol was also studied by testing the ataxia. Administration of these compounds had differential effects in a test of ethanol-induced ataxia. LY 134046 significantly attenuated ethanol-induced ataxia whereas CGS 19281A was without effect or (at 50 mg kg-1) potentiated ethanol's effect. These results suggest that the ethanol attenuating properties of LY 134046 may not solely be due the inhibition of PNMT and that its alpha 2-adrenoceptor blocking properties may be playing a role.

Selective effects of triazolam on memory.

The effects of benzodiazepine (triazolam 0.25 and 0.50 mg) on different aspects of cognitive function were assessed. Triazolam impaired free recall and recognition of information presented after drug administration. In contrast to these impairments in explicit memory, a memory function that did not require conscious awareness was not altered by triazolam. Similarly, triazolam did not affect subjects' abilities to access semantic memory.

Social status and voluntary alcohol consumption in mice: interaction with stress.

Dominant rats are found to consume less alcohol than their subordinate cage-mates. It is unclear whether the difference is due to dominant, aggressive animals consuming low levels of alcohol or whether social stress increases alcohol intake in subordinate animals. The present study investigated alcohol drinking patterns in aggressive alpha mice, their fight-stressed submissive cage-mates and non-fighting control mice before and after the establishment of social hierarchies. The results revealed that both moderately and severely fight-stressed submissive mice showed increased consumption of 5% alcohol, expressed as g/kg, but only severely wounded submissive mice showed increased alcohol preference over total fluid consumption, as compared with alpha mice. The difference in alcohol consumption was not seen prior to the establishment of submissive and alpha status, indicating that the submissive mice increased their alcohol consumption only after experiencing fight-stress. The amount of alcohol consumed did not differ between alpha and non-fighting control mice. To further investigate the possible connection between alcohol intake and aggressivity, the mice were studied in the resident-intruder test before group-housing. The results failed to show a consistent pattern of correlations between the time spent in aggression in this test and subsequent alcohol intake measures. The data indicate that severe fight-stress increases alcohol consumption in mice. Alcohol intake of aggressive, dominant alpha mice is not significantly altered, as compared with non-fighting animals. Furthermore, the level of aggressiveness prior to the establishment of social status does not directly affect alcohol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol, the chloride ionophore and endogenous ligands for benzodiazepine receptors.

Considerable evidence suggests that at least some of the effects of ethanol are mediated by an action on the GABAA receptor chloride channel complex. More speculative is the suggestion that ethanol might interact with endogenous ligands for the benzodiazepine receptor on the complex. This paper considers the evidence for such interactions.

Evidence for central alpha-2 adrenoceptors, not imidazoline binding sites, mediating the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.

The role of central adrenoceptors in the ethanol-attenuating effects of alpha-2 adrenoceptor blockers was investigated in mice; the centrally active antagonist atipamezole was compared with L 659,066, which penetrates the brain poorly. L 659,066 (1-10 mg/kg) had no effect on the hypothermia induced by ethanol (2 g/kg) or ethanol ataxia (2.4 g/kg), whereas atipamezole (1 mg/kg) significantly attenuated both ethanol-induced hypothermia and ataxia. Atipamezole (1-3 mg/kg) significantly attenuated the ethanol-induced reduction in exploratory head-dipping in a holeboard test whereas L 659,066 was only effective at a dose of 1 mg/kg, higher doses (3 and 10 mg/kg) and a lower dose (0.3 mg/kg) were ineffective. Atipamezole was without effect on ethanol's locomotor stimulant effect in the holeboard but L 659,066 attenuated this effect at doses less than 3 mg/kg Many alpha-2 adrenoceptor ligands also have affinity for nonadrenergic imidazoline-binding sites. The role these sites may play in attenuating ethanol's effects was investigated by comparing RX 821002 (methoxy idazoxan), which has little or no affinity for imidazoline-binding sites with atipamezole. Both atipamezo 1 e (1 mg/kg) and RX 821002 (0.06-0.2 mg/kg) significantly attenuated ethanol-induced hypothermia, ataxia and reduction in head-dipping, but were without effect on ethanol-induced locomotor stimulation. These results suggest that nonadrenergic imidazoline-binding sites are not implicated in the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.

Interactions of intracerebroventricular pertussis toxin treatment with the ataxic and hypothermic effects of ethanol.

Pretreatment with pertussis toxin (0.5 and 1.0 microgram/animal, i.c.v., seven days prior to testing) reversed the reduction in locomotor activity in the holeboard test caused by administration of the alpha 2-adrenoceptor agonist, medetomidine (0.1 mg/kg, i.p.). Intrinsic behavioral effects of pertussis toxin treatment were also observed, these included a reduction in exploratory head-dipping and an increase in locomotor activity. These doses of pertussis toxin also reduced the ataxia induced by a 2.4 g/kg dose of ethanol. Pertussis toxin treated animals also exhibited a diminished hypothermic response to ethanol (2 g/kg), although the pertussis toxin treated animals had lower body temperatures prior to ethanol administration compared to sham treated animals. Neither the behavioral effect of pertussis holotoxin in the holeboard nor its effects on reversing medetomidine hypolocomotion or ethanol-induced ataxia were seen following administration of the binding oligomer of pertussis toxin which binds to the cell membrane but does not possess the enzymatically active subunit. These findings implicate mechanisms involving pertussis toxin sensitive G-proteins in modulating some behavioral and physiological effects of ethanol.

Effects of early postnatal handling on brain beta-adrenoceptors and behavior in tests related to stress.

The present study investigated the effects of early postnatal handling and temporary maternal isolation, between the 5th and 20th postnatal days, on various behaviors related to stress measured in adulthood in male Wistar rats. In addition, beta-adrenoceptor binding in the brain was measured. The handling consisted of daily 3-min sessions during which a pup was gently held by an investigator. The isolated rat pups were kept separated from their nursing mothers for 1 h daily. Subsequently, it was found that the time spent immobile in Porsolt's swim test was shortened, and voluntary alcohol (5% v/v) consumption was reduced in the handled rats, as compared with the non-handled and isolated animals. No differences in the measure of anxiety--food consumed in a novel environment--or the time spent in social, aggressive and defensive behaviors in a resident-intruder paradigm, were noted. Neither did the density or affinity of beta-adrenoceptors in the frontal cortex or hippocampus differ significantly between the groups. The results indicate that short-lasting maternal separation does not cause sustained effects on behavior in the rat. Early postnatal handling leads to shortened immobility in the swim test and reduced voluntary alcohol consumption, suggesting that handled rats show an improved ability to cope with stress.

Dissociation of the acute effects of alcohol on implicit and explicit memory processes.

The effects of alcohol (0, 0.3 and 0.6 g/kg) on learning and memory were assessed in independent groups of male student volunteers. Subjects were shown a list of words and asked to form an image of a scene involving each word 1 hr after drinking an alcohol-containing beverage. Alcohol consumption impaired the ability of subjects to explicitly remember the words in a test of free recall. However, no impairment was observed if memory for the same material was assessed implicitly using a backwards-reading or word-completion task. That is, both alcohol-and placebo-treated subjects showed similar degrees of priming. The data indicate that alcohol's effects on memory are selective.

Effect of tryptophan on the behavior of nonstressed and stressed mice in Porsolt's swim test.

The effect of tryptophan on immobility in Porsolt's swim test was studied in male NIH Swiss mice. Preexposure to a swim or fight-stressor was included in the design. Doses of tryptophan (0, 12.5, 50, 75, 100, 125 and 200 mg/kg) were administered intraperitoneally 60 min prior to the swim test. In the nonstressed mice tryptophan had an U-shaped dose-response relationship: immobility in the water was dose-dependently shortened after doses from 0 to 100 mg/kg, whereas after 125 and 200 mg/kg tryptophan the immobility times did not differ from the values obtained after a saline injection. Preexposure to a swim- or fight-stressor did not make mice more sensitive to the effects of tryptophan. Tryptophan (0-300 mg/kg) had no effect on exploratory behavior or locomotor activity in the holeboard, suggesting that sedation was not a factor in the swim test results. The findings suggest that tryptophan has antidepressant -like properties in Porsolt's swim test.

Correlations between behavior of mice in Porsolt's swim test and in tests of anxiety, locomotion, and exploration.

This study examined whether the behavior of male NIH Swiss mice in a putative animal model of depression, Porsolt's swim test, is related to that in other behavioral tests. The other tests were the plus-maze test of anxiety, the holeboard test of exploration and locomotor activity, and a test of seizure threshold to bicuculline. The immobility of the mice in the swim test did not correlate with their behavior in any of the other tests used. The only significant correlations found occurred between individual measures in the holeboard and plus-maze tests. The data suggest that immobility in the swim test is not related to behavior in the tests of anxiety, directed exploration, locomotor activity, or seizure threshold.

Antagonism of ethanol intoxication in rats by inhibitors of phenylethanolamine N-methyltransferase.

The probable involvement of brain epinephrine in the expression of the acute sedative and intoxicating effects of ethanol and pentobarbital is demonstrated. Two selective inhibitors of phenylethanolamine N-methyltransferase (PNMT), LY134046 and LY78335, proved to be potent and long-lasting antagonists of ethanol intoxication in rats. Acute antagonism of pentobarbital-induced intoxication was observed with LY134046. The present results are compatible with a role for central epinephrine synthesis in ethanol and pentobarbital-induced sedation and intoxication in rats.

Ethologically-based animal models of anxiety disorders.

An overview of ethologically-based animal models suitable for investigating the pharmacological treatment of anxiety disorders is presented. The DSM-IIIR classification provides a framework for the discussion. The limitations of the models in current use are considered. It is suggested that there is a need for a greater emphasis on animal models of anxiety with an etiological basis.

Behavioral effects of the inhibitors of phenylethanolamine-N-methyltransferase, LY 78335 and LY 134046, and their interactions with ethanol.

The centrally active inhibitors of phenylethanolamine-N-methyltransferase (PNMT), LY 78335 and LY 134046, were investigated both alone and in combination with ethanol (2 g/kg) in a holeboard test of directed exploration and locomotor activity. Both PNMT inhibitors showed dose-related reductions in exploratory head-dipping but were without effect on locomotor activity. In combination with ethanol both PNMT inhibitors tended to attenuate the ethanol-induced reductions in exploratory head-dipping but did not effect ethanol's locomotor stimulant properties. LY 134046 showed neither an anxiolytic nor an anxiogenic profile in the plus-maze test of anxiety, nor did it alter the anxiolytic effects of either 1.2 g/kg or 2 g/kg ethanol. LY 134046 did, however, attenuate the ataxic effects of a 2.4 g/kg dose of ethanol. These results may suggest a role for adrenaline synthesis in some, but not all, of the behavioral effects of ethanol.

Effects of ethanol on fight- or swim-stressed mice in Porsolt's swim test.

The effects of ethanol in Porsolt's swim test on mice preexposed to fight- or swim-stressors were investigated. The control mice did not change their behavior in the swim test after an acute injection of 0.4 or 0.8 g/kg ethanol; 1.2 g/kg ethanol increased their immobility in one but not in another experiment. The mice exposed to continuous fight-attacks in their home cage by one dominant mouse shortened immobility after 0.8 g/kg ethanol as well as tended to shorten it after 0.4 g/kg ethanol. The mice that were forced to swim in the water twice before the actual swim test responded to 0.4 g/kg ethanol by shortening immobility; 0.8 g/kg tended to have the same effect; 1.2 g/kg ethanol just failed to lengthen immobility of the fight-stressed mice and had no effect on the swim-stressed mice. Because antidepressant drugs decrease and stressors increase immobility in the swim test, the test may serve as a putative animal model of depression. The present findings showed that low doses of ethanol reverse lengthened immobility of mice preexposed to a stressor. This suggests that ethanol either has antidepressant-like properties, or it improves animal's ability to cope with a stressful situation, or both.

Behavioral, hormonal and neurochemical characteristics of aggressive alpha-mice.

The present study examined the behavioral, neurochemical and endocrinological characteristics of aggressive, male alpha-mice. These mice inflict severe bite marks on other male mice in their cage, but are not attacked themselves. The characteristics of the alpha-mice were compared with those of submissive mice, and of control mice taken from cages in which no severe fighting was observed. The behavioral tests used were Porsolt's swim test of behavioral 'despair', a plusmaze test of anxiety, a holeboard test of exploration and locomotor activity, and a test of seizure threshold to bicuculline. The alpha-mice were found to be immobile in the swim test for a shorter time than the submissive and control mice, and the submissive mice for a longer time than the controls. In the holeboard, the alpha-mice spent less time making exploratory head-dips than the other mice. Submissive mice had elevated 5-HIAA levels in the hypothalamus, hippocampus and brainstem, and the alpha mice had reduced concentrations of dopamine in the brainstem. There were no significant differences in plasma corticosterone or testosterone concentrations between the groups. These findings indicate that in alpha-mice, a number of behavioral and neurochemical characteristics appear together with the unusually high aggressiveness towards cage-mates.

Effect of ethanol on the social behavior of group-housed and isolated mice.

The interaction between isolation and the response to ethanol was investigated with a social behavior test and a loss of righting reflex paradigm. The time a pair of mice spent in active social interaction, aggressive behavior, and avoidance-irritability showed an isolation-related increase, while locomotor activity was not affected by 0-10 days of isolation. Ethanol (0.8 g/kg) reduced the social interaction time in mice isolated for 10 days and 2.0 g/kg ethanol reduced it in all groups. Ethanol induced a locomotor stimulatory effect both in group-housed and isolated animals. An aggression-inducing effect of 0.8 g/kg ethanol was observed only in mice isolated for 5 days, while mice isolated for 10 days reduced their aggressive behavior after this dose of ethanol. The loss of righting reflex after 3.5 g/kg ethanol did not appear to vary with isolation. The results suggest that isolation alters some effects of ethanol qualitatively (e.g., its effects on aggressive behavior) but leaves other effects (e.g., its locomotor stimulant and hypnotic effects) unchanged.

Attenuation of hypothermic effects of ethanol by alpha 2-adrenoceptor blockers.

Effects of selective alpha 2-adrenoceptor antagonists, atipamezole and idazoxan, on ethanol-induced hypothermia were investigated in mice. Ethanol significantly reduced (P less than 0.001) core temperature whilst both alpha 2-adrenoceptor antagonists were without effect when administered alone. However, both the 1 and 3 mg/kg doses of atipamezole significantly (P less than 0.05) attenuated the ethanol-induced reduction in body temperature 20 and 40 min after administration. The 3 mg/kg dose of idazoxan (but not the 1 mg/kg dose) also significantly (P less than 0.05) attenuated ethanol's hypothermic effect 20 min after administration but this effect was not statistically significant at 40 min. In a subsequent experiment using lower doses of atipamezole (0.03-1.0 mg/kg) the attenuation of ethanol-induced hypothermia caused by atipamezole was found to be dose-related. The effect of the benzodiazepine inverse agonist Ro 15-4513 on ethanol-induced hypothermia was also investigated. This compound possessed an intrinsic hypothermic action but neither attenuated nor enhanced the hypothermic effect of ethanol. These results suggest that alpha 2-adrenoceptor can, at least partially, modulate the hypothermic effects of ethanol.