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D S Janowsky

Publications and source records attributed to D S Janowsky.

At least 19 recordsLinked to original sources
PubMed1992

Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, Goe 5438.

The effect of the novel 1,4-dihydronaphthyridine Ca2+ channel inhibitor Goe 5438 (CI-951) on voluntary ethanol consumption was examined in selectively bred alcohol-preferring (P) rats in a free choice two bottle preference test versus water. Intraperitoneally injected Goe 5438 dose-dependently (5, 10 or 20 mumol/kg, twice daily) inhibited ethanol and increased water intake over the 24 h period (injection day). The drug decreased ethanol preference, originally above 90%, by 6%, 19% and 45% at respective doses, on the injection day. That inhibitory effect of the highest dose of Goe 5438 on ethanol preference remained significant also on days 2 and 3 after injections (-51% and -18%, respectively). Goe 5438, in the highest dose, also tended to decrease granulated chow consumption during the injection day only. To further test whether the inhibition of ethanol preference is secondary to decrease in reinforcing properties of ethanol and not due to interference with satiety mechanisms, we compared the effect of two higher doses (10 and 20 mumol/kg, intraperitoneally, twice daily) of Goe 5438 on spontaneous preference for a non-caloric 0.04% saccharin solution in Sprague-Dawley rats. We observed a dose-dependent suppression of preference (by 44% and 58%, respectively) during the injection day, but not the subsequent 24 h period. However, Goe 5438 also significantly alleviated food pellet intake on the injection day. In conclusion, Goe 5438 produces potent and long-lasting inhibition of voluntary ethanol consumption, which may be secondary to attenuation of reinforcing properties of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1992

Maudsley reactive and nonreactive rats differ only in some tasks reflecting emotionality.

The behavior of Maudsley reactive and nonreactive rats, along with that of Wistar controls, was studied using three behavioral tasks which have been associated with emotionality. Consistent with the hypothesis that they are more emotional, the Maudsley reactive rats were more immobile in the forced swim test and spent less time in the open arms of an elevated plus maze than the Maudsley nonreactive or Wistar control rats. However, they learned a two-way active avoidance task just as well as the other two groups. These findings suggest that emotionality is heterogeneous and/or that it is involved to different degrees in the three behavioral tasks.

Animals↗
PubMed1992

Attenuation of alcohol preference in alcohol-preferring rats by a novel TRH analogue, TA-0910.

Experiments were performed to characterize the acute effect of different doses of a novel thyrotropin-releasing hormone (TRH) analogue (TA-0910) on ethanol intake in rats. Selectively bred alcohol-preferring (P) rats received a single intraperitoneal injection of normal saline or 0.083, 0.25 and 0.75 mg/kg of TA-0910 at 9:30 AM, and their consumption of ethanol, water, and food was measured for 24 hr. TA-0910 dose-dependently attenuated ethanol intake and commensurately increased water consumption. Only the highest dose of TA-0910 increased the total caloric intake. TA-0910 did not affect the pharmacokinetics of ethanol. These findings indicate involvement of TRH systems in ethanol preference and suggest that centrally acting TRH analogues may be therapeutic in the treatment of alcoholism.

Alcohol Drinking↗
PubMed1992

Ethanol and complement hemolytic activity of selectively bred hypercholinergic rats.

Depression and alcoholism are associated with impaired immune responses. Complement proteins and fragments participate in the induction and modulation of both specific and non-specific immune reactions. This study examined the effect of prolonged ethanol ingestion on complement CH50 levels in two strains of rats, the Flinders Resistant Line (FRL) and the Flinders Sensitive Line (FSL), that differ in cholinergic sensitivity and depressive tendencies. Chronic ethanol exposure given as either the source of drinking fluid or as a liquid diet had a significant inhibition on mean CH50 unit responses in both FSL (41-48%) and FRL (23-24%) rats. The difference in group response to ethanol was confirmed by a significant interaction of ethanol treatment versus group in the two-way ANOVA. The FSL rats appear to be more easily affected than FRLs. Genetic differences in the neurotransmitter systems, therefore, may play a role in susceptibility to immunosuppression resulting from ethanol exposure.

Alcoholism↗
PubMed1991

Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats.

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.

Animals↗
PubMed1991

Effect of calcium-channel blockers on alcohol consumption in alcohol-drinking monkeys.

Experiments were performed to determine the effect of the calcium-channel blockers verapamil and diltiazem on ethanol preference in monkeys. Two days of administration of 10 mg/kg verapamil but not diltiazem or saline significantly decreased ethanol intake in all monkeys tested. Chronic treatment with verapamil, but not saline, dose-dependently attenuated alcohol intake, without significantly influencing water intake. These findings suggest that verapamil exerts an inhibitory action on ethanol preference in chronically alcohol-drinking monkeys, possibly by interfering with Ca(2+)-channels and/or by interacting with the activity of certain central neurotransmitters.

Alcohol Drinking↗
PubMed1991

Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats.

The Flinders Sensitive Line of rats (FSL) has been selectively bred to have increased sensitivity to cholinergic drugs. Typically, these rats react with twice as great a hypothermic effect to muscarinic agonists such as oxotremorine, as do similarly bred Flinders Resistant Line rats (FRL). We compared the effects of three chemically different calcium channel inhibitors (diltiazem, nicardipine and verapamil) on the hypothermia induced in FRL and FSL rats by oxotremorine (0.2 mg kg-1 s.c.). Each drug was injected i.p. in a dose of 20 mumol kg-1 30 min before oxotremorine. Methylatropine (2 mg kg-1 s.c.) was administered 15 min before oxotremorine to block the peripheral effects of the agonist. The hypothermic effect of oxotremorine in FSL rats was antagonized by nicardipine and diltiazem. In contrast, verapamil failed to influence the hypothermic response in FSL rats. Verapamil significantly (P less than 0.05) augmented oxotremorine hypothermia in FRL rats. Diltiazem and nicardipine were without effect on oxotremorine-induced hypothermia in FRL rats. There were no significant changes in temperature in separate groups of FRL and FSL rats treated with calcium channel inhibitors alone.

Animals↗
PubMed1991

Drug-induced reductions in ethanol intake in alcohol preferring and Fawn-Hooded rats.

The ethanol intake of Fawn-Hooded rats, a serotonin deficient strain, was examined under a two bottle choice between ethanol (10%) and tap water. The Fawn-Hooded rats drank as much ethanol as the alcohol preferring strain of rats (approximately 6 times that of the control Wistar rats), but drank more fluid and ate more. In general, direct and indirect serotonin agonists, reduced ethanol intake to a smaller degree in the Fawn-Hooded rats compared to the P rats. In contrast the centrally acting antimuscarinic scopolamine reduced ethanol intake to a similar degree in the two strains.

Alcohol Drinking↗
PubMed1991

Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animal model of depression with genetic muscarinic supersensitivity.

Rats from the Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL), which have been bred for differences in sensitivity to cholinergic agonists, were killed by decapitation under quiet, nonstressful conditions and the concentrations of corticotropin-releasing factor (CRF) in various brain regions, the concentrations of CRF receptors in the anterior pituitary, and plasma ACTH and corticosterone concentrations were determined. A first study revealed that the cholinergically hypersensitive FSL rats exhibited lower concentrations of CRF in the median eminence, locus ceruleus, and prefrontal cortex, but no such changes in some 13 other brain regions. In this first study, the FSL rats had significantly lower plasma ACTH concentrations. However, there were no differences in plasma corticosterone concentrations between the two groups. A second study confirmed the results of the first study and revealed that the density of anterior pituitary CRF receptor binding sites was elevated in the FSL rats. The observed pattern of alterations in these measures of HPA axis activity suggest that the cholinergically supersensitive FSL rats may possess diminished HPA activity.

Adrenocorticotropic Hormone↗
PubMed1990

Effect of verapamil on submissive behavior in genetically bred hypercholinergic rats in a water competition test.

Male hypercholinergic FSL (Flinders Sensitive Line) and control FRL (Flinders Resistant Line) rats were placed on a water deprivation schedule and tested for dominance behavior with FSL/FRL pairs competing for water. FSL rats spent significantly less time drinking than their FRL partners. Acute injection of 10 mg/kg of verapamil, a calcium channel inhibitor, to FSL rats markedly increased their drinking time without influencing water intake in individually tested rats. This effect of the drug was no longer seen after prolonged 4 day treatment. It is suggested that submissiveness of FSL animals in the water competition test might be due to increased fear which is alleviated by verapamil treatment. Tolerance seems to develop to this effect of the drug.

Animals↗
PubMed1990

MK-801 potently inhibits alcohol withdrawal seizures in rats.

The ability of MK-801, an N-methyl-D-aspartate (NMDA)-channel antagonist, to suppress alcohol withdrawal seizures generated audio-genically was studied in adult male rats using a cross-over experimental design. MK-801 treatment reduced overall seizure score and proportion of rats seizing. In comparison to other seizure models, alcohol withdrawal seizures seem to be particularly sensitive to MK-801, suggesting that mechanisms which result in seizure susceptibility after withdrawal of chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes.

Acoustic Stimulation↗
PubMed1990

Pilocarpine, an orally active muscarinic cholinergic agonist, induces REM sleep and reduces delta sleep in normal volunteers.

The effect of oral pilocarpine, a direct-acting muscarinic, cholinergic agonist, on polygraphic sleep parameters was studied in 13 healthy male volunteers. Subjects received placebo and oral pilocarpine (25 mg) in a double-blind, counterbalanced, crossover design. Pilocarpine shortened the latency of rapid eye movement (REM) sleep and increased total REM time, REM%, and the duration of the first REM period. In addition, it reduced Stage 4 sleep and Delta sleep. Pulse rate was not significantly changed during the first hour of darkness after administration of pilocarpine. Subjective sleep experience and the subjects' condition in the morning were not altered. These results suggest that pilocarpine has central effects (i.e., induction of REM sleep) that are similar to those of other centrally acting muscarinic cholinomimetic agents.

Administration, Oral↗
PubMed1990

Effects of bright light on responsiveness to a muscarinic agonist in rats selectively bred for endogenously increased cholinergic function.

The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding those animals exhibiting a high level of sensitivity to an anticholinesterase. The Flinders Resistant Line (FRL) was simultaneously developed as a control line. These lines exhibit nonoverlapping distributions of their thermic responsiveness to oxotremorine. Bright light prevents the development of supersensitivity to oxotremorine occurring as a result of forced stress or treatment with a muscarinic receptor antagonist in the rat. The authors now report that treatment with bright light during the regular photoperiod (i.e., a time that does not produce a phase-shift or free-running) differentially affects the hypothermic response and activity-suppressing effect of oxotremorine in both the FSL and FRL. Both lines exhibit decreased hypothermia without reduction in motor activity in response to oxotremorine following 6 days of treatment with bright light. The magnitude of blunting of the hypothermic response was greater in the FSL than the FRL. These findings suggest that (1) studies of the effects of bright light are contingent on the end point one measures and (2) the capacity of this treatment to blunt the hypothermic response to a muscarinic agonist is greater in an animal model with endogenously hyperactive muscarinic cholinergic systems.

Animals↗
PubMed1990

Decreased alcohol consumption by verapamil in alcohol preferring rats.

1. Calcium channel blockers have been proposed, in addition to inhibiting the influx of Ca++ into the cells, to possess a wide variety of pharmacological effects, including interference with certain neurotransmitters involved in mood, mental disorders and alcohol craving. Further, it has been documented that certain neurotransmitters are involved in alcohol craving both in animals and humans. 2. To investigate the effects of Ca(++)-channel antagonist on alcohol preference, verapamil in three doses (5, 10 and 15 mg/kg) was injected (S.C.) twice daily over a period of one day in alcohol-preferring (P) and alcohol non-preferring (NP) rats at 9:00 a.m. and 4:00 p.m. 3. Water, alcohol and food intake were monitored. 4. Our results show that verapamil in doses of 10 and 15 mg/kg significantly (p less than 0.02 and 0.01, respectively) reduced the intake of ethanol and increased the intake of water by P rats. However, injection of an equal volume of saline did not change the pattern of alcohol intake. 5. These results suggest that a (++(+)-channel blocker such as verapamil, could, at least partially, attenuate alcohol preference in alcohol preferring rats. It is possible that verapamil exerts an inhibitory effect on alcohol preference by interfering with Ca++ channels, blocking serotonin uptake or through another mechanism(s).

Alcohol Drinking↗
PubMed1990

Selective antagonistic effects of exposure to bright light on the hypothermic action of ethanol.

Flinders Sensitive and Resistant Lines of rats, which are differentially sensitive to the hypothermic effects of both muscarinic agonists and ethanol, were exposed to full spectrum artificial bright light for eight days, because exposure to bright light has been shown to blunt hypothermic responses to muscarinic agonists. There was a selective blunting of the hypothermic effects of ethanol, but no significant change in the intoxicating effects of ethanol, as measured by evaluation of the righting reflex. The selective effect of exposure to bright light on the hypothermic actions of ethanol suggests that bright light may be modifying the function of only a limited number of brain regions, including the hypothalamus.

Alcoholic Intoxication↗