Biomedical subjects
Publications and source records attributed to D S Janowsky.
It was found that the Flinders Sensitive Line (FSL) of rat, selectively bred for increased cholinergic function, performed poorly in a tone-cued two-way active avoidance task in comparison with the control Flinders Restraint Line (FRL) of rat. These findings are consistent with the suggestion that the FSL rats may be a genetic animal model of depression.
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.
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.
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).
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.
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Selectively bred alcohol-preferring (P) and alcohol non-preferring (NP) lines of rats were administered saline subcutaneously, and doses of 0.5 and 2.0 mg/kg of two antimuscarinic agents scopolamine (centrally acting) and methscopolamine (peripherally acting), twice daily respectively for a period of one day. Compared to saline, both doses of scopolamine and methscopolamine induced a significant reduction in ethanol consumption in the P line of rats, and both antimuscarinic agents significantly increased water intake. Thus, ethanol preference was dramatically reduced in these rats. In contrast, scopolamine had relatively little effect on either ethanol or water intake in the NP line of rats, while methscopolamine tended to suppress both ethanol and water intake. These findings suggest that peripheral muscarinic mechanisms may be involved in ethanol preference in P rats.
Experiments were performed to determine the ability of verapamil to reverse ethanol-induced hypothermia and behavioral changes. Permanent cannulae for intracerebroventricular (i.c.v.) infusion were implanted bilaterally in rats following standard stereotaxic procedures. Following post-operative recovery, either verapamil or artificial cerebral spinal fluid (ACSF) was infused i.c.v., followed by 4.0 g/kg ethanol in saline administered by intragastric gavage. Changes in body temperature and overall activity were monitored. In another series of experiments, rats were given either i.c.v. verapamil or ACSF followed by 1.5 g/kg intraperitoneal ethanol. Ability to turn over and open-field activity were monitored. In addition, to investigate the action of verapamil alone on body temperature, rats were infused i.c.v. either with verapamil or control ACSF, followed by intragastric administration of a volume of saline equal to 4.0 g/kg ethanol (20% v/v). At an ambient temperature of 22 degrees C, verapamil, infused prior to ethanol administration, significantly and rapidly attenuated the thermolytic action of ethanol. Central administration of verapamil alone did not induce a significant change in body temperature until more than 1.5 hr after injection, at which time temperature began to gradually increase. Pretreatment with verapamil induced significantly faster recovery from ethanol-induced changes in overall activity. Only a non-significant reversal of ethanol's effects on open-field activity and time taken to turn over occurred. These results demonstrate that verapamil can significantly antagonize ethanol-induced hypothermia and possibly motor disturbances in rats, leading us to postulate the possible involvement of neuronal Ca2+ channels in these effects of ethanol.
The behavioral and hypothermic effects of ethanol were studied in the Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats, selectively bred for differences in cholinergic sensitivity. The FSL hypercholinergic rats exhibited a significantly greater degree of hypothermia than the FRL rats, or a group of weight-matched randomly bred rats. Although there were some trends for the FSL rats to appear more depressed behaviorally after receiving ethanol, there were no significant differences between the FSL and FRL rats on quantitative behavioral measures. Blood ethanol concentrations were slightly lower in the FRL rats, but there were no differences between the FSL and control rats. These findings suggest an association between cholinergic mechanisms and ethanol sensitivity with regard to body temperature effect, but a direct causal relationship cannot be established because of similar differential sensitivities of FSL and FRL rats to a range of other neurotransmitter-altering drugs on this parameter.
The effects of lithium on the circadian rhythms of body temperature and rapid eye movement (REM) sleep were examined in a patient with bipolar depression. The acrophase of body temperature showed a phase delay of 74 min after 1 week of lithium treatment. REM latency increased significantly with lithium, and the onset of subsequent REM periods was also delayed. The proportion of the night spent in REM sleep decreased significantly. There was no effect of lithium on the patient's mood. The data are consistent with the hypothesized phase-delaying properties of lithium but do not support the causal link between circadian phase and affective state.
To determine the effects of brief naps on mood and electroencephalographic (EEG) sleep in sleep-deprived depressed patients, data from 19 hospitalized patients with depression were analyzed; all were kept awake from 0700h until the following day, when they were allowed 10-min naps at either 0830h or 1500h. Six of the patients showed a clinically significant improvement (greater than 40% change) on the Hamilton Rating Scale for Depression (HRSD) before the nap after all-night sleep deprivation, and the group as a whole showed a significant improvement on the HRSD, the Profile of Mood States, and the Brief Psychiatric Rating Scale subscale for depression. Naps did not alter mood in the responders, but did improve measured depression on the HRSD in the non-responders. Morning and afternoon naps did not differ significantly in their effects on mood or nap sleep. On the recovery sleep, patients who were classified as responders after the nap showed a significantly greater increase in delta (Stage 3 + 4) sleep compared with baseline than nonresponders.
1. Five minute bright light exposures reduced plasma levels of melatonin in eight normal subjects. 2. No significant change in ACTH levels occurred. 3. These results raise the possibility that short intense light exposures can synchronize circadian rhythms as well as benefit patients with seasonal affective disorder. They also indicate that short pulses of bright light do not affect pituitary ACTH production.
Patients with panic disorder (N = 11) and age- and sex-matched normal control subjects (N = 11) were challenged with human growth hormone-releasing factor (GH-RF) (1 microgram/kg i.v.) or placebo in random order. The control subjects had significantly increased plasma growth hormone (GH) levels after GH-RF infusion whereas panic disorder patients did not. At 15 and 30 minutes after GH-RF infusion, GH concentrations were significantly higher in the control subjects than in the patients. These findings with GH-RF extend findings from earlier reports that patients with panic disorder show blunted GH response to phobic stimulation and clonidine.
Changes in anergia/inhibition, mood, and pulse rate induced by intravenous physostigmine were significantly less pronounced in 26 patients with primary alcoholism than in 36 normal control subjects. These results suggest possible abnormalities in central cholinergic functioning in primary alcoholics.
There is an overlap between alcoholism and depressive disorders. However, alcoholics tend to be resistant to the effect of cholinergic agonists, whereas depressives tend to be more sensitive. A recently developed animal model of depression which is more sensitive to cholinergic agonists is also more sensitive to the acute effects of ethanol. These consistent human and animal studies suggest that cholinergic challenges may be helpful in separating alcoholics from depressives.
Increased muscarinic sensitivity has been associated with altered hormonal states (hypothyroidism and hyperadrenocorticism), chronic administration of muscarinic antagonists or antidepressants with muscarinic actions, selective breeding for anticholinesterase sensitivity, and certain inbred strains of rats and mice. Thus, both genetic and environmental factors may influence muscarinic receptor sensitivity. The reasonably detailed studies on the selectively-bred rats have revealed that the Flinders Sensitive Line (FSL) rats weigh less, are less active, are more sensitive to muscarinic agonists and to stressors, and have higher concentrations of hippocampal and striatal muscarinic receptors than 'normal', or the selectively-bred, Flinders Resistant Line (FRL) rats. Thus, there are a number of parallels between FSL rats and depressed humans. The FSL rats may be the first animal model of depression to mimic the actual trait of depression, and not just the state.
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