Phenelzine produces subsensitivity to nicotine.

1. The authors attempted to detect a possible effect of treatment with phenelzine on a physiological response to nicotine in the rat. 2. Positive findings in an animal model suggest the feasibility of more complicated experiments in animals and the possibility of studies involving human subjects. 3. Treatment of Sprague Dawley rats (n = 10) with phenelzine sulfate (15.0 mg/kg ip) every 48 hours for 14 days was associated with a 73.3% decrease in the hypothermic response to nicotine. 4. Treatment with phenelzine did not enhance the rate of elimination of nicotine. 5. The authors discuss a possible relationship between changes in nicotinic mechanisms and the therapeutic actions of drugs used to treat affective illness.

Antipsychotic agents: a review.

Antipsychotic agents are useful in the treatment of psychosis due to both functional disorders (i.e., idiopathic disorders that are usually treated by psychiatrists) and organic mental disorders. These drugs are classified as low- and high-potency agents. Low-potency agents such as chlorpromazine block muscarinic and alpha 1-adrenergic receptors. Consequently, they produce anticholinergic side effects and orthostatic hypotension. High-potency antipsychotic agents have a higher affinity for dopamine receptors and a relatively negligible affinity for muscarinic and alpha 1 receptors. The high-potency agents frequently cause extrapyramidal side effects, such as dystonia and parkinsonism. Serious reactions to antipsychotic drugs include tardive dyskinesia and neuroleptic malignant syndrome.

The efficacy of bupropion in winter depression: results of an open trial.

BACKGROUND: Seasonal affective disorder (SAD) refers to regularly recurring episodes of affective illness bearing a fixed relationship to season. Wintertime depression is its most widely recognized form. This study was undertaken to assess the efficacy of bupropion as a treatment for this disorder. METHOD: Fifteen consecutively presenting patients were treated with bupropion (200 to 400 mg/day). All met DSM-III-R criteria for major depression with a seasonal pattern. All were moderately to severely depressed. A modified version of the Hamilton Rating Scale for Depression (mHAM-D) including ratings of hypersomnia, increased appetite and carbohydrate craving, and weight gain was used to quantify the severity of illness. Up to 5 weeks of treatment was allowed before the subjects were categorized as nonresponders, partial responders, or responders. RESULTS: The mean +/- SD mHAM-D scores before and after treatment were 25.5 +/- 6.4 and 4.1 +/- 3.1, respectively. Ten (66.7%) of the subjects had a complete response to treatment (mHAM-D score less than or equal to 5). The other 5 (33.3%) had a partial response (mHAM-D score = 6-10). Five of the subjects had chronic pain and 3 had panic attacks restricted to episodes of depression. These problems resolved simultaneously with the symptoms of depression. CONCLUSION: The results of this open trial suggest that bupropion is an effective treatment for winter depression. However, controlled studies are required to confidently determine whether this is the case.

Chronic treatment with ethanol alters the physiological action of nicotine.

1. Ethanol decreases the release of acetylcholine through effects on presynaptic neurons at both muscarinic and nicotinic junctions. 2. Blockade of the release of acetylcholine should produce denervation supersensitivity at both muscarinic and nicotinic cholinergic junctions. 3. Chronic but not acute treatment with ethanol produces supersensitivity to the hypothermic effects of a muscarinic agonist in the rat. 4. The authors now report that chronic treatment with orally administered ethanol blunts (rather than enhances) the hypothermic response to nicotine in the rat. 5. This could have major public health implications. 6. Smoking and the use of ethanol containing beverages positively covary. 7. Ethanol induced reduction in sensitivity to nicotine suggests that the heavy consumption of ethanol may necessitate that one drink more than otherwise in order to obtain the desired effects of nicotine.

The Flinders Sensitive Line exhibits enhanced thermic responsiveness to nicotine relative to the Sprague-Dawley rat.

The Flinders Sensitive Line (FSL) was derived from the Sprague-Dawley rat by selectively breeding animals with heightened sensitivity to an anticholinesterase. The FSL now consistently exhibits enhanced behavioral and physiological responses to muscarinic agonists relative to its progenitor. The authors now report the FSL exhibits enhanced thermic responsiveness to nicotine relative to the Sprague-Dawley rat. The possible relevance of this finding to investigators interested in the disorders of mood is briefly discussed.

Chronic forced swim stress produces subsensitivity to nicotine.

Twice daily injections of saline reduce the thermic response to nicotine in the rat. The authors hypothesized that this was due to the stress of twice-daily handling and injection. However, the injection of saline is not a classic stressor. The hypothesis that stress blunts thermic responsiveness to nicotine was, therefore, tested using a classic form of chronic inescapable stress. Rats (n = 12) were subjected to a 14-day, twice daily course of inescapable cold water swim stress using a repeated measures design. Thermic responsiveness of nicotine was measured at baseline and every 7 days thereafter for 49 days. The mean response to nicotine (1.0 mg/kg IP) differed significantly across time, F(7,88) = 10.6, p less than 0.0001. Mean thermic responsiveness (+/- SEM) decreased from -0.75 +/- 0.09 at baseline to -0.41 +/- 0.18 degrees C (54.7% of baseline) following 14 days of forced swim stress. This change was not significant. However, the thermic response to nicotine was -0.14 +/- 0.13 degrees C (p less than 0.05), +0.55 +/- 0.12 degrees C (p less than 0.05), and +0.04 +/- 0.11 degrees C (p less than 0.05) 7, 14, and 21 days following the discontinuation of forced swim stress. The mean response did not differ from baseline 28 days following the last session of forced swim stress. The data suggest that in the recovery phase the animals ceased to be sensitive to nicotine. These findings support the hypothesis that a chronic stressor can produce subsensitivity to nicotine.

Constant exposure to darkness produces supersensitivity to nicotine.

Treatment with full-spectrum bright artificial light produces subsensitivity to the hypothermic effect of nicotine in the rat. The authors hypothesized that prolonged exposure to darkness would produce the opposite effect. The thermic responsiveness of 11 rats to nicotine (base), 0.25 mg/kg IP, was telemetrically measured at baseline, after 7 days of exposure to constant darkness, and 2, 5, and 12 days after being returned to standard vivarium conditions. Exposure to constant darkness enhanced the hypothermic response to nicotine. The sample exhibited a hyperthermic response to nicotine 2 and 5 days after being returned to the standard vivarium conditions with a 12-hour-light/12-hour-dark cycle. The magnitude of the hyperthermia observed is characteristic of the response to the injection of saline. Twelve days after return to standard vivarium conditions the thermic response of the sample was at baseline.

Pharmacological responsiveness of winter depression.

Seasonal affective disorders (SADs) are disturbances of mood bearing a fixed relationship to season. Wintertime depression is the most widely accepted form of SAD. Full-spectrum, bright artificial light is the standard treatment for this syndrome. Tranylcypromine was effective in the treatment of 14 patients meeting both the National Institute of Mental Health and DSM-III-R criteria for winter depression. The average patient experienced a 91 percent reduction in depressive symptoms within 3 to 4 weeks of the initiation of this treatment. Desipramine initially appeared to be an effective treatment for winter depression. Eight patients started treatment with desipramine in October or November. One patient was unresponsive, and 8 patients appeared to be responsive but relapsed in the following 2 to 4 months. Twenty-five patients were subsequently treated with bupropion. One patient was unresponsive to bupropion, but the others experienced a substantial reduction in symptoms. Chronobiologic properties that might explain or predict the effectiveness of drugs used to treat winter depression are discussed.

Chronic injections of saline produce subsensitivity to nicotine.

The routine handling of rats and the injection of saline is a stressor. The authors report that chronic twice daily injections of normal saline (1 ml/kg IP) for 14 days produced subsensitivity to the hypothermic effects of nicotine (1 ml/kg IP). The weekly injection of nicotine (1 mg/kg IP) does not produce this effect. The investigators propose that their findings reflect the effect of chronic stress on a nicotinic mechanism. Lithium, desipramine, fluoxetine, and amitriptyline also alter the thermic response to systemically injected nicotine. A nicotinic mechanism(s) may be involved in the neurobiology of chronic stress, actions of antidepressants, and conceivably the pathophysiology of depression.

Neurobiologic effects of bright artificial light.

Bright light is an effective treatment of winter depression. Study of the effects of this treatment on mechanisms thought to be involved in the pathophysiology of depressive disorders is reviewed. Measurement of a physiological parameter, namely the change in core temperature using an intraperitoneally implanted radio transmitter sensitive to temperature in freely moving rats, indicates that treatment with bright light under various experimental conditions tends to powerfully subsensitize muscarinic and nicotinic mechanisms. Pulses of bright light during the phase delay portions of the PRC blunt sensitivity to clonidine. Our studies with bright light are consistent with those indicating that heterocyclic antidepressants and a monoamine oxidase inhibitor produce subsensitivity to the thermic effects of nicotine. Reports of the influences of full-spectrum bright light and its impact on targeted neurotransmitter mechanisms call attention to the anatomical substratum mediating its effects. Possible receptor changes are measurable using receptor binding techniques and quantitative autoradiography. The physiological effects of this interesting treatment raises questions of its impact on coupling mechanisms and second messengers.

Antipsychotic withdrawal phenomena in the medical-surgical setting.

The literature describing nondyskinetic antipsychotic withdrawal symptoms is reviewed. The withdrawal of antipsychotic agents can result in nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgias, paresthesias, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness, and insomnia. However, the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.

Bright artificial light produces subsensitivity to nicotine.

Bright artificial light is a treatment for seasonal depression. Eleven (11) rats were exposed to bright artificial light (11,500 lux) for two consecutive weeks. The thermic response to nicotine was measured prior to light exposure and after one and two weeks of treatment. The thermic response to nicotine at baseline was -1.69 +/- 0.25 degrees C (mean +/- SEM). The thermic response to nicotine was -0.66 +/- 0.12 degrees C (p less than 0.002) after one and +0.31 +/- 0.14 degrees C (p less than 0.000025) after two weeks of light exposure. The change in temperature was different between weeks one and two (p less than 0.000025). The exposure of animals to constant light at an intensity of 300 lux did not blunt the hypothermic response to nicotine. These findings suggest that bright artificial light, like other antidepressant treatments, produces subsensitivity of a nicotinic mechanism involved in the regulation of core temperature.

Chronic treatment with amitriptyline produces supersensitivity to nicotine.

The authors used a thermoregulation paradigm to evaluate effects of amitriptyline (AMI) on the sensitivity of a nicotinic mechanism involved in the regulation of core temperature in rats. Treatment with this tricyclic was associated with a significant increase in the hypothermic response to nicotine. Supersensitivity persisted for a minimum of 7.5 days following the last dose of AMI, and a significant proportion of animals displayed increased sensitivity after 14.5 days of abstinence. Implications for the mechanism of action of AMI are highlighted.