Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg s.c.) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the alpha4beta2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the alpha7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders.

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Physostigmine, a cholinesterase inhibitor which increases central acetylcholine levels, has been found in man to decrease manic symptoms, antagonize methylphenidate-induced behavioral activation, and induce severe depression and psychomotor retardation in marijuana intoxicated normals. In the current study, physostigmine was found to increase depressed mood in patients with an affective component to their symptoms (manics, depressives, and schizoaffectives). Schizophrenics without an affective component did not become depressed. After physostigmine administration, all subject groups showed a significant increase in symptoms including lethargy, slowed thoughts, withdrawal, apathy, decreased energy, decreased thoughts, motor retardation, and feeling drained, indicating a state of psychomotor retardation; and all became less cheerful, friendly, and talkative. The above information is compatible with the hypothesis that acetylcholine may be involved in the etiology of affective disorders.

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these "therapeutic" effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond "therapeutically" to antidepressants and not psychomotor stimulants.

The recent literature on the involvement of cholinergic muscarinic mechanisms and adrenergic/cholinergic balance in affective disorders is reviewed and integrated with the older literature. There is strong evidence supporting the presence of exaggerated responses (behavioral, neuroendocrine, sleep) to cholinergic agents in affective disorder patients relative to normal controls and certain other psychiatric patients. There is also some, albeit less, conclusive evidence that these exaggerated responses may occur in euthymic individuals with a history of affective disorders, or in children at risk for development of affective disorders. Despite these promising results, suggesting a role for acetylcholine in the genetics of the affective disorders, further work in biochemistry and genetics is needed to link specific muscarinic receptors or other cholinergic variables to affective illness.

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