Mood and behavioral effects of physostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol.

Administration of physostigmine to normal volunteers produced significant elevations in plasma cortisol and beta-endorphin immunoreactivity as well as alterations in mood, cognition, and behavior. These observations might be explained by a cholinergically mediated stress syndrome. However, peak elevations in plasma beta-endorphin immunoreactivity (but not in plasma cortisol) were significantly correlated with physostigmine-induced increases in depression ratings. These results suggest that a cholinergically mediated beta-endorphin pathway may be involved in the observed affective changes.

Central cholinergic stimulation causes adrenal epinephrine release.

Cholinergic drugs administered into the cerebral ventricles of animals selectively stimulate the adrenal medulla. However, the effects of central cholinergic stimulation on the sympathoadrenal system have not been studied in man. We stimulated central cholinergic activity in man by administering the cholinesterase inhibitor physostigmine to subjects pretreated with peripheral cholinergic blocking agents. A dose of 0.022 mg/kg physostigmine dramatically increased plasma epinephrine levels and slightly increased norepinephrine levels, which is consistent with selective adrenomedullary stimulation. A smaller dose of physostigmine increased epinephrine but did not alter norepinephrine levels. Subjects had increased pulse rates and blood pressures, and felt anxious while they had high plasma epinephrine levels.

Methylphenidate, dextroamphetamine, and levamfetamine. Effects on schizophrenic symptoms.

Methylphenidate hydrochloride dextroamphetamine sulfate, and levamfetamine succinate have potential as pharmacologic tools for the indirect evaluation of the role of neurotransmitters in schizophrenia. In actively ill schizophrenic patients, methylphenidate administered intravenously causes a brief but clear intensification of preexisting psychotic symptoms, such as hallucinations and delusions. In our study, methylphenidate, dextroamphetamine, and levamfetamine were administered in equimolar doses to schizophrenic patients. Methylphenidate was a more effective activator of symptoms than dextroamphetamine, which in turn was more effective than levamfetamine. Levodopa (L-dopa) given orally also reportedly produces a temporary worsening of schizophrenic symptoms. While these findings augment a body of information suggesting that dopamine and norepinephrine may play a role in the activation of schizophrenic symptoms, our findings with methylphenidate (reportedly weak in eliciting stereotyped behaviour in rat) and our review of the literature indicate complexities that remain to be resolved. There is some utility of the procedure for differential diagnosis and selective therapy, but this is still of occasional and limited potential.

Methylphenidate hydrochloride effects on psychological tests in acute schizophrenic and nonpsychotic patients.

Actively psychotic schizophrenic and nonpsychotic psychiatric inpatients received intravenous methylphenidate hydrochlroide (0.5 mg/kg). Each patient was rated for level of psychosis and talkativeness, and each received the Holtzman projective ink blot tests and the Kent-Rosanoff word-association tests before, during, and after methylphenidate infusion. Minnesota Multiphasic Personality Inventory Goldberg Index scores were also obtained as a general measure of psychosis. For the entire patient group, methylphenidate infusion was followed by a significant increase in talkativeness and psychosis ratings and in pathological responses to the Holtzman ink blot test. There was a significant decrease in common word associations. Since neither of the psychological tests allow more than one response per item, it appears that methylphenidate truly effects pathological thought processes and decreases common word associations as such, rather than merely making these processes more evident by increasing verbalization.

The effect of methylphenidate on serum growth hormone: influence of antipsychotic drugs and diagnosis.

Intravenously administered methylphenidate, 0.5 mg/kg, causes a consistent rise in human serum growth hormone level, with peak values usually occurring 30 minutes after infusion. This rise is attenuated in patients receiving various antipsychotic medications administered on a long-term basis and is decreased in schizophrenic and drug-dependent patients. Methylphenidate causes increases in talkativeness, blood pressure, and pulse that generally parallel increases in serum growth hormone level. However, in contrast to the methylphenidate-induced rise in serum growth hormone level, methylphenidate-induced changes in cardiovascular variables and talkativeness are not altered by antipsychotic medications or diagnostic classification.

Interpersonal effects of marijuana. A model for the study of interpersonal psychopharmacology.

The effect of marijuana on affective changes and interpersonal skills, including empathy, acceptance, warmth, and genuineness, was studied in 20 dyadic relationships in which the experimental subject smoking marijuana containing 6 mg of delta-9-tetrahydrocannabinol and a placebo in separate trials. Marijuana caused a relative decrease in the ratings of the interpersonal skills of the experimental subjects and decreased affective resonance between the experimental subjects and their partners.

Naloxone-induced behavioral and physiological effects in normal and manic subjects.

Intravenous naloxone hydrochloride (20 mg) was administered to eight normal control subjects and 12 affective disorder patients manifesting manic or hypomanic symptoms. On two consecutive days, in a counterbalanced order, naloxone and placebo were given in a double-blind crossover design. The overall effect of naloxone was to decrease pulse rate and to promote lethargy and inactivation. The normal controls manifested reduced feelings of well-being, and the manic patients noted a subjective sense of slowing. There was a variable response pattern to naloxone in the manic patients in which four of the 12 patients manifested an observable reduction in their manic symptoms and behavior after the naloxone administration. Naloxone seems to have had a nonspecific subduing effect in both normal subjects and patients and may also have had a selectively greater effect in a small subsample of the manics.

The effect of lithium carbonate on affect, mood, and personality of normal subjects.

Data reflecting affect, mood, and personality attributes of 23 normal men were compared after two weeks of placebo administration and two weeks of therapeutic serum lithium levels (mean, 0.91 mEq/liter). The study was a placebo-controlled, split-half crossover, double-blind design. Affect and mood were measured by three self-rating instruments, independent rater observation, and by the subjects' "significant others." Two personality inventories were administered. Substantial affect and mood changes are induced by lithium carbonate. Lethargy, dysphoria, a loss of interest in interacting with others and the environment, and a state of increased mental confusion were reported. No generalized effects were found in the responses to ther personality inventories.

The effect of lithium carbonate on the cognitive functions of normal subjects.

The responses of 24 normal male subjects were compared after weeks of placebo administration and two weeks of lithium carbonate administration (mean serum lithium level, 0.9 mEq/liter) on a series of tasks of intellectual function, aesthetic judgement, and semantic creativity. This was a placebo-controlled, split-half crossover, double-blind design. There were no significant changes on semantic creativity or aesthetic perception measures following lithium carbonate maintenance. There were lithium carbonate-related performance deficits on three of five performance tasks concerned with cognitive and/or motor functions. The deficit is probably due to a lithium carbonate-induced slowing of performance, consistent with our previous report of subjective effects in normal subjects. The implications of slowing on possible behavioral mediating mechanisms by which lithium carbonate exerts its clinical effects are discussed.

Blunted prolactin response. A neuroendocrine abnormality manifested by depressed patients.

Prolactin concentrations of 30 unmedicated psychiatric inpatients and 11 normal controls were measured at baseline and at 30 and 60 minutes after the administration of 10 mg of intramuscular methadone hydrochloride. Methadone raised the prolactin level at 60 minutes to more than twice the mean baseline level for the full subject sample. Patients with depressive disorders had lower mean basal prolactin levels than did the other subjects, and also manifested attenuated prolactin responses to methadone. Eight of 16 depressives had markedly blunted prolactin responses, a finding consistent with other studies reporting deficient responses in depression. These data are consistent with the hypothesis that the pathophysiology of depressive disorders involves dysfunctions in the anterior pituitary itself or in the hypothalamic neurotransmitter and neuromodulator systems (eg, endorphins) that regulate the secretion of prolactin and other neurohormones.

Lithium carbonate and ethanol induced "highs" in normal subjects.

The responses of twenty-three normal male subjects to a standardized dose of 95% ethanol (1.32 ml/kg of body weight) were compared after two weeks of placebo and two weeks of therapeutic serum lithium ion levels (mean 0.91 mEq/liter). The study was a placebo controlled, split-half crossover, double-blind design. Prealcohol and postalcohol responses were assessed by self-rating scales of affect and mood, independent rater observation, perceptual-motor, and cognitive performance tasks. Pretreatment by lithium carbonate neither blocked nor dampened an alcohol-induced subjective "high" in normal subjects. A complex reciprocal interaction may exist between the effects of lithium and alcohol upon other behavioral attributes. Alcohol was seen to reverse aspects of lithium-induced dysphoria and there is a suggestion that lithium may attenuate alcohol-induced cognitive inefficiency.

Central cardiovascular effects of physostigmine in humans.

Central cholinergic control of pulse rate and blood pressure has seldom been studied in humans. In the current study we contrasted the cardiovascular effects of the centrally acting cholinesterase inhibitor physostigmine, which increases central and peripheral acetylcholine levels, with those of saline placebo and with those of the non-centrally acting cholinesterase inhibitor neostigmine, which only increases peripheral acetylcholine levels. We found that physostigmine, in contrast to neostigmine and saline, caused significant and often profound increases in pulse rate and blood pressure levels in humans. Thus, we conclude that acetylcholine may have a role in central cardiovascular regulation in humans. We also found that administration of physostigmine may cause net increases in pulse of up to 74 beats/minute, systolic blood pressure increases of up to 50 mm Hg, and diastolic increases of up to 45 mm Hg. Such increases could be dangerous in elderly patients with concomitant cerebrovascular or coronary circulation disorders.

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.

Neuroendocrine responses in psychiatric and pain patients with major depression.

Basal and postdexamethasone concentrations of cortisol and prolactin were studied in three groups of male patients: chronic pain patients with no psychiatric diagnosis (n = 12), chronic pain patients with coexisting major depression by Research Diagnostic Criteria (RDC) (n = 24), and pain-free psychiatric patients meeting RDC criteria for major depression (n = 28). Basal cortisol concentrations were significantly higher in pain-major depression and psychiatric-major depression patients compared to pain patients without psychiatric illness. The frequency of cortisol nonsuppression after dexamethasone was significantly greater in pain patients with major depression (41.7%) compared to pain patients without psychiatric disorder (8.3%), and was comparable to that of psychiatric patients (21.4%). Prolactin concentrations, but not cortisol levels, were significantly correlated with observer-rated severity of depression in pain patients. These findings suggest that cortisol and prolactin abnormalities in chronic pain may be related to psychiatric disorder rather than to pain per se, at least in male patients, and may indicate a role for cholinergic mechanisms in the interface of pain and depression.

Stress-induced immobility in rats with cholinergic supersensitivity.

Immobility during forced swimming or after mild footshock (1 mA for 2 sec) was observed in five groups of rats. The Flinders Sensitive Line (FSL) of rats, known to be more sensitive to cholinergic agonists, exhibited the greatest degree of immobility in the forced swim test. Rats chronically treated with, and subsequently withdrawn from, either scopolamine (2 mg/kg, once daily) or amitriptyline (10 mg/kg, once daily) were also significantly more immobile than either a control group treated chronically with isotonic saline or the Flinders Resistant Line (FRL) of rats in the forced swim test. Similar trends were observed for locomotor depression in the open field following exposure to footshock. Receptor binding studies indicated significantly greater concentrations of muscarinic acetylcholine receptors in the hippocampus of the scopolamine, and amitriptyline, withdrawn rats. These findings indicate that rats with increased cholinergic sensitivity are more sensitive to the immobility-inducing effects of mild stressors. Thus, they may prove to be useful models for studying the relationship between affective disorders and the cholinergic system.

Impaired speed of visual information processing in marijuana intoxication.

The authors conducted a double-blind crossover study to investigate the effects of marijuana on visual information processing. The authors used a tachistoscopic paradigm, and the results show no marijuana effect on the critical stimulus duration, a measure of stimulus intake. The visual backward masking data are compatible with a marijuana-induced slowness of information processing from labile unconscious iconic memory to more permanent memory processes. These results are discussed in relation to reports of marijuana's effects on perception and early information processing.

Behavioral hyporeactivity to physostigmine in detoxified primary alcoholics.

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.

Blunted growth hormone response to peripheral infusion of human growth hormone-releasing factor in patients with panic disorder.

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.

Physostigmine-induced epinephrine release in patients with affective disorder.

Infusion of the cholinomimetic drug physostigmine led to profound increases in serum epinephrine levels and slight increases in serum norepinephrine levels among 38 patients with affective disorder and 22 control subjects. Preliminary results suggest that physostigmine may induce relatively blunted increases in serum epinephrine levels in patients with affective disorders.

Effects of lithium carbonate on memory and other cognitive functions.

The authors studied the effects of lithium carbonate on memory and cognitive function in 16 psychiatric patients, who received lithium for 2 weeks and placebo for 2 weeks in a double-blind cross-over design. At the end of each treatment phase, subjects were administered a battery of memory and cognitive tests. As reported previously, lithium induced slowing of performance on certain of the perceptual motor tests; however, lithium did not cause memory impairment or a change in self-assessment of memory functions.