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The brain tripeptide thyrotropin-releasing hormone (TRH) has been demonstrated to facilitate cholinergic neurotransmission. To test its interaction with the cholinergic system in humans, high-dose TRH (0.5 mg/kg) or placebo was administered intravenously (IV) to normal controls pretreated with scopolamine (0.5-0.75 mg IV), a centrally active muscarinic antagonist, which has been used to model aspects of the memory impairment of normal aging and of dementia. Compared to placebo, TRH markedly attenuated scopolamine-induced impairment of some measures of memory, most notably on a selective reminding task. This cognitive study is the first in humans to suggest a neuromodulatory effect of a peptide on the cholinergic system, and suggests a facilitatory role for TRH in human memory processes.

Deprenyl has previously been reported to be a selective monoamine oxidase (MAO) type B inhibitor, which is associated with little or no enhancement of the pressor effects of tyramine. Employing an intravenous steady-state tyramine infusion technique, the effects of different doses of deprenyl and, for comparison, the mixed inhibitor tranylcypromine on the pressor response to tyramine were studied in 11 depressed patients. After 3 weeks of treatment, deprenyl produced dose-proportionate increases in tyramine sensitivity at all three doses (10, 30, and 60 mg/day) when compared to placebo baseline tyramine responses. While only a modest (3.7-fold) increase in tyramine sensitivity was found with the 10 mg/day deprenyl dose, the increase in tyramine sensitivity at the 60 mg/day dose of deprenyl (22-fold) approached that found with tranylcypromine. Reductions in plasma 3-methoxy,4-hydroxyphenylglycol (MHPG), used as a possible index of in vivo MAO-A inhibition, were highly correlated with increases in tyramine pressor sensitivity (r = 0.82). The data suggest that deprenyl acts as a relatively selective MAO-B inhibitor at low doses, but that this selectivity is lost at higher doses, resulting in a significant "crossover" inhibition of MAO-A and increased tyramine pressor sensitivity.

The effects of 4 weeks of treatment with the selective monoamine oxidase (MAO) inhibiting antidepressant clorgyline and pargyline on the sleep of affectively disordered patients were studied. Both inhibitors resulted in near total suppression of REM sleep, a decrease in total sleep time, and an increase in the percent of stage 2 sleep. Clorgyline also increased awake time and decreased total recording period and sleep latency. In general, changes were greater for clorgyline than for pargyline and were about 50% slower to return to baseline after clorgyline compared to pargyline discontinuation. The results were consistent with the hypothesis that selective inhibition of the MAO type A, as produced by clorgyline, is sufficient to induce marked sleep changes. MAO inhibitor-induced receptor changes are proposed to account for the time course of the REM suppression and the REM rebound observed upon withdrawal.

The relationship between changes in IV tyramine pressor sensitivity accompanying selective monoamine oxidase (MAO) inhibitor treatment and estimates of MAO-A and MAO-B inhibition in vivo were studied. Reductions in platelet MAO activity provided an index of MAO-B inhibition, while changes in plasma 3-methoxy-4-hydroxyphenethylene glycol (MHPG) were used as an hypothesized reflection of MAO-A inhibition. Chronic treatment with the MAO-A inhibitor clorgyline and the MAO-B inhibitor pargyline showed significant inhibition of the alternate MAO enzyme as well, although this crossover effect was greater for pargyline than clorgyline. The MAO-B inhibitor deprenyl appeared to maintain the greatest degree of MAO inhibition selectivity in vivo. Tyramine pressor sensitivity changes accompanying administration of the MAO inhibitors were highly correlated with decreases in plasma MHPG (r = 0.92), supporting our previous data indicating the rank order of clorgyline greater than pargyline greater than deprenyl for enhancement of tyramine pressor sensitivity and, thus, suggesting that tyramine potentiation is primarily a function of MAO-A rather than MAO-B inhibition. Changes in plasma MHPG are suggested to provide a potentially useful clinical index of in vivo MAO-A inhibition.

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.

Deprenyl, a monoamine oxidase (MAO) inhibitor with selective effects on MAO type-B at low doses, was administered to 13 patients with dementia of the Alzheimer type (DAT), a disorder reported to be associated with increased brain MAO-B activity. Cerebrospinal fluid was obtained for measurement of three monoamine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), by high pressure liquid chromatography with electrochemical detection. Deprenyl treatment (10 mg/day) for 3-4 weeks was associated with small but statistically significant reductions in HVA (21%) and 5-HIAA (15%) compared to baseline values. Subsequent administration of deprenyl at the higher dose of 40 mg/day for 3-4 more weeks led to greater reductions in HVA (40%) and MHPG (43%) than 5-HIAA (20%). These dose-dependent reductions are consistent with in vitro biochemical and anatomical data from primate brain suggesting that at low doses of deprenyl, MAO-B inhibition might be expected to selectively affect dopamine and serotonin-containing neurons, while at higher doses (which lead to MAO-A as well as MAO-B inhibition), noradrenergic neurons may become relatively more affected by the drug.

Ten patients with Alzheimer's disease and ten age-matched normal controls were studied in a double-blind, placebo-controlled acute trial of 1 mg PO lorazepam to test the effects of low-dose benzodiazepine on memory and behavior in a mostly older population. Cognitive effects differed somewhat between Alzheimer patients and normal controls, with Alzheimer patients revealing predominantly "attentional" impairments and age-matched controls showing possible "disinhibition." Specifically, Alzheimer patients made more omission errors on a continuous performance task, whereas controls made more commission and intrusion errors with lorazepam versus placebo. This low dose of lorazepam (1 mg), which was associated with mild but statistically significant sedation in both groups, also produced no significant decrease in recent memory or in access to semantic memory. These cognitive findings contrast markedly to the reported effects of scopolamine on recent memory; therefore, supporting the idea that cholinergic interruption has a more specific effect on human memory and on learning than that of low-dose benzodiazepines. Further studies with a wider dose range of benzodiazepines are necessary to evaluate the possibility of differential sensitivity between Alzheimer patients and normal elderly controls.

8 mg of naloxone were administered IV to 14 normal volunteers in a placebo-controlled, double-blind experiment. Plasma levels of beta-endorphin, cortisol, prolactin, growth hormone, HVA and MHPG were determined before and 45 min after administration. Naloxone elicited significant increases in cortisol and MHPG but did not change plasma levels of the other compounds. In an additional experiment on two subjects, 20 mg of naloxone caused elevations of beta-endorphin as well as of cortisol. This parallel increase indicates that the linkage between the secretion of beta-endorphin and ACTH/cortisol may be dose-dependent. The increase in MHPG is in agreement with the hypothesized association of noradrenergic hyperactivity and opiate withdrawal.

The enhanced sensitivity to the pressor effects of tyramine, an indirect-aging sympathomimetic found abundantly in the diet, is a well-known potentially dangerous side effect occurring during treatment with commonly used non-selective monoamine oxidase (MAO) inhibitors. The effects of treatment with the selective MAO-A inhibitor clorgyline and the partially selective MAO-B inhibitors pargyline and deprenyl on tyramine's pressor effects were studied in depressed patients using an IV steady-state tyramine infusion technique. After 4 weeks of treatment, clorgyline produced a significantly greater increase in tyramine sensitivity in comparison to a medication-free baseline (29-fold) than did pargyline (12-fold) or deprenyl (1.7-fold). The pressor effects of tyramine were significantly prolonged after cessation of infusion during both clorgyline and pargyline, but not deprenyl treatment. These data from IV tyramine administrations suggest that intestinal MAO inhibition is not the major determinant of the enhanced tyramine pressor sensitivity produced by clorgyline and pargyline.

A challenge paradigm was designed to test the functional sensitivity to anticholinergic agents in Alzheimer's disease. Ten patients with dementia of the Alzheimer type were serially administered three different intravenous doses of the centrally active anticholinergic drug scopolamine and placebo. Testing was carried out in a placebo-controlled, double-blind fashion to measure cognitive, physiologic and behavioral changes. Alzheimer patients showed a marked, dose-related behavioral and cognitive sensitivity to temporary cholinergic blockade. Scopolamine testing may serve as an index of the status of central cholinergic functional integrity, and ultimately may prove useful as a diagnostic or staging test in the evaluation of the cholinergic system in dementia. Research is currently under way with elderly age-matched controls and populations with other neuropsychiatric disorders to explore this hypothesis further.

Monoamine neurotransmitter systems, along with cholinergic systems, are known to play important roles in cognition, and are disrupted in at least some patients with dementia of the Alzheimer type (DAT). This suggests that monoamine-enhancing drugs might ameliorate cognitive symptoms in certain patients with DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor which may selectively inhibit MAO-B at low doses, while at high doses it nonselectively inhibits MAO-A as well as MAO-B. We studied its effects on several types of cognitive function in 17 patients with DAT. Two doses of L-deprenyl (10 mg/day and 40 mg/day) and placebo were compared in a double-blind, serial treatment design. Episodic learning and memory, knowledge memory, attention, recognition, and performance on a continuous performance task were assessed at baseline and under these drug and placebo conditions. Statistically significant improvement was noted in performance on an episodic memory and learning task requiring complex information processing and sustained conscious effort during treatment with L-deprenyl 10 mg/day. Knowledge memory, intrusions, and other cognitive functions relevant to DAT were not altered by L-deprenyl at either dose.