Neuroscience findings in AIDS: a review of research sponsored by the National Institute of Mental Health.

1. The human immunodeficiency virus (HIV-1) infects cells in both the immune system and the brain, but these effects are not independent. 2. Research funded by the National Institute of Mental Health (NIMH) has been directed at identifying some of the mechanisms by which HIV-1 infects the brain, produces pathology, causes behavioral changes, and alters immune responses. 3. HIV-1-associated peptides have been shown to produce immunological changes without active virus present and there is also evidence that neurological damage may result not from direct viral action, by via excitotoxin production. 4. Rhesus macaque monkeys infected with simian immunodeficiency virus (SIV) are proving to be a useful model of the neurological and behavioral changes identified in human AIDS patients; behavioral changes observed in monkeys are similar to those seen in humans infected with HIV-1. 5. Studies examining the relationship between the brain and immune system are identifying the role that the macrophage cytokine interleukin-1 may play in suppressing T-lymphocyte activity by two pathways, both mediated by corticotropin releasing factor (CRF). 6. One pathway involves the pituitary-adrenal axis and release of glucocorticoids while the other involves direct interaction with the sympathetic noradrenergic nervous system, which has been shown to innervate T-lymphocytes in the spleen and thymus. 7. These observations are relevant because macrophages infected with HIV-1 infiltrate the brain and may release substances that damage the brain. 8. Stress may affect these pathways via the CRF-mediated release of glucocorticoids; a model of stress has also demonstrated that stress can suppress the cellular immune response.

Plasma amine oxidase activities in Norrie disease patients with an X-chromosomal deletion affecting monoamine oxidase.

Two individuals with an X-chromosomal deletion were recently found to lack the genes encoding monoamine oxidase type A (MAO-A) and MAO-B. This abnormality was associated with almost total (90%) reductions in the oxidatively deaminated urinary metabolites of the MAO-A substrate, norepinephrine, and with marked (100-fold) increases in an MAO-B substrate, phenylethylamine, confirming systemic functional consequences of the genetic enzyme deficiency. However, urinary concentrations of the deaminated metabolites of dopamine and serotonin (5-HT) were essentially normal. To investigate other deaminating systems besides MAO-A and MAO-B that might produce these metabolites of dopamine and 5-HT, we examined plasma amine oxidase (AO) activity in these two patients and two additional patients with the same X-chromosomal deletion. Normal plasma AO activity was found in all four Norrie disease-deletion patients, in four patients with classic Norrie disease without a chromosomal deletion, and in family members of patients from both groups. Marked plasma amine metabolite abnormalities and essentially absent platelet MAO-B activity were found in all four Norrie disease-deletion patients, but in none of the other subjects in the two comparison groups. These results indicate that plasma AO is encoded by gene(s) independent of those for MAO-A and MAO-B, and raise the possibility that plasma AO, and perhaps the closely related tissue AO, benzylamine oxidase, as well as other atypical AOs or MAOs encoded independently from MAO-A and MAO-B may contribute to the oxidative deamination of dopamine and 5-HT in humans.

Intravenous physostigmine increases cerebrospinal fluid neuropeptide-Y.

The ability to measure directly central nervous system (CNS) neurotransmitter changes after an acute pharmacological challenge would be a useful clinical tool in psychiatric research. As one approach to this possibility, we attempted to measure cerebrospinal fluid (CSF) neuropeptide changes produced by an intravenous infusion of the indirect cholinergic agonist physostigmine. Six rhesus monkeys, with indwelling CSF catheters, had serial CSF samples removed before and after a 15 micrograms/kg physostigmine infusion. Five of six monkeys studied showed at least a 50% increase in CSF neuropeptide-Y (NPY) levels. Normal human subjects (n = 27) had CSF sampled before and 15, 30, and 45 min after an acute intravenous infusion of physostigmine (either 0, 5, or 15 micrograms/kg). An Analysis of Variance revealed a significant (p = 0.04) dose-time interaction, suggesting that physostigmine increased CSF NPY at the 15 micrograms/kg dose. CSF levels of seven other neuropeptides remained unchanged. These results suggest that the pharmacological challenge paradigm can be adapted to CSF neuropeptides, providing new measures of CNS stimulus-induced response beyond the peripheral plasma determinations usually employed.

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the dog: effect of pargyline pretreatment.

Adult beagle dogs of either sex were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-HCl (2.5 mg/kg, i.v.) alone or after pretreatment with pargyline (5.0 mg/kg, s.c., twice), with pargyline alone, or were uninjected. Groups were killed 2 h, 3 weeks, or 3 months after injection, and several brain areas were assayed for biogenic amines and their synthetic and degradative enzymes. MPTP caused a massive and permanent loss of striatal dopamine, tyrosine hydroxylase, and 3,4-dihydroxyphenylalanine decarboxylase activities and the loss of cells within the substantia nigra pars compacta. Dopamine and norepinephrine also were depleted to various degrees in cortex, olfactory bulb, and hypothalamus; however, dopamine beta-hydroxylase activity in cortex was normal. There was no cell loss in the ventral tegmental area or locus ceruleus. The activities of monoamine oxidase (MAO)-A and MAO-B in cortex and caudate were not affected by MPTP. Despite a permanent loss of the nigrostriatal system, the dogs exhibited only a transient hypokinesia lasting 1-2 weeks. Pargyline pretreatment prevented the loss of striatal dopamine and cells from the substantia nigra, but did not prevent a prolonged but reversible decrease in the concentration of dopamine metabolites. It is argued that this apparent inhibition of MAO is due not to suicide inactivation of the enzyme by MPTP, but to reversible inhibition by accumulation of the pyridinium metabolite, 1-methyl-4-phenylpyridinium, selectivity in aminergic terminals.

Effects of xylazine on cerebrospinal fluid catecholamines in the rhesus monkey.

The i.v. administration of xylazine, a potent, selective alpha 2-adrenergic receptor agonist, resulted in a 76% decrease in cerebrospinal fluid (CSF) norepinephrine in chair-adapted rhesus monkeys. A significant decrease was observed within 1.5 h of administration and continued through the 3 h course of sampling. Dopamine was maximally decreased by 24% at 1.5 h. Epinephrine was not significantly decreased following xylazine administration. These data suggest that norepinephrine release into monkey CSF, as an index of central or peripheral norepinephrine turnover, is more sensitive to alpha 2-adrenergic agonists than in CSF dopamine or epinephrine.

Effects of fenfluramine, m-chlorophenylpiperazine, and other serotonin-related agonists and antagonists on penile erections in nonhuman primates.

Fenfluramine, m-chlorophenylpiperazine (m-CPP), 1-phenylpiperazine, and the buspirone metabolite, 1-(2-pyrimidyl)piperazine given intravenously to adult rhesus monkeys regularly elicited penile erections. In contrast, serotonin (5-HT) agonists with 5-HT1A site specificity (8-OH-DPAT, buspirone) as well as trazodone, ritanserin, and metergoline were no different from saline in producing penile erections. Fenfluramine's effects were blocked by the 5-HT2 antagonists, ritanserin and metergoline, while m-CPP's effects were not blocked by the peripheral 5-HT antagonist, xylamidine, indicating that tumescence can be elicited by serotonergic agents which act at non-5-HT1A sites in the central nervous system.

Corticotropin-releasing factor: a marked circadian rhythm in primate cerebrospinal fluid peaks in the evening and is inversely related to the cortisol circadian rhythm.

Continuous sampling of cerebrospinal fluid (CSF) over 24-h periods in 10 rhesus monkeys revealed a 2-fold, highly reproducible circadian rhythm in CRF concentrations. Peak CRF values of 77.9 +/- 6.4 pg/ml occurred in the evening at 1930 h, while the CRF nadir (38.4 +/- 4.2 pg/ml) occurred at 0745 h. Simultaneously sampled CSF cortisol peaked at 0913 h, with a nadir at 2226 h. Both CRF and cortisol rhythms closely fit sinusoidal circadian models, with r2 values of 0.94 and 0.92, respectively. While hypothalamic CRF is regarded as a major physiological regulator of pituitary ACTH secretion and, thereby, of the circadian and stress-related release of cortisol from the adrenal gland, CRF and CRF receptors are also widely distributed in other brain areas of primates and rodents. The marked difference in the circadian rhythm of CRF vs. that of cortisol suggests that CRF in CSF reflects or mediates some nonhypophysiotropic brain functions of this peptide.

Marked enhancement by clorgyline of nocturnal and daytime melatonin release in rhesus monkeys.

The type A monoamine oxidase (MAO)-inhibiting antidepressant clorgyline (1 mg/kg/24 days) administered to rhesus monkeys increased night-time cerebrospinal fluid (CSF) melatonin concentrations 3-fold and day-time maltonin values 5-fold. Other circadian parameters of melatonin release, including the peak time and duration of nocturnal melatonin elevation measured during continuous CSF collection periods of 90 min duration over 24-h cycles, were unaffected by clorgyline. While pinealocytes are thought to contain only MAO-B, treatment with the selective MAO-B inhibitor deprenyl (2 mg/kg/24 days) did not alter day or night-time melatonin concentrations. These results are consistent with MAO-A and non-selective MAO inhibitors acting via blockade of degradation of the preferential substrates of MAO-A, serotonin and/or norepinephrine, in adrenergic neurons entering the pineal gland. Further study is needed to evaluate the relative contributions of an increased availability of the melatonin precursor, serotonin, or a sustained net increase in alpha 1-or beta adrenoceptor-mediated input on pinealocytes to these marked changes in melatonin production.

Use of serotonergic agents in the clinical assessment of central serotonin function.

To assess the status of the brain serotonergic system in relation to ongoing behavior, agents with predominant actions on serotonin synthesis, release, uptake, and receptor mechanisms are being evaluated. Abnormalities in the neuroendocrine responses to tryptophan, 5-hydroxytryptophan, fenfluramine, and m-chlorophenylpiperazine are under exploration in depressed patients. These agents are also being used to assess postulated changes in serotonin metabolism and serotonin receptor adaptation during longer term treatment with antidepressant drugs, lithium, and other psychoactive agents. Concurrent studies in rodent and nonhuman primate models are helping to validate these approaches to the exploration of the role of serotonin in psychiatric and neurologic disorders.

Human plasma melatonin is elevated during treatment with the monoamine oxidase inhibitors clorgyline and tranylcypromine but not deprenyl.

Melatonin was measured in plasma collected between 8:00 and 8:30 a.m. from 27 depressed patients studied before and after 21- to 24-day treatment with three monoamine oxidase (MAO) inhibitors. Baseline plasma melatonin concentrations determined by radioimmunoassay were 4.0 +/- SD 4.7 pg/ml. Tranylcypromine, a nonselective MAO inhibitor given in doses of 20-40 mg/day for 3 weeks, significantly elevated plasma melatonin to 10.6 +/- SD 2.0 pg/ml. Clorgyline, given in doses of 15-30 mg/day for 3 weeks, produced a significant, approximately three-fold increase in plasma melatonin (13.6 +/- SD 13.5 pg/ml). This clorgyline dose was selective for MAO type A inhibition, as MAO-B activity measured in platelets from the same blood samples was unaffected by clorgyline. In contrast, the selective MAO-B inhibitor deprenyl (10-30 mg/day for 3 weeks) led to a 96 +/- 4% inhibition of platelet MAO-B activity but no significant change in plasma melatonin (5.1 +/- SD 4.2 pg/ml). As both serotonin and norepinephrine are preferentially metabolized by MAO-A rather than MAO-B, an increased availability of serotonin (the precursor of melatonin) or enhanced noradrenergic function might mediate the melatonin changes observed to follow MAO-A but not MAO-B inhibition.

Effects of antidepressants and other psychotropic drugs on melatonin release and pineal gland function.

Antidepressants and some other psychotropic drugs affect the synthesis and release of melatonin through several mechanisms. Monoamine oxidase (MAO)-inhibiting antidepressants increase pineal concentrations of the melatonin precursors, serotonin (5-HT) and N-acetyl serotonin (NAS), in rodents, and also increase pineal N-acetyl transferase activity as well as both daytime and nighttime plasma melatonin concentrations; they also elevate melatonin, 5-HT and NAS in the cerebrospinal fluid of non-human primates. In humans treated with the MAO-A selective inhibitor, clorgyline, or the nonselective inhibitor, tranylcypromine, increased plasma melatonin also occurs; in contrast, the MAO-B selective inhibitor, 1-deprenyl, does not affect plasma melatonin. Chronically-administered tricyclic antidepressants with prominent effects on monoamine uptake and on beta-adrenoceptors reduce pineal and plasma melatonin in rodents; however, in two studies in depressed patients, either no change or a significant elevation in nocturnal plasma melatonin followed 3 to 4 weeks treatment with desipramine. As depressed patients in these and several other recent studies had lower pretreatment nighttime melatonin peaks than controls, these findings may be relevant to the presynaptic and receptor adaptational consequences of chronic antidepressant drug treatment. The significant effects on melatonin of other drugs which affect monoamine function and have psychotropic effects, including lithium, propranolol, amphetamine and several monoamine precursors, together with recent observations of the existence of muscarinic and benzodiazepine receptors in the pineal gland are in accord with previous suggestions that the study of pineal function and melatonin production provides a valuable model system for psychopharmacological investigations.

How antidepressants work: cautionary conclusions based on clinical and laboratory studies of the longer-term consequences of antidepressant drug treatment.

Time-dependent alterations in the functional activity of adrenergic and serotonergic neurotransmitter systems and, in particular, a frequently observed down-regulation of brain beta-adrenoceptors have been implicated in antidepressant drug effects. Current studies of catecholamine and serotonin neurotransmitter systems suggest that the net physiological output changes in neuroendocrine responses, blood pressure, sleep and motor activity which follow various antidepressant treatments in psychiatric patients, normal controls and different experimental animals are not indicative of a common response pattern to all therapeutically effective agents. Rather, antidepressant treatment effects differ according to many variables, including the pre-existing state of the organism (e.g. depressed, stressed or normal), the species, the duration of treatment and the particular brain or peripheral circuits investigated. Examples are cited from our studies of the effects of monoamine oxidase inhibitors and other antidepressants on noradrenergic-serotonergic interactions that affect melatonin release and other neuroendocrine responses, on some additional functional end-points, and on depressive mood and other symptoms in patients with depression or other tricyclic-responsive disorders. These examples illustrate the complexity found in attempts to identify a unitary mechanism of antidepressant drug action.

The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey.

Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.

Rhesus monkey cerebrospinal fluid amine metabolite changes following treatment with the reversible monoamine oxidase type-A inhibitor cimoxatone.

The effects of cimoxatone, a reversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine, and serotonin were examined in continuously collected rhesus monkey cerebrospinal fluid (CSF). Cimoxatone, 0.5-8 mg/kg given PO, produced dose-proportionate reductions of 24-h mean CSF 3-methoxy, 4-hydroxy phenylglycol (MHPG) concentrations of 21%-52%. Homovanillic acid (HVA) concentrations also decreased 27%-55%, while CSF 5-hydroxyindoleacetic acid (5-HIAA) decreases were somewhat smaller (7%-32% from baseline). All three metabolite concentrations reached a nadir approximately 6-10 h after drug administration, and required over 40 h to gradually return towards baseline following drug discontinuation. HVA concentration reductions in particular persisted during the entire 24-h period following treatment and were the slowest to return to baseline values. CSF concentrations of cimoxatone and its MAO-inhibiting O-demethyl metabolite showed a parallel time course, peaking 6-10 h after treatment and persisting for up to 24 h in the case of cimoxatone and over 48 h for its metabolite. Single simultaneous time point determinations revealed 10-to 20-fold lower concentrations of cimoxatone and its metabolite in CSF compared to plasma 2 h after treatment. MAO-B activity in platelet-rich plasma was not inhibited by 8 mg/kg cimoxatone, indicating that this drug maintains MAO-A selectivity in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain and liver monoamine oxidase type A and type B activity in alcoholics and controls.

Monoamine oxidase activity in human postmortem brain and liver samples was measured in a group of patients with a prior history of alcoholism and compared to a control group with no prior history of alcoholism. Liver samples from patients with a prior history of alcoholism showed significantly lower monoamine oxidase activity with both phenylethylamine and serotonin as substrates. Postmortem brain samples, however, were not different in the two groups.

New contributions from basic science to understanding the effects of monoamine oxidase inhibiting antidepressants.

Recent studies have provided almost conclusive evidence for the existence of the two separate MAO isozymes previously postulated to exist on the basis of indirect evidence. Important differences in the proportions and distribution of these two enzyme forms across species and in various tissues are responsible for some puzzling anomalies in earlier studies and contribute to differences in behavioral responses, blood pressure changes, and toxic responses to tyramine and other sympathomimetic agents. Substrate-selective, irreversible inhibitors, as well as several new classes of reversible MAO-A and MAO-B selective inhibitors, may provide a spectrum of clinical effects different from the nonselective irreversible MAO inhibitors.

Differential effects of clorgyline on catecholamine and indoleamine metabolites in the cerebrospinal fluid of rhesus monkeys.

The effects of acute and chronic administration of clorgyline, an irreversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine and serotonin were examined in rhesus monkey cerebrospinal fluid (CSF). Acute clorgyline treatment resulted in highly significant, dose-dependent reductions in 3-methoxy-4-hydroxyphenylglycol (MHPG) of 50% (1 mg/kg) and 68% (2 mg/kg) compared to pretreatment values. Chronic clorgyline administration (0.25 to 0.5 mg/kg X 24 days) resulted in a 67% reduction in CSF MHPG. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were less affected by acute clorgyline administration, being reduced significantly only after the 2 mg/kg dose, which lowered 5-HIAA 27% and HVA 48%. Chronic clorgyline treatment had no significant effect on the CSF concentrations of HVA and 5-HIAA. These data, which suggest that MAO-A inhibition by clorgyline in vivo is more closely associated with changes in the noradrenergic than the serotonergic or dopaminergic systems in nonhuman primates, are in general agreement with the effects of clorgyline on CSF and urinary biogenic amine metabolites in man. They differ from several in vitro studies which indicate a primary role of MAO-A in the metabolism of serotonin and of MAO-B in norepinephrine degradation in primate brain. The discrepancies may reflect modulating effects of synaptic feedback mechanisms on the actions of clorgyline in vivo or perhaps a failure of CSF metabolites to adequately reflect brain amine metabolism changes. The lack of change in platelet MAO-B activity during clorgyline treatment together with the minimal changes in HVA concentrations indicate that the selective inhibitory effects of clorgyline on MAO-A were maintained during chronic administration of low drug doses.

Effect of clorgyline (a MAO type A inhibitor) on locomotor activity in the Syrian hamster.

Syrian hamsters in a lighting schedule of 14 h of light per day (LD 14:10) and housed in cages equipped with running wheels exhibited a clear onset of locomotor activity during the 1st h after lights off. Implantation of osmotic minipumps containing clorgyline (2 mg . kg-1 . day-1), an irreversible inhibitor of monoamine oxidase type A, caused a 1.5-h delay in the onset of wheel running by the 7th day of treatment. Increasing dosages of clorgyline (0.5, 1, 2, or 4 mg . kg-1 . day-1) caused increasing delays. Hamsters shifted from LD 14:10 to LD 10:14 underwent a 3-h advance in the onset of wheel running. Animals treated with clorgyline (2 mg . kg-1 . day-1) exhibited a markedly slowed rate of advance in activity onset, which did not prevent the short photoperiod from inhibiting reproductive function. Additionally, removal of the pineal gland did not affect wheel-running onset and did not prevent the delay in activity onset during clorgyline treatment. Hamsters in LD 14:10 were "released" into constant darkness (DD) for 3 days to prevent masking of activity onsets and offsets by light. Delays in activity onset in LD 14:10 caused by clorgyline (2 mg . kg-1 . day-1) persisted when these animals were released into DD. Activity offset in LD 14:10 occurred at lights on before and during clorgyline treatment but was delayed when the treated animals were maintained in DD. Drug-induced delays in both activity onset and offset suggest that clorgyline is not simply shortening the duration of activity or changing the expression of activity relative to the light-dark cycle, but is delaying the phase position of the circadian rhythm in locomotor activity. Clorgyline may act directly on the central oscillatory mechanism that drives the rhythm.