Contribution of development to buspirone effects on REM sleep: a preliminary report.

In order to assess whether development influences the regulation of rapid eye movement (REM) sleep by serotonergic (5-HT) systems, the REM sleep responses to the partial 5-HT(1A) agonist, buspirone, were assessed in 14 normal adolescent and adult volunteers. Subjects were studied on three separate sessions for three consecutive nights. On the second night of each session, subjects received placebo or one of two doses of buspirone (0.14 mg/kg and 0.28 mg/kg, orally). Night 3 was considered the "recovery" night. In adolescents, both doses of buspirone significantly delayed REM latency. In contrast, low-dose buspirone had no effect on REM latency in the adults, and there was only a tendency for prolongation of REM latency with the higher dose. Other measures of REM sleep on nights 2 and 3 were comparable between the two groups. These preliminary results suggest that post-synaptic 5-HT(1A) acceptor-coupled REM sleep responses, particularly REM latency, may be relatively greater in youngsters than in adults, possibly due to reduced presynaptic input. The findings are discussed in relation to the age-dependent expression of REM sleep changes associated with depression.

Relationship between ethnicity and sleep patterns in normal controls: implications for psychopathology and treatment.

The purpose of the study was to examine ethnic influences on sleep regulation. Seventy-three normal volunteers from four ethnic groups (17 African-Americans, 10 Asians, 30 Caucasians and 16 Hispanics) were studied for two consecutive nights with sleep polysomnography recordings in the laboratory. The subjects were in good physical and psychological health, and were asymptomatic with respect to sleep/wake complaints or sleep disorders. With the exception of minor differences, sleep continuity, sleep architecture and rapid eye movement (REM) sleep patterns were comparable among the four groups. African-Americans had evidence of more stages 1 and 2 and diminished stage 4 sleep, whereas the Hispanics had higher REM density. These preliminary findings suggest that sleep patterns are remarkably similar across cultures. There are, however, important cross-ethnic differences, specifically in the depth of sleep and in phasic REM measures. Because sleep disturbances are common symptoms of emotional disorders and since many psychoactive agents affect sleep, cross-ethnic differences in sleep patterns may have potential implications for the treatment and prevention of psychiatric disorders.

Brain N-acetyl aspartate concentrations measured by H MRS are reduced in adult male rats subjected to perinatal stress: preliminary observations and hypothetical implications for neurodevelopmental disorders.

The present study was undertaken to determine if the concentration of brain N-acetyl-aspartate (NAA), a putative neuronal marker, is reduced in adult rats subjected to stress during the perinatal period. As the prenatal stressor, pregnant rats were subjected to restraint stress for one hour twice daily from days 14-21 of gestation; stressed offspring were reared by normal dams and studied as adults. As the postnatal stressor, normal pups were reared by prenatally 'stressed' dams and studied as adults. As compared to non-stressed controls (n=6), NAA concentrations were significantly reduced 21 and 25% in left frontal cortex from the prenatal (n=4) and postnatal (n=6) stress groups. respectively. The data suggest that in perinatally stressed adult offspring permanent neuronal damage or loss has occurred. While no direct causal associations between perinatal stress and the developmental of particular disorders can be inferred from these limited data, the effects of perinatal stress on subsequent brain neuropathology are reviewed. particularly in relation to NAA. For hypothesis-generating purposes, the possible relevance of stress and NAA to the neurodevelopmental hypothesis of schizophrenia is discussed in greater detail.

Age-related effects of scopolamine on REM sleep regulation in normal control subjects: relationship to sleep abnormalities in depression.

In order to assess the influence of development on the regulation of rapid eye movement (REM) sleep by cholinergic systems, the REM sleep responses to scopolamine were assessed in five normal adolescent and seven adult control subjects in this preliminary investigation. Subjects were studied on two separate occasions for three consecutive nights. Subjects received placebo or scopolamine (1.5 ug/kg, i.m.) on night 2; night 3 was considered the "recovery" night. As expected, scopolamine delayed REM latency and suppressed REM sleep on night 2 in both the adolescents and adults. Subtle developmental differences occurred, with scopolamine having a tendency to suppress REM sleep less effectively in younger subjects. On night 3, REM latency was shortened and REM sleep was increased to comparable extent in both the adolescents and adults. The comparable REM sleep responses to scopolamine between normal adolescents and adults, particularly on night 3, are discussed in relation to the age-related expression of REM sleep abnormalities in depression.

REM sleep in depression is influenced by ethnicity.

The influence of ethnicity on the manifestation of EEG sleep changes in depression was studied in 95 patients (21 African-Americans [AA], 17 Asians [AS], 37 Caucasians [C] and 20 Hispanics [H]) with unipolar major depression. Subjects were studied twice for 2 consecutive nights. On the second night of each 2-night session, placebo or scopolamine (1.5 microg/kg, IM, at 23.00 h) was administered. On the baseline (placebo) night, sleep architecture, sleep continuity and rapid eye movement (REM) sleep variables were generally comparable among the groups. However, REM sleep was less in AA and AS subjects than in C and H subjects. Furthermore, the distribution of REM sleep over the course of the night in AA and AS subjects differed significantly from that in the C and H groups. Although scopolamine significantly affected sleep continuity and REM sleep measures, no significant differential effects of scopolamine were observed. Because many antidepressants suppress REM sleep, the differences in baseline REM sleep observed might be related to the greater sensitivity of some ethnic-minority depressed patients to pharmacotherapy.

Sleep electroencephalographic abnormalities in adolescent depressives: effects of scopolamine.

In contrast to sleep studies of adult depressives that have consistently demonstrated abnormalities of sleep continuity, slow-wave sleep, and REM sleep, existing studies of depressed children and adolescents have been conflicting. Furthermore, only one study has explored the cholinergic regulation of sleep in early-onset depressives. In the present study, the electroencephalographic sleep of 20 adolescent outpatients with major depressive episodes and 13 normal control adolescents was obtained on two separate 2-night sessions, 1 night incorporating challenge with scopolamine. Depressed adolescents showed increased baseline phasic REM sleep measures, increased arousals, a trend toward reduced slow-wave sleep, and a greater difference in the change of first REM period density on the scopolamine night versus placebo night compared to controls. These findings support the continuity of some sleep abnormalities of depression into adolescence, and suggest that adolescent depression may be associated with alterations of cholinergic neurotransmission in some patients.

Abnormal ACTH and prolactin responses to fenfluramine in rats exposed to single and multiple doses of MDMA.

The present study examined the persistent functional consequences associated with exposure to single and multiple doses of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) as reflected by the neuroendocrine responses to d,l-fenfluramine (FEN). Adult male rats were administered a single dose of MDMA (20 mg/kg, s.c.) and challenged 2 weeks later with saline or FEN (2, 4, 6 and 8 mg/kg, s.c.). The corticotropin (ACTH) response to FEN (6 and 8 mg/kg) was blunted and the prolactin response to FEN (4 and 6 mg/kg) was enhanced in MDMA pre-treated rats. The ACTH and prolactin responses to FEN (6 mg/kg, s.c.) were then evaluated 4, 8 and 12 months after exposure to single and multiple doses MDMA (20 mg/kg, s.c. and 20 mg/kg, s.c., bid, x 4 days, respectively). The ACTH response to FEN was significantly reduced at 4 and 8 months in both MDMA treatment groups, and at 12 months in the multiple dose group only. In contrast, the prolactin response to FEN was enhanced in both groups of MDMA treated rats at 4 months, but only in the multiple dose group at 8 months. By 12 months, the prolactin response to FEN had normalized. Following multiple doses of MDMA, 5-HT concentrations were reduced significantly in the frontal cortex at 4 and 12 months. The results indicate that exposure to single or multiple doses of MDMA can produce functional alterations which can persist for months, whereas the biochemical sequelae were less robust and shorter lived.

Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects.

The degree of cholinergic dysregulation of sleep in adult depression was evaluated using scopolamine. On separate sessions, placebo and scopolamine (4.5 micrograms/kg, IM) were administered to 14 patients with unipolar major depression, 16 recovered/remitted patients, and 18 normal controls. Scopolamine increased rapid eye movement (REM) latency (RL), reduced REM activity (RA), REM density (RD), and REM duration, and increased the percentage of stage 4 sleep in all groups. There was a differential effect of scopolamine on RL, RA, and REM duration for the first REM period, and on percentage of stage 4 sleep. Whereas a primary cholinergic hyperactivity could account for the RA and RD responses, the response profile for RL was more compatible with reduced aminergic tone as the proximal cause of the cholinergic hyperactivity. Whether the sleep abnormalities observed in remitted patients reflect an underlying vulnerability for development or recurrence of depression, and/or a scar, remains to be determined.

Exposure to threshold doses of nicotine in utero: III. Augmentation of the prolactin and ACTH response to 8-OH DPAT by desipramine treatment is compromised in adult male offspring.

Gravid female rats were injected subcutaneously with saline (SAL) or nicotine (3.0 mg/kg and 0.05 mg/kg, bid) from days 14-21 of gestation. Adult 105-day old male offspring from each of the three groups were treated daily with saline or desipramine (DMI) (10 mg/kg, sc) for 14 days. Twenty-four hours after the last injection, animals were challenged with saline or 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH DPAT) (0.1 mg/kg, sc), a serotonin IA(5-HT(IA)) agonist, and plasma prolactin and ACTH concentrations were measured 15 minutes later. DMI treatment augmented both the prolactin and ACTH responses to 8-OH DPAT in the SAL controls. Neither the prolactin nor the ACTH response was augmented significantly in the animals exposed prenatally to either nicotine dosage regimen, although there was a strong trend for the augmentation to occur in the low-dose nicotine exposed animals. The results indicate the capacity of 5-HT systems to adapt normally to DMI administration, as manifested by neuroendocrine responsivity to 8-OH DPAT, was compromised in adult animals exposed to nicotine in utero.

Prenatal stress prevents the desensitization of the corticosterone response to TFMPP by desmethylimipramine, but not by phenelzine, in adult male offspring.

Gravid female rats were subjected to one hour of restraint stress twice daily or left undisturbed from days 14-21 of gestation. Adult 105-day old male non-stressed (NS) and stressed (S) offspring were treated once daily with saline, desipramine (DMI) (10 mg/kg, sc) or phenelzine (5.0 mg/kg, sc) for 14 days. Twenty-four hours after the last injection, animals were challenged with saline or 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (5.0 mg/kg, sc), a serotonin1B/2C (5-HT1B/2C) agonist, and plasma prolactin and corticosterone concentrations were measured one hour later. As compared to acute saline administration, TFMPP significantly increased prolactin and corticosterone concentrations in all groups. In NS offspring, both DMI and phenelzine treatment augmented the prolactin response, but blunted the corticosterone response, to TFMPP. In S offspring, the prolactin response to TFMPP also was augmented by phenelzine or DMI treatment, whereas the corticosterone response to TFMPP was blunted during phenelzine treatment. However, DMI treatment was not able to desensitize the corticosterone response to TFMPP in the S rats. The results indicate the adaptive capacity of 5-HT systems to DMI administration was compromised in adult animals exposed to stress in utero.

Exposure to threshold doses of nicotine in utero: II. Neuroendocrine response to nicotine in adult male offspring.

Groups of gravid female rats were injected subcutaneously with saline (SAL), a low-dose of nicotine (LN) (0.05 mg/kg, bid) or a high-dose of nicotine (HN) (3.0 mg/kg, bid) from day 4 to day 20 of gestation, or were left undisturbed. In adult 120-day-old male offspring, the ACTH and prolactin responses to acute nicotine challenge were evaluated. The experiment was performed on three separate occasions. Based upon dose-response and time-course studies with nicotine in normal animals, the neuroendocrine responses to nicotine (0.75 and 1.0 mg/kg, sc) were measured 7.5 min after nicotine administration, the peak response-time for both hormones. The ACTH response to acute nicotine administration was blunted significantly in the HN rats, but normal in the LN rats, for all three experiments. In two experiments, the prolactin response to acute nicotine administration was blunted significantly in the HN rats, but enhanced significantly in the LN offspring. The results indicate that prenatal nicotine administration can produce long-term neuroendocrine effects involving nicotinic-receptor coupled circuits, with long-term functional sequelae produced by dosages of nicotine considerably smaller than previously shown to be pharmacologically/toxicologically active.

Exposure to threshold doses of nicotine in utero: I. Neuroendocrine response to restraint stress in adult male offspring.

Gravid female rats were injected subcutaneously with saline or nicotine (3.0 mg/kg and 0.05 mg/kg, bid) from day 4 to day 20 of gestation or were left undisturbed. In adult 120-day old male offspring, the ACTH, corticosterone and prolactin concentrations before, during (15, 30, 45 and 60 minutes) and after (30, 60, 90 and 120 minutes) one hour of restraint stress were studied. Baseline (non-stress) concentrations of each hormone were comparable among the groups. As compared to saline controls, ACTH concentrations were significantly higher during stress at 30 and 60 minutes in the high-dose nicotine (HN) animals, with the average ACTH concentration during stress also being significantly higher in the HN rats. Neither nicotine regimen affected the corticosterone response to stress at any time-point. The prolactin response to stress was significantly reduced in the HN group at 45 and 60 minutes as compared to saline controls, with the average prolactin concentration also reduced during stress. During recovery, average ACTH concentrations were significantly higher in the HN group, and significantly lower in the LN group, with no differences found for either corticosterone or prolactin. The results indicate that exposure to a high-dose of nicotine during gestation, and to a very low-dose as well, produced functional alterations in adult male offspring as manifested by abnormal neuroendocrine responses to restraint stress. However, the differences between the nicotine and saline controls were sometimes as great as between the non-injected controls and the saline controls. Thus, any conclusions drawn about the long-term effects of prenatal nicotine on neuroendocrine responsivity to stress must be tempered by the influence of the repeated injection procedure.

Effects of low-dose dexamethasone on sleep EEG patterns, plasma cortisol, and the TSH response to TRH in major depression.

Dexamethasone (DEX) (0.5 mg, P.O.) and placebo were administered at 2300 h in randomized design to 19 patients with major depression and the effects on the sleep electroencephalogram (EEG) were studied. In addition, the thyroid stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) and basal plasma cortisol concentrations were assessed the following morning. DEX did not affect sleep architecture or continuity variables, including rapid eye movement (REM) latency, REM activity and REM density. Similarly, DEX did not significantly influence the TSH response to TRH (delta max TSH). In contrast, plasma cortisol concentrations were significantly suppressed by DEX. The results indicate that, as opposed to higher dosages of glucocorticoids, 0.5 mg DEX had minimal effects on the sleep EEG or delta max TSH in depressed patients.

Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range.

OBJECTIVE: To examine the relationship between serum T levels and sexual function when T levels are varied in the normal male range by pharmacological means. Two groups of healthy men were treated with a depot form of GnRH agonist leuprolide acetate (Lupron depot; TAP Pharmaceuticals, Chicago, IL) on days 1 and 31 to suppress endogenous T production and either 4 (n = 6) or 8 (n = 5) mg/d T replacement by a sustained release, long-acting T microcapsule formulation on day 1. OUTCOME MEASURES: Sexual function was evaluated by daily logs of sexual activity and electroencephalogram-coupled nocturnal penile tumescence recording before and after 9 weeks of treatment. RESULTS: Serum T levels in 4 and 8 mg/d groups were at low and high ends of the normal male range, respectively (10.5 +/- 1.7 versus 26.5 +/- 3.4 nmol/L). The number and duration of rapid eye movement (REM) periods, latency to REM sleep, erections/REM period, magnitude, and duration of tumescence were not significantly different between the 4 and 8 mg groups. Sexual logs also did not show significant differences in overall scores or in subcategories of intensity of sexual feelings (libido) and sexual activity between the two doses. CONCLUSIONS: These data indicate that erectile function and sexual activity and feelings are restored by relatively low T levels. These data may help explain why some partially hypogonadal men continue to have normal sexual function and the absence of good correlation between serum T levels in the normal range and sexual function.

Relationship between REM sleep latency and nocturnal cortisol concentrations in depressed patients.

Due to conflicting reports on the possible association between shortening of rapid eye movement (REM) latency and increased cortisol secretion in patients with severe depression, this study examined the relationship between REM sleep latency and nocturnal cortisol concentration in 12 outpatients with major depression. The results showed a significant inverse correlation (r = -0.71, P < 0.01) between REM sleep latency and mean (23.00 hours-03.00 hours) plasma cortisol concentration. Age and severity of depression did not contribute to the inverse relationship. REM activity and density during the first REM period showed no significant correlations with the cortisol measures. A review of the literature suggests that this relationship might be unique to subjects with major depression, and again raises the possibility that these biological disruptions may have a common neurochemical basis.