Total sleep deprivation increases extracellular serotonin in the rat hippocampus.

Sleep deprivation exerts antidepressant effects after only one night of deprivation, demonstrating that a rapid antidepressant response is possible. In this report we tested the hypothesis that total sleep deprivation induces an increase in extracellular serotonin (5-HT) levels in the hippocampus, a structure that has been proposed repeatedly to play a role in the pathophysiology of depression. Sleep deprivation was performed using the disk-over-water method. Extracellular levels of 5-HT were determined in 3 h periods with microdialysis and measured by high performance liquid chromatography coupled with electrochemical detection. Sleep deprivation induced an increase in 5-HT levels during the sleep deprivation day. During an additional sleep recovery day, 5-HT remained elevated even though rats displayed normal amounts of sleep. Stimulus control rats, which had been allowed to sleep, did not experience a significant increased in 5-HT levels, though they were exposed to a stressful situation similar to slee-deprived rats. These results are consistent with a role of 5-HT in the antidepressant effects of sleep deprivation.

CYP2D6 polymorphism in a Mexican American population.

BACKGROUND: Pharmacogenetic data are largely unavailable for Mexican Americans, despite being one of the largest populations in America. METHODS: The CYP2D6 genotype (n = 349) and dextromethorphan hydroxylation phenotype (n = 285) were studied in 380 Mexican American subjects from Los Angeles County. RESULTS: The allelic frequency was 22.8% for CYP2D6*2, 10.3% for CYP2D6*4, 7.4% for CYP2D6*10, 2.3% for CYP2D6*5, 1% for CYP2D6*XN (duplication), and <1% for CYP2D6*3 and CYP2D6*17. By using the published antimode for Caucasians, we identified nine subjects as poor metabolizers, an incidence of 3.2%. Of the eight poor metabolizers who were also genotyped, five either were homozygous for the CYP2D6*4 allele (4 cases) or had a combination of CYP2D6*4 and CYP2D6*5 alleles. The mean log(10) dextromethorphan/dextrorphan ratio was -2.47 for those classified as extensive metabolizers. The number of functional alleles among the extensive metabolizers correlated strongly with the phenotype, suggesting a gene-dose effect. CONCLUSION: Compared with previous reports on Caucasian populations, studies show that Mexican Americans appear to possess a lower rate of CYP2D6*4. Frequencies for the other alleles appear to be less divergent between the two groups. This genotypic pattern might be responsible for the lower rate for the poor metabolizer status, as well as for the faster enzyme activity in the extensive metabolizer subjects that was also reflected in our data.

Analysis of the CYP2D6 gene polymorphism and enzyme activity in African-Americans in southern California.

Despite its importance in drug metabolism and disease susceptibility, CYP2D6 activity and genetic polymorphism have rarely been investigated in African-American populations. In order to bridge this gap, we examined the genotype and phenotype of the enzyme in 154 African-American (AA) and 143 Caucasian (C) normal volunteers. AAs are significantly more likely to possess *17 and *5, but less likely to have *4. Overall, the two groups were similar in their CYP2D6 activity as measured with dextromethorphan as the probe (metabolic ratio 2.21 +/- 0.78 for AAs; 2.11 +/- 0.86 for Cs; t = 1.02, NS). Two of four AAs and six of seven Cs were classified as poor metabolizers and have two nonfunctioning alleles. CYP2D6 activity is determined by *17, *4, *5 and age in AAs (r2 = 0.33, f = 18.8, P < 0.001) and by *4 and *XN in Cs (r2 = 0.14, f = 10.8, P < 0.001). These results support previous findings demonstrating the importance of *17 in determining CYP2D6 activity in AAs.

Pharmacokinetics of reboxetine in healthy volunteers with different ethnic descents.

RATIONALE: Ethnicity can affect the pharmacokinetics and pharmacodynamics of psychopharmacologic drugs. OBJECTIVES: Reboxetine disposition differences among Asians, blacks, and Caucasians were examined. METHODS: Healthy subjects (12 Asians, 12 blacks, 12 Caucasians) received a single oral dose of one 4-mg reboxetine tablet in an open label, parallel study design. Plasma concentrations of reboxetine enantiomers [R,R(-) reboxetine and predominantly active S,S(+) reboxetine] were quantified using HPLC-MS-MS. Plasma unbound fractions of reboxetine enantiomers were evaluated by equilibrium dialysis. Ethnic group effects on pharmacokinetic parameters were assessed by ANOVA. RESULTS: Mean S,S(+) reboxetine CLPO for blacks was significantly greater, compared to Asians and Caucasians (154+/-82 ml/min, 101+/-19 ml/min and 101+/-18 ml/min, respectively). Mean S,S(+) reboxetine free fractions (fu) were significantly greater for Asians and blacks, compared to Caucasians (3.04+/-1.28%, 2.89+/-0.69%, and 1.99+/-0.58%, respectively). S,S(+) Reboxetine unbound clearance (CLu) was significantly less for Asians, compared to blacks and Caucasians (3742+/-1468 ml/min, 5187+/-2027 ml/min, and 5294+/-1163 ml/min, respectively). S,S(+) Reboxetine mean unbound AUC (AUCu) in these groups were 20.2+/-7.1 ng.h/ml, 14.6+/-5.1 ng.h/ml, and 13.2+/-3.2 ng.h/ml, respectively. AUCu was significantly greater for Asians. CLu and AUCu did not differ significantly between blacks and Caucasians. Ethnic effects of R,R(-) reboxetine were similar to those observed for S,S(+) reboxetine. CONCLUSIONS: The AUCu difference between Asian and black and Caucasian subjects was modest. Tolerability differences among groups were not observed. No dosage adjustment is necessary for Asians or blacks.

Brain proton magnetic resonance spectroscopy and imaging in children exposed to cocaine in utero.

OBJECTIVE: The effects of prenatal cocaine exposure have been examined using neurobehavioral and brain structural evaluations; however, no study has examined the effects of prenatal cocaine on brain metabolism. Proton magnetic resonance spectroscopy ((1)H-MRS) is a noninvasive method to examine the biochemistry of various brain regions. The purpose of this study was to examine the possible neurotoxic effects of prenatal cocaine exposure on the developing brain using (1)H-MRS. METHODS: Cocaine-exposed children (n = 14) and age-matched unexposed control participants (n = 12) were evaluated with MRI and localized (1)H-MRS. Metabolite concentrations of N-acetyl-containing compounds (NA), total creatine (Cr), choline-containing compounds, myoinositol, and glutamate + glutamine were measured in the frontal white matter and striatum. RESULTS: Despite an absence of structural abnormalities in either group, children exposed to cocaine in utero had significantly higher Cr (+13%) in the frontal white matter. NA, primarily a measure of N-acetyl aspartate and neuronal content, was normal in both regions examined by (1)H-MRS. Normal NA suggests no significant neuronal loss or damage in the 2 brain regions examined in children exposed to cocaine prenatally. CONCLUSIONS: Consistent with findings in abstinent adult cocaine users, we found increased Cr in the frontal white matter, with normal NA in children exposed to cocaine. These findings suggest the need to investigate further possible abnormalities of energy metabolism in the brain of children exposed to cocaine in utero. In addition, this study demonstrates the feasibility of using (1)H-MRS to investigate the effects of prenatal drug exposure on the developing brain.

Effect of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study.

3,4-methylenedioxymethamphetamine (MDMA), an illicit recreational drug, damages serotonergic nerve endings. Since the cerebrovasculature is regulated partly by the serotonergic system, MDMA may affect cerebral blood flow (CBF) in humans. We evaluated 21 abstinent recreational MDMA users and 21 age- and gender-matched healthy subjects with brain SPECT and MRI. Ten of the MDMA subjects also had repeat SPECT and MRI after receiving two doses of MDMA. Abstinent MDMA users showed no significantly different global or regional CBF (rCBF) compared to the control subjects. However, within 3 weeks after MDMA administration, rCBF remained decreased in the visual cortex, the caudate, the superior parietal and dorsolateral frontal regions compared to baseline rCBF. The decreased rCBF tended to be more pronounced in subjects who received the higher dosage of MDMA. Two subjects who were scanned at 2-3 months after MDMA administration showed increased rather than decreased rCBF. Low-dose recreational MDMA use does not cause detectable persistent rCBF changes in humans. The lack of long-term rCBF changes may be due to a non-significant effect of serotonergic deficits on rCBF, or regeneration of serotonergic nerve terminals. The subacute decrease in rCBF after MDMA administration may be due to the direct effect of MDMA on the serotonergic system or the indirect effects of its metabolites on the dopaminergic system; the preliminary data suggest these effects may be transient.

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.

Comparison of noncontingent versus contingent cocaine administration on plasma corticosterone levels in rats.

The purpose of the present study was to compare the effects of contingent and noncontingent cocaine administration on plasma levels of corticosterone in rats. Male rats were trained to self-administer cocaine under a fixed-ratio 5 schedule. The rats were yoked such that the delivery of cocaine (0.25 mg/kg/infusion) to one rat (contingent cocaine) produced the simultaneous noncontingent delivery of the same dose of cocaine (noncontingent cocaine) or saline (noncontingent saline) to other rats. Although saline administration had no effect, plasma corticosterone levels were significantly higher in rat receiving contingent cocaine compared to those receiving noncontingent cocaine. These results demonstrate that the active vs. passive administration of cocaine can differentially affect this neuroendocrine response.

Effect of cigarette smoking on coumarin metabolism in humans.

Extant data, mostly from studies in vitro, suggest that coumarin and nicotine are both metabolized by CYP2A6, a cytochrome P450 isozyme. In order to investigate this issue further, the activity of this enzyme in vivo was measured in 37 non-smokers and 37 smokers using coumarin (2.0 mg, PO) as the metabolic probe. The percentage of coumarin metabolized to 7-hydroxycoumarin in 8 h was measured in urine by high-pressure liquid chromatography. There was more than 10-fold variability in coumarin metabolism in both groups. Coumarin metabolism was significantly reduced in smokers (46.6 +/- 4.4%) as compared to non-smokers (66.4 +/- 3.5%; p < or = .001). The results support previous in vitro findings that both coumarin and nicotine are metabolized, at least in part, by a common pathway, which most likely is CYP2A6.

Prenatal stress is associated with depression-related electroencephalographic sleep changes in adult male rats: a preliminary report.

1. Prenatal stress in rats has been shown to produce long-term behavioral, neuroendocrine and neurochemical changes. These changes may model aspects of human depressive illness. 2. In this pilot investigation, adult male offspring exposed to stress in utero and non-stressed controls were studied using 24-hour electroencephalographic sleep recordings. 3. Prenatally stressed animals demonstrated reduced latency to the onset of rapid eye movement (REM) sleep, prolongation of the first REM episode, and diminished slow-wave sleep. 4. Although preliminary, the observed changes parallel those seen in studies of human depression. These data further support the face validity of the prenatal stress model as a potential tool for future studies on the pathophysiology of depressive disorder.

Cerebral (1)H MRS alterations in recreational 3, 4-methylenedioxymethamphetamine (MDMA, "ecstasy") users.

3,4-methylenedioxymethamphetamine (MDMA) is an illicit drug that has been associated with serotonergic axonal degeneration in animals. This study evaluates neurochemical abnormalities in recreational MDMA users. Twenty-two MDMA users and 37 normal subjects were evaluated with magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) in the mid-frontal, mid-occipital, and parietal brain regions. (1)H MRS showed normal N-acetyl (NA) compounds in all brain regions. The myo-inositol (MI) concentration (+16.3%, P = 0.04) and the MI to creatine (CR) ratio (+14.1%, P = 0. 01) were increased in the parietal white matter of MDMA users. The cumulative lifetime MDMA dose showed significant effects on [MI] in the parietal white matter and the occipital cortex. The normal NA concentration suggests a lack of significant neuronal injury in recreational MDMA users. However, the usage-related increase in MI suggests that exposure to MDMA, even at recreational doses, may cause increased glial content. J. Magn. Reson. Imaging 1999;10:521-526.

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.

Pharmacokinetics of Hoasca alkaloids in healthy humans.

N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such 'teas' has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine's.

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.

Proton spectroscopy in myotonic dystrophy: correlations with CTG repeats.

OBJECTIVES: To seek cerebral metabolite abnormalities in patients with myotonic dystrophy and to determine whether the degree of cerebral abnormalities (measured by proton magnetic resonance spectroscopy) correlates with severity of the genetic defect (measured by trinucleotide repeats). DESIGN: Fourteen patients with myotonic dystrophy were compared with 24 healthy control subjects. SETTING: A university-affiliated medical center. RESULTS: Compared with healthy subjects, patients with myotonic dystrophy had elevated levels of myoinositol (+19% in the occipital region and +12.9% in the temporoparietal region), total creatine (+7.6% and +6.8%), and choline-containing compounds (+21% and +7.7%). Furthermore, the creatine and myoinositol peak areas correlated with the number of trinucleotide cytosine-thymine-guanine(n) (CTG)n repeats from leukocytes, especially in the temporoparietal brain region (r=0.76; P=.004). CONCLUSIONS: Neurochemical alterations observed with proton magnetic resonance spectroscopy are proportional to the cytosine-thymine-guanine repeat size. Increases in myoinositol and creatine concentrations may be caused by increased glial content, while elevated levels of choline-containing compounds are most likely caused by increased glial content and cell membrane abnormalities. Proton magnetic resonance spectroscopy is a powerful noninvasive tool to study brain biochemistry, which may reflect the extent of neuropathological involvement in patients with myotonic dystrophy.

Genetic polymorphism of CYP2E1, ADH2, and ALDH2 in Mexican-Americans.

The major enzymes involved in the metabolism of ethanol are alcohol dehydrogenases (ADH) and aldehyde dehydrogenase (ALDH). Some of the isozymes of ADH are expressed polymorphically. Studies investigating a causal link between ADH expression and alcoholic liver disease (ALD) have so far produced conflicting results. The cytochrome P450 2E1 (CYP2E1) represents a second enzyme that can metabolize ethanol. Although normally a minor route of metabolism, its role in chronic alcoholics may be proportionately greater than in nonalcoholics because CYP2E1 is inducible by ethanol. An Rsa I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified. Studies have shown that the mutant allele demonstrates greater transcriptional rate, protein level, and enzyme activity when compared with the wild-type allele. The association between the Rsa I site polymorphism and ALD has been reported. In this report, we examined the genotypes of ADH2(2), ALDH2(2), and CYP2E1 in a group of healthy subjects of Mexican-American descent. The ADH2(2) and ALDH2(2) frequencies are 6% and 0%, respectively, which are similar to those which have been reported for Caucasians. In contrast, the Rsa I allele frequency of the CYP2E1 gene is 16%, which is significantly higher than in Caucasians. The high RsaI allele frequency found in Mexican-Americans suggests that it might play a role in the development of ALD in this rapidly growing minority population where ALD is common.