Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503

SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG > (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity.     

Monoamines and seizures: microdialysis findings in locus ceruleus and amygdala before and during amygdala kindling

We used microdialysis to determine extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) before and during a 1-day amygdala kindling paradigm. Subjects were young cats (<1 year old; n=8; 6 female, 2 male). Consecutive 5-min samples (2 microl/min infusion rate) were obtained from left amygdala and ipsilateral locus ceruleus complex (LC) under 3 experimental conditions lasting 1-h each (n=12 samples per cat per condition): (1) just before amygdala stimulation (baseline), (2) during focal afterdischarge (AD) and (3) during generalized AD. ADs were elicited by electrical stimulation applied to establish thresholds immediately before dialysate collection as well as during each sample collected in focal vs. generalized AD conditions. Sample concentrations were time-adjusted to correspond with sleep vs. waking state and/or focal vs. generalized ADs. Seizure activity was indexed by AD threshold (mA) and duration (s) as well as number and duration of specific clinically evident (behavioral) seizure manifestations. Main results were: (1) Lower baseline concentrations (fmoles per sample) of NE, DA and 5-HT correlated with subsequent increases in duration of focal and generalized AD as well as number of behavioral seizure correlates. (2) When compared to baseline levels, NE, DA and 5-HT concentrations significantly increased only in amygdala during focal AD and in both amygdala and LC during generalized AD. (3) NE and 5-HT concentrations were higher than DA at both collection sites and were selectively associated with increased wakefulness throughout the study.     

Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.     

Expression and regulation of cholecystokinin and cholecystokinin receptors in rat nodose and dorsal root ganglia

Cholecystokinin (CCK) is an important satiety factor, acting via the vagus nerve to influence central feeding centers. CCK binding sites have been demonstrated in the vagal sensory nodose ganglion and within the nerve proper. Using in situ hybridization, expression of the CCK(A) and (B) receptors (Rs), as well as of CCK itself, was studied in the normal nodose ganglion (NG), and after vagotomy, starvation and high-fat diet. CCK(A)-R mRNA expression in dorsal root ganglia (DRGs) was also explored. In the NG, 33% of the neuron profiles (NPs) contained CCK(A)-R mRNA and in 9% we observed CCK(B)-R mRNA. CCK mRNA was not found in normal NGs. Peripheral vagotomy decreased the number of CCK(A)-R mRNA-expressing NPs, dramatically increased the number of CCK(B)-R mRNA, and induced CCK mRNA and preproCCK-like immunoreactivity in nodose NPs. No significant differences in the number of NPs labelled for either mRNA species were detected following 48 h food deprivation or in rats fed a high-fat content diet. In DRGs, 10% of the NPs expressed CCK(A)-R mRNA, a number that was not affected by either axotomy or inflammation. This cell population was distinct from neurons expressing calcitonin gene-related peptide mRNA. These results demonstrate that the CCK(A)-R is expressed by both viscero- and somatosensory primary sensory neurons, supporting a role for this receptor as a mediator both of CCK-induced satiety and in sensory processing at the spinal level. The stimulation of CCK and CCK(B)-R gene expression following vagotomy suggests a possible involvement in the response to injury for these molecules.     

Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus

Iodine is essential for the synthesis of triiodothyronine (T(3)) and thyroxine (T(4)). Iodine deficiency leads to inadequate thyroid hormone. Thyroid hormones deficiency during brain development affects cognitive functions, such as attention, learning, and memory. However, the mechanism underlying these deficits is unclear. To investigate the role of iodine deficiency and hypothyroidism in synaptic plasticity, this study examined the induction of long-term synaptic plasticity (LTP) and expression of immediate early (IEA) gene proteins in rat hippocampus following congenital iodine deficiency or hypothyroidism. Through gestation and lactation, iodine-deficient or hypothyroid dam rats were administered with either iodine-deficient diet or methimazole-added drinking water. Exposure was terminated on postnatal day (PN) 30. In hippocampus of pup rats, the induction of LTP in area CA1 was determined on PN60 and the expression of c-fos and c-jun proteins was examined on PN20, PN30 and PN60. Compared to control pups, both treated groups have shown: (1) significantly lower concentrations of serum FT(3) and FT(4), (2) much smaller population spike (PS) amplitude (p<0.01) and field-excitatory postsynaptic potential (f-EPSP) slope induced by high-frequency stimulation (HFS) (P<0.01), and (3) significantly lower integrated optical density (IOD) total of c-fos and c-jun expression (P<0.05 or P<0.01). In summary, iodine deficiency and hypothyroidism during critical periods of brain development impair LTP induction and decrease the expression of c-fos and c-jun proteins in hippocampus.     

Post-aversive relief and relaxation and their implications for behavior therapy

This paper attempted to (a) introduce the notions of relief and relaxation as they relate to the framework of elicitation theory; (b) emphasize and exploit that aspect of the theory that deals with the extinction of learned behavior, especially behavior that is in some way mediated by aversive stimuli; and (c) show how the data and theory probably relate to: (1) high resistance to extinction of some fears and avoidance responses, (2) generalized anxiety and its treatment, (3) implosive therapy or flooding, and (4) relief therapy.     

Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal

There is an increasing awareness that a psychosis, similar to that of schizophrenic psychosis, can be derived from cocaine addiction. Thus, the prototypical atypical antipsychotic medication, clozapine, a 5-HT(2)/DA(2) antagonist, was studied for its effects on cocaine-induced dopamine (DA) and serotonin (5-HT) release in nucleus accumbens (NAcc) of behaving male Sprague-Dawley laboratory rats with In Vivo Microvoltammetry, while animals' locomotor (forward ambulations), an A(10) behavior, was monitored at the same time with infrared photobeams. Release mechanisms for monoamines were determined by using a depolarization blocker, gamma-butyrolactone (gammaBL). BRODERICK PROBE microelectrodes selectively detected release of DA and 5-HT within seconds and sequentially in A(10) nerve terminals, NAcc. Acute and subacute studies were performed for each treatment group. Acute studies are defined as single injection of drug(s) after a stable baseline of each monoamine and locomotor behavior has been achieved. Subacute studies are defined as 24-h follow-up studies on each monoamine and locomotor behavior, in the same animal at which time, no further drug was administered. Results showed that (1) acute administration of cocaine (10 mg/kg ip) (n=5) significantly increased both DA and 5-HT release above baseline (P<.001) while locomotion was also significantly increased above baseline (P<.001). In subacute studies, DA release decreased significantly below baseline (P<.001) and significant decreases in 5-HT release occurred at the 15-min mark and at each time point during the second part of the hour (P<.05); the maximum decrease in 5-HT was 40% below baseline. Locomotor behavior, on the other hand, increased significantly above baseline (P<.05). (2) Acute administration of clozapine/cocaine (20 and 10 mg/kg ip, respectively; n=6) produced a significant block of the cocaine-induced increase in DA (P<.001) and 5-HT release (P<.001). Cocaine-induced locomotion was blocked simultaneously with each monoamine by clozapine as well (P<.001). In subacute studies, DA release continued to be blocked presumably via clozapine by exhibiting a statistically significant decrease (P<.001), but 5-HT release increased significantly (P<.001), while cocaine-induced locomotor activity also continued to be antagonized by clozapine, i.e., locomotor activity exhibited no difference from baseline (P>.05). In summary, acute studies (a) support previous data from this laboratory and others that cocaine acts as a stimulant on the monoamines, DA and 5-HT and on locomotor behavior as well and (b) show that clozapine, 5-HT(2)/DA(2) antagonist, blocked enhanced DA, 5-HT and psychomotor stimulant behavior induced by cocaine. Subacute studies (a) suggest that withdrawal responses occurred in the cocaine group, based on recorded deficiencies in monoamine neurotransmitters (b) show that withdrawal effects in the cocaine group likely presynaptic, were distinguished from locomotor behavior, classically known to be mediated postsynaptically, and finally, (c) suggest that clozapine, with longer lived pharmacokinetic properties, reversed 5-HT cocaine-related withdrawal effects, but was unable to reverse DA cocaine-related withdrawal responses. Taken together with data from this laboratory, in which the 5-HT(2A/2C) antagonist, ketanserin, affected cocaine neurochemistry in much the same way as did clozapine, a mediation by either separate or combined 5-HT(2A/2C) receptors for these clozapine/cocaine interactions, is suggested. Further studies, designed to tease out the responses of selective 5-HT(2A) and 5-HT(2C) receptor compounds to cocaine and clozapine/cocaine, are underway.     

Afferent and efferent connections of the medial, inferior and lateral vestibular nuclei in the cat and monkey

Attempts were made to determine the afferent and efferent connections of the medial (MVN), inferior (IVN) and lateral (LVN) vestibular nuclei (VN) in the cat and monkey using retrograde and anterograde axoplasmic transport technics. Injections of HRP and [3H]amino acids were made selectively into MVN, IVN and LVN and into: (1) MVN and IVN, (2) LVN and IVN and (3) all 4 VN. Contralateral afferents to MVN arise from (1) the nuclei prepositus (NPP) and intercalatus (NIC), (2) all parts of MVN and cell group 'y' and (3) parts of the superior vestibular nucleus (SVN), IVN and the fastigial nucleus (FN). Ipsilateral projections to MVN arise from: (1) a central band of the flocculus and the nodulus and uvula, (2) the interstitial nucleus of Cajal (INC), and (3) visceral nuclei of the oculomotor nuclear complex (OMC). Efferent projections of MVN are to: (1) the ipsilateral supraspinal nucleus (SSN), and (2) the contralateral central cervical nucleus (CCN), MVN, SVN, cell group 'y', the rostroventral region of LVN, the trochlear nucleus (TN) and the INC. Projections to the abducens nuclei (AN) and the OMC are bilateral. Some ascending fibers in the cat cross within the OMC. In the monkey fibers from MVN end in a central band of the ipsilateral flocculus. Afferents to IVN arise ipsilaterally from SVN, the nodulus, the uvula and the anterior lobe vermis. Contralateral afferents arise from: (1) parts of CCN, MVN, SVN, IVN and cell group 'y' and (2) the central third of the FN. IVN receives bilateral projections from the perihypoglossal nuclei (PH) and the visceral nuclei of the OMC. Efferents from IVN project: (1) ipsilaterally to nucleus beta of the inferior olive, (2) contralaterally to parts of MVN, SVN and cell group 'y' and (3) bilaterally to the paramedian reticular nuclei. No commissural fibers interconnect cell groups 'f' and 'x'. Ascending fibers from IVN terminate contralaterally in the TN and the OMC. In the monkey fibers from IVN terminate in the ipsilateral nodulus, uvula and anterior lobe vermis; no fibers project to FN in either the cat or the monkey. Afferents to the LVN arise primarily from the ipsilateral anterior lobe vermis and bilaterally from rostral parts of the FN. No commissural fibers interconnect the LVN. Projections of the LVN are primarily to spinal cord via the vestibulospinal tract (VST); collaterals of the VST terminate in the lateral reticular nucleus (LRN). Ascending uncrossed projections from LVN in the cat terminate in the medial rectus subdivision of the OMC.(ABSTRACT TRUNCATED AT 400 WORDS)     

Urinary 5-hydroxyindoleacetic acid and whole blood serotonin and tryptophan in autistic and normal subjects

Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in two consecutive collection periods (5:00 PM-11:00 PM and 11:00 PM-8:00 AM) and whole blood serotonin (5-HT) and tryptophan (TRP) were measured in groups of unmedicated autistics (n = 16), medicated autistics (n = 20), and normal controls (n = 27). Whole blood 5-HT values were significantly higher in unmedicated autistics compared to normal controls. No significant differences were found in 5-HIAA excretion (microgram/mg creatinine, mean +/- SD) between unmedicated autistics (4.07 +/- 1.52) and normal controls (3.50 +/- 1.07), or between medicated (5.35 +/- 2.93) and drug-free autistic individuals. No correlations were found between 5-HT values and urinary 5-HIAA excretion. Urinary 5-HIAA (microgram/mg creatinine, mean +/- SD) was significantly greater in hyperserotonemic autistic subjects (4.88 +/- 0.87) compared to normal controls (3.50 +/- 1.07, total collection period; p = 0.002). The relevance of these findings to the possibility that increased gut production of 5-HT might cause the elevated whole blood 5-HT levels seen in autism is discussed.     

Social deprivation and prevalence of epilepsy and associated health usage

OBJECTIVES: To examine the relation between social deprivation and the prevalence of epilepsy and associated morbidity using hospital activity data as a proxy. METHODS: The study was conducted in the health district of South Glamorgan, United Kingdom (population 434 000). Routinely available hospital data (inpatient and outpatient), an epilepsy clinic database, and mortality data underwent a process of record linkage to identify records relating to the same patient and to identify patients with epilepsy. Each patient was allocated a Townsend index deprivation score on the basis of their ward of residence. Age standardised correlations were calculated between deprivation score and prevalence of epilepsy, inpatient admissions, and outpatient appointments. Standardised mortality ratios (SMR) were also calculated. All analyses were performed on two cohorts: (1) all patients with epilepsy and (2) those patients with epilepsy without any underlying psychiatric illness or learning disability. RESULTS: The prevalence of epilepsy ranged between 2.0 and 13.4 per 1000 with a median of 6.7. There were positive correlations between social deprivation and prevalence in both populations: (1) r=0.75 (p<0.001) and (2) r=0.70 (p<0.001). After standardising for underlying prevalence there were also correlations for mean inpatient admissions: (1) r=0.62 (p<0.001), (2) r=0.59, (p<0.001) and for outpatient appointments: (1) r=0.53, (p=0.001) and (2) r=0. 51 (p=0.001). The SMR for those deprived was (1) 1.66 (95% confidence interval (95% CI) 1.27-2.05) and (2) 1.80 (95% CI 0.71-1. 67). For the population as a whole (with and without epilepsy) the SMR was 1.25 (95% CI 1.27-2.32). CONCLUSION: This study shows a strong correlation between the prevalence of epilepsy and social deprivation and weaker correlations between social deprivation and mean hospital activity.     

DNA and RNA antibodies in serum and CSF of multiple sclerosis and subacute sclerosing panencephalitis patients.

DNA and RNA (nucleic) antibodies were found in the CSF of 18 patients with multiple sclerosis (MS) (out of 45), 11 with subacute sclerosing panencephalitis (SSPE) (out of 12) and 9 controls (out of 30). Viral (measles and rubella, by HAI) antibodies were present in all SSPE, 23 MS and 11 control patients. A clear correlation exists between (1) CSF immunological patterns, (2) oligoclonal aspect, (3) simultaneous presence of nucleic and viral antibodies, suggesting the local synthesis of both. This is confirmed by the comparison of the ratios IgG/antibodies in serum and CSF: the CSF ratio may be higher for nucleic and/or viral antibodies in SSPE and MS patients. Thus nucleic antibodies seem to be related to a persistent active infection within the central nervous system.     

Effects of somatostatin-28 and some of its fragments and analogs on open-field behavior, barrel rotation, and shuttle box learning in rats

The effect of intracerebroventricular (ICV) administration of somatostatin-28 (SS-28) and some of its fragments, SS-28 (1-12), SS-28(15-28), and analogs, des-AA-(1,2,4,5,12,13)-(DTrp8)SS-14, ODT8-SS, and (DTrp8,DCys14)SS-14 were studied in different behavioral tests on rats. SS-28 (6.0 nM) decreased, SS-28(15-28) (0.6 nM) increased, and SS-28(15-28) (6.0 nM) decreased activity of the animals in an open-field test. SS-28(1-12) (0.6, 3.0, and 6.0 nM) did not influence this behavior. ODT8-SS (0.6, 3.0, and 6.0 nM) decreased activity of the rats, while (DTrp8,DCys14)SS-14 increased it, only at a high dose (6.0 nM). Similar results were obtained for barrel rotation, except that (DTrp8,DCys14)SS-14 even in high dose (12.0 nM) had no effect. In a shuttle-box learning paradigm, SS-28(15-28) (0.6 nM) facilitated, while SS-28(1-12) (0.6 nM) did not influence, the performance of the animals. These results suggest that the isomeric Cys(28) form of the SS-28(15-28) molecule may be crucial for the expression of the behavioral effects of these peptides.     

Handedness and aphasia

The report is based on matched data of 57 right-handed (RH) and 57 non-right-handed patients (NRH) with almost identical lesions in one cerebral hemisphere. The brain lesions were verified by post-mortem examination. It was found: (1) Aphasia occured in RH only on left cerebral lesions; (2) in NRH aphasia occured in patients with left and with right hemispheric damage; (3) the most transient aphasias were found in the NRH; (4) in all NRH patients agraphia and alexia occured significantly more frequently in lesions controlateral to the hand used for writing; (5) the cerebral areas affected by aphasia-producing lesions are not different in RH and NRH; (6) typical syndromes like Broca's, Wernicke's and total aphasia occured in both groups; (7) in the NRH there are significantly more unclassifiable aphasias than in the RH.     

Effect of glycosaminoglycans on thrombin- and atroxin-induced fibrin assembly and structure

This study was performed to quantitate the impact of several glycosaminoglycans (GAG) on fibrin assembly and structure. Gel formation was monitored as the increase in optical density at 633 nm subsequent to thrombin (2 NIH u/ml) or atroxin (0.10 mg/ml) addition to solutions of buffered fibrinogen (1 mg/ml) or plasma. Gel absorbance was measured as a function of wavelength (400 to 800 nm) and gel fiber diameter and mass/length ratio (mu) were calculated. Chondroitin sulfate A (CSA) shortened the lag phase, enhanced the maximal rate of turbidity increase, and increased the final gel turbidity of fibrin gels formed by thrombin or atroxin. CSA (16 mg/ml) increased fiber mu from 1.3 to 3.1 x 10(13) dalton/cm and fiber radius from 6.0 to 8.6 x 10(-6) cm in thrombin-induced gels. Mu increased from 0.7 to 2.7 x 10(13) dalton/cm and fiber radius from 4 to 7.8 x 10(-6) cm for atroxin-induced gels. Above 16 mg/ml, CSA caused fibrinogen precipitation in purified solutions but not in plasma. CSA inhibited thrombin-induced plasma clotting of plasma but effects in atroxin-mediated plasma gels paralleled those seen in purified solutions. Chondroitin sulfate B (CSB)-induced changes in fibrin were similar but slightly less dramatic than those seen with CSA. Mu increased from 0.9 to 2.0 x 10(13) dalton/cm for atroxin-induced fibrin gels and from 0.8 to 2.3 x 10(13) dalton/cm for atroxin-induced gels. Low molecular weight heparin (Mr = 5100) slowed fibrin assembly and reduced fiber size by 50% in thrombin-induced gels. Changes in mu of atroxin-induced gels were much less pronounced (less than 20%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dendritic morphology of amygdala and hippocampal neurons in more and less predator stress responsive rats and more and less spontaneously anxious handled controls

We investigated the neurobiological bases of variation in response to predator stress (PS). Sixteen days after treatment (PS or handling), rats were grouped according to anxiety in the elevated plus maze (EPM). Acoustic startle was also measured. We examined the structure of dendritic trees of basolateral amygdala (BLA) output neurons (stellate and pyramidal cells) and of dorsal hippocampal (DHC) dentate granule cells of less anxious (LA) and more (extremely) anxious (MA) stressed animals (PSLA and PSMA). Handled controls (HC) which were less anxious (HCLA) and spontaneously more anxious (HCMA) equivalently to predator stressed subgroups were also studied. Golgi analysis revealed BLA output neurons of HCMA rats exhibited longer, more branched dendrites with higher spine density than the other groups of rats, which did not differ. Finally, spine density of DHC granule cells was equally depressed in HCMA and PSMA rats relative to HCLA and PSLA rats. Total dendritic length of BLA pyramidal and stellate cells (positive predictor) and DHC spine density (negative predictor) together accounted for 96% of the variance of anxiety of handled rats. DHC spine density was a negative predictor of PSMA and PSLA anxiety, accounting for 70% of the variance. Data are discussed in the context of morphological differences as phenotypic markers of a genetic predisposition to anxiety in handled controls, and a possible genetic vulnerability to predator stress expressed as reduced spine density in the DHC. Significance of findings for animal models of anxiety and hyperarousal comorbidities of PTSD are discussed.     

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.     

Epilepsy and Education

Summary: Epilepsy education continues to be an essential component of every epilepsy organization'smission. Ongoing educational programs are an essential part of epilepsy patient care. A few basic rules to ensure success are to: (a) identify needs by users, not providers; (b) target programs to the specific audience; (c) remember that people learn by different methods; (d) take advantage of teachable moments; (e) account for transcultural differences; and (f) modify programs based on systemative evaluation and feedback.     

Menopause, hormone replacement and RR and QT modulation during sleep

BACKGROUND AND PURPOSE: Sleep affects the RR interval in electrocardiogram (ECG) recordings and ventricular repolarization differentially in men and women. Compared to men, pre-menopausal women have a more pronounced shortening of RR interval and prolongation of QT and QT corrected (QTc, by Bazett's formula) ECG waves during rapid eye movement (REM) sleep. The aim of the present study was to evaluate sleep-related RR and QT changes: (1) with the physiological decline in female hormones occurring with menopause, and (2) after hormone replacement therapy with estrogen and progesterone (HRT). PATIENTS AND METHODS: We analyzed ECG recordings from 14 post-menopausal women (48-61 years old) who underwent polysomnography before HRT (T1) and after 6 months of HRT (T2) with estrogen and progesterone. Eight of the post-menopausal women (48-54 years) were also compared to eight age-matched pre-menopausal women. In all subjects, mean RR interval, mean QT interval and QTc, were obtained from 1-min recordings selected from wakefulness, stage 2 and REM sleep. RESULTS: Pre-menopausal and post-menopausal women showed similar changes in RR, QT and QTc intervals from wakefulness through sleep. Specifically, in both pre-menopausal and post-menopausal women the RR interval was shorter during REM sleep compared to wakefulness (P=0.009) and stage 2 sleep (P=0.001); the QT interval was more prolonged during stage 2 (P=0.002) and REM (P=0.006); and the QTc interval was significantly prolonged during stage 2 (P=0.01) and REM (P=0.0003) sleep compared to wakefulness. Among post-menopausal women, both before and after HRT (T1 and T2), RR interval shortened significantly during REM compared to wakefulness (P=0.03) and to stage 2 (P=0.002); the absolute QT interval was longer during stage 2, compared to both wakefulness (P<0.001) and REM (P<0.001); the QTc interval was increased during REM sleep compared to wakefulness (P=0.003). CONCLUSIONS: Sleep-related RR and QT changes in women are not altered by menopausal status nor by post-menopausal hormonal replacement with estrogen and progesterone.     

An interaction study between the new antiepileptic and CNS drug carisbamate (RWJ-333369) and lamotrigine and valproic acid

PURPOSE: To characterize possible pharmacokinetic interactions between the new antiepileptic drug carisbamate (RWJ-333369) and valproic acid (VPA) or lamotrigine (LTG) following multiple dosing in healthy subjects. METHODS: Two open-label, sequential-design studies were conducted in 24 healthy adults. In Study 1, subjects received carisbamate alone (5 days 250 mg q12h; 5 days 500 mg q12h), then VPA alone (7 days 300 mg q12h; 7 days 500 mg q12h), and then a combination of VPA (500 mg q12h) and carisbamate (5 days 250 mg q12h; 5 days 500 mg q12h). In Study 2, subjects received carisbamate alone as in Study 1, then LTG alone (14 days 25 mg q12h; 14 days 50 mg q12h), and then combination of LTG (50 mg q12h) and carisbamate (3 days 250 mg q12h; 14 days 500 mg q12h). RESULTS: Coadministration of VPA or LTG had minimal effect on carisbamate mean C(max) and AUC(ss) values. Mean VPA-C(max) and AUC(ss) values were approximately 15% lower when given concomitantly with carisbamate. However, the 90% confidence intervals (CIs) for the C(max) and AUC(ss) ratio with/without carisbamate were within the 80-125% equivalence range, C(max) 82-89%; AUC(ss) 81-88%. Mean LTG C(max) and AUC(ss) values were approximately 20% lower when given concomitantly with carisbamate. The 90% CIs with and without carisbamate for LTG C(max) and AUC(ss) were 79-86% and 75-81%, respectively. This modest change is not considered clinically significant. CONCLUSIONS: There were no clinically significant interactions between carisbamate and VPA or LTG. Concomitant administration of carisbamate with VPA or LTG was generally safe and well tolerated.     

Hair cell and supporting cell density and distribution in the normal and regenerating posterior crista ampullaris of the pigeon

The numbers of supporting cells and the numbers and types of hair cells in three distinct longitudinal regions through the posterior canal cristae of control and streptomycin-treated pigeons were determined using stereological techniques. For control cristae, type I (3758) and type II (3517) hair cells occurred in approximately equal numbers. However, the proportions varied in different longitudinal zones: Zone I (peripheral region) had four times more type II hair cells (2083) than type I (483), while Zone II (intermediate region) had almost seven times more type I (2517) than type II (367) hair cells and Zone III (central region) had relatively equal numbers of type I (758) and type II (1067) hair cells. Novel findings included the following: (1) immediately after the post-injection sequence (PIS) of streptomycin, there was a significant reduction in both hair cells (−93%) and supporting cells (−45%); (2) by 70 days after the PIS, the population of type I hair cells returned to control values (however, the normal complement of complex calyces took 1 year to recover); (3) during the first 143 days after the PIS, the number of type I and type II hair cells across all zones returned linearly with about the same slope (46 and 43 cells per day, respectively), although the rate of return differed significantly in different zones; (4) there was a massive overproduction of hair cells (+150%) and supporting cells (+120%) during the first 5 months of recovery; and (5) during the first year after the PIS, both hair cells and supporting cells increased and their increases in numbers were correlated (r=0.88, P<0.01). Knowledge of the sequence and numbers of regenerating hair cells may help elucidate common modes of cell survival, recovery, and compensation from neural insult.