Multidimensional Evaluation of Screening Brief Intervention and Referral to Treatment Training for Medical Students.

OBJECTIVE: Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an evidence-based approach to identifying and addressing alcohol use in non-specialty settings. Many medical schools teach SBIRT, but most published evaluations of these efforts exclude rigorous skill assessments and teaching methods. METHODS: During the 2017-2018 academic year, 146 third-year medical students received classroom-based learning on SBIRT and motivational interviewing (MI) and at least two SBIRT practices with feedback as part of a 4-week psychiatry clerkship. The objective of this curriculum was to improve SBIRT knowledge, attitudes, and confidence and enable learners to skillfully deliver SBIRT. Outcomes evaluated included satisfaction, knowledge, attitudes and confidence, and clinical skill in delivering SBIRT to a standardized patient (rated by the actor, as well as an expert). RESULTS: Results indicated acceptable satisfaction at post-curriculum and significant improvements in attitudes and knowledge from pre- to post-curriculum. On the clinical skills exam, all students were rated as having mastered at least 80% of SBIRT elements by standardized patients and 91.8% were rated at this level by a faculty expert. Student attitudes and knowledge were unrelated to expert ratings, and standardized patient ratings had limited associations with expert ratings. CONCLUSIONS: These results suggest curriculum objectives were achieved and provide unique contributions to the SBIRT curricular outcome research for healthcare trainees. Other findings included that trainee knowledge and confidence may not relate to skill, and standardized patient feedback provides different information on SBIRT and MI skill than expert ratings.

Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats.

Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40-100 mmHg in young DM rats but was reduced at 140-180 mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30-60 mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and long-term memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly DM.

Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects.

RATIONALE: Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids. OBJECTIVES: The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats. METHODS: Male Sprague-Dawley rats (N = 7/group) were placed into an elevated zero maze apparatus following injections of multiple doses of triazolam and pregnanolone, alone and combined, or clonazepam and ganaxolone, alone and combined. These drugs/drug combinations also were evaluated in rats (N = 8) trained to discriminate triazolam (0.1 mg/kg, i.p.) from vehicle. Drug interactions were evaluated using isobolographic and dose-addition analysis. RESULTS: In the elevated zero maze, all drugs engendered dose-dependent increases in time spent in the open quadrant when administered alone. Triazolam and pregnanolone, as well as clonazepam and ganaxolone combinations produced additive or supra-additive effects depending on the fixed-proportion that was tested. In triazolam discrimination, all drugs engendered dose-dependent increases in triazolam-lever responding. In combination, triazolam and pregnanolone and clonazepam and ganaxolone produced predominantly additive discriminative stimulus effects, except for one fixed proportion of clonazepam and ganaxolone which had supra-additive effects. CONCLUSIONS: Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.

Attenuation of social interaction-associated ultrasonic vocalizations and spatial working memory performance in rats exposed to chronic unpredictable stress.

Exposure to unpredictable chronic mild stress (CUS) is a commonly used protocol in rats that is reported to evoke antidepressant-reversible behaviors such as loss of preference for a sweetened water solution which is taken as an analog of the anhedonia seen in major depression. However, the induction of anhedonic-like behavior by chronic mild stress, gauged by an animal's preference for sucrose solution, is not fully reproducible and consistent across laboratories. In this study, we compared a widely used behavioral marker of anhedonia - the sucrose preference test, with another phenotypic marker of emotional valence, social interaction-associated ultrasonic vocalizations as well as a marker of an anxiety-like phenotype, novelty-suppressed feeding, and cognitive performance in the eight arm radial maze task in adult male Sprague-Dawley rats. Chronic four-week exposure to unpredictable mild stressors resulted in 1) attenuation of social interaction-associated ultrasonic vocalizations 2) attenuation of spatial memory performance on the radial arm maze 3) attenuation of body weight gain and 4) increased latency to feed in a novelty-suppressed feeding task. However, chronic exposure to CUS did not result in any significant change in sucrose preference at one-week and three-week intervals. Our results argue for the utility of ultrasonic vocalizations in a social interaction context as a comparable alternative or adjunct to the sucrose preference test in determining the efficacy of CUS to generate an anhedonic-like phenotypic state.

Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders.

RATIONALE: Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in autistic spectrum disorders (ASDs). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear. OBJECTIVE: We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT1A and/or 5-HT1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure. METHODS: Male and female rat pups were treated from postnatal days 8 to 21. In Experiment 1, pups received citalopram (20 mg/kg/day), saline, (±)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT; 0.5 mg/kg/day) or 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]-quinoxaline dimaleate (CGS-12066B; 10 mg/kg/day). In Experiment 2, a separate cohort of pups received citalopram (20 mg/kg/day), or saline which was combined with either N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo-hexanecarboxamide maleate (WAY-100635; 0.6 mg/kg/day) or N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1'-biphenyl-4-carboxamide (GR-127935; 6 mg/kg/day) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development. RESULTS: Direct and indirect neonatal stimulation of 5-HT1A or 5-HT1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD. CONCLUSION: Increased stimulation of 5-HT1A and 5-HT1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats.

Manipulation of serotonin (5HT) during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT) immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM). Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB) and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days), OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs), these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

Memantine prevents cognitive impairment and reduces Bcl-2 and caspase 8 immunoreactivity in rats injected with amyloid ß1-40.

Amyloid-beta peptides (Aß) can trigger apoptotic cascades in neurons. We found previously that memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors approved for the treatment of moderate to severe Alzheimer's disease, can prevent neurodegeneration induced by intracranial Aß(1-40) injection. In this study, we tested the hypothesis that memantine prevents Aß(1-40)-mediated cognitive impairment, neurodegeneration, and apoptosis of hippocampal neurons in rats. In addition, we hypothesized that Aß(1-40) injection would induce changes in the levels of one or more apoptosis-related proteins, and that these changes would be attenuated by memantine treatment. Female Sprague-Dawley rats were administered memantine (continuous subcutaneous application, 9.6-14.4mg/kg/day; n=8) or vehicle (water; n=8) for 9 days. Two days after treatment initiation, the animals were bilaterally injected with Aß(1-40) into the CA1/DG region of the hippocampus, subjected to active avoidance testing for 7 days, and sacrificed for immunohistochemical examination of four caspases (3, 6, 8, and 9) and three proteins of the Bcl-2 family (Bcl-2, Bax, and Bad). Injection of Aß resulted in neurodegeneration, DNA fragmentation, increased Bcl-2 immunostaining, and significantly impaired performance in an active avoidance task, all which were significantly attenuated in rats treated with memantine. No differences in immunoreactivity of caspases 3, 6, 8, and 9 were discovered between groups after 7 days. Additional experiments demonstrated that an increase in caspase 8 immunostaining, observed 3 days after Aß(1-40) injection, was significantly attenuated in memantine-treated rats. These data suggest that, in rats, memantine can prevent amyloid-triggered expression of apoptosis-related markers and concomitant cognitive deficits.

Mechanistic role for a novel glucocorticoid-KLF11 (TIEG2) protein pathway in stress-induced monoamine oxidase A expression.

Chronic stress is a risk factor for psychiatric illnesses, including depressive disorders, and is characterized by increased blood glucocorticoids and brain monoamine oxidase A (MAO A, which degrades monoamine neurotransmitters). This study elucidates the relationship between stress-induced MAO A and the transcription factor Kruppel-like factor 11 (KLF11, also called TIEG2, a member of the Sp/KLF- family), which inhibits cell growth. We report that 1) a glucocorticoid (dexamethasone) increases KLF11 mRNA and protein levels in cultured neuronal cells; 2) overexpressing KLF11 increases levels of MAO A mRNA and enzymatic activity, which is further enhanced by glucocorticoids; in contrast, siRNA-mediated KLF11 knockdown reduces glucocorticoid-induced MAO A expression in cultured neurons; 3) induction of KLF11 and translocation of KLF11 from the cytoplasm to the nucleus are key regulatory mechanisms leading to increased MAO A catalytic activity and mRNA levels because of direct activation of the MAO A promoter via Sp/KLF-binding sites; 4) KLF11 knockout mice show reduced MAO A mRNA and catalytic activity in the brain cortex compared with wild-type mice; and 5) exposure to chronic social defeat stress induces blood glucocorticoids and activates the KLF11 pathway in the rat brain, which results in increased MAO A mRNA and enzymatic activity. Thus, this study reveals for the first time that KLF11 is an MAO A regulator and is produced in response to neuronal stress, which transcriptionally activates MAO A. The novel glucocorticoid-KLF11-MAO A pathway may play a crucial role in modulating distinct pathophysiological steps in stress-related disorders.

Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat.

Neonatal exposure to antidepressants produces lasting impairments in male sexual behavior. Although perturbation of the serotonin system during neonatal life has been implicated in the long-term behavioral effects of neonatal antidepressant exposure, dose-response studies were necessary to confirm that inhibition of the serotonin transporter during the neonatal period is sufficient to produce impairments in sexual behavior. Therefore, the present study examined the dose-response effects of neonatal citalopram exposure on sexual behavior. In addition, the effects of exposure on anxiety-related behavior were examined since alterations in this behavioral measure could affect sexual behavior. Male Long-Evans rats were injected subcutaneously with citalopram (CTM) in one of three doses (5, 10 or 20mg/kg/d), or saline (SAL) in a volume of 0.1 ml twice daily (07:00 and 14:00 h) from PD8 to PD21. The rats were tested as adults (>PD90) for anxiety-like behavior and exploration in the elevated plus maze test and sexual behavior. Neonatal citalopram exposure produced persistent reductions in male sexual behavior characterized by significant dose-dependent reductions in the percentage of male rats displaying mounting as well as dose-dependent reductions in the number of mounts and mount latency. Neonatal citalopram exposure also produced significant dose-dependent linear trends for reductions in intromission and ejaculation behavior. However, neonatal SSRI exposure was not found to produce any effects on exploration or anxiety-like behavior in the elevated plus maze test. The present findings support the hypothesis that inhibition of the serotonin transporter during neonatal life by an SSRI is directly responsible for the long-term effects on male sexual behavior.

Perinatal citalopram exposure selectively increases locus ceruleus circuit function in male rats.

Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), have been widely prescribed for major depressive disorder, not only for adult populations, but also for children and pregnant mothers. Recent evidence suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels in the raphe system and decreases norepinephrine (NE) locus ceruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long-lasting downregulation of the 5-HT-raphe system, which is opposite to that seen with chronic adult treatment. Therefore, the goal of the present investigation was to test the hypothesis that perinatal CTM exposure (20 mg/kg/d) from postnatal day 1 (PN1) to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). Our single-neuron LC electrophysiological data demonstrated an increase in spontaneous and stimulus-driven neural activity, including an increase in phasic bursts in CTM-exposed animals. In addition, we demonstrated a corresponding immunoreactive increase in the rate-limiting catalyzing catecholamine enzyme (tyrosine hydroxylase) within the LC and their neocortical target sites compared to saline controls. Moreover, these effects were only evident in male exposed rats, suggesting a sexual dimorphism in neural development after SSRI exposure. Together, these results indicate that administration of SSRIs during a sensitive period of brain development results in long-lasting alterations in NE-LC circuit function in adults and may be useful in understanding the etiology of pervasive developmental disorders such as autism spectrum disorder.

Perinatal antidepressant exposure alters cortical network function in rodents.

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.

Altered expression of tyrosine hydroxylase in the locus coeruleus noradrenergic system in citalopram neonatally exposed rats and monoamine oxidase a knock out mice.

In rodents, noradrenergic (NE) locus coeruleus (LC) neurons are well known to express tyrosine hydroxylase (TH) immunoreactivity. However, due to its very low enzyme activity, NE cortical fibers do not typically express TH immunoreactivity, thus dopamine-ß-hydroxylase (DBH) immunoreactivity is commonly utilized as a marker for NE cortical fibers. In this study, we performed double and/or triple immunofluorescent staining using antibodies against TH, DBH, and/or norepinephrine transporter (NET) to investigate the altered NE TH expression of cortical fibers in citalopram (CTM)-exposed rats and monoamine oxidase (MAO) A knock out (KO) mice. We have noted the following novel findings: (1) neonatal exposure to the selective serotonin reuptake inhibitor (SSRI) CTM enhanced NE TH immunoreactive fibers throughout the entire neocortex, and a few of them appeared to be hypertrophic; (2) slightly enhanced NE cortical TH immunoreactive fibers were also noted in MAO A KO mice, and many of them revealed varicosities compared with the rather smooth NE cortical TH immunoreactive fibers in wild-type (WT) mice; (3) LC dendrites of MAO A KO mice exhibited beaded morphology compared with the smooth LC dendrites in WT mice. Our findings suggest that both genetic and environmental factors during early development may play a critical role in the regulation and proper function of NE TH expression in the neocortex.

Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders.

We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty, and impairs social interactions in a manner similar to that observed in ASD. Male and female Long-Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8-21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32-P34) and later, we assessed sexual response to an estrus female in male rats (P153-184). Antidepressant exposure increased freezing after tone, diminished novel object exploration, and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant-exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD.

Ethanol increases TIEG2-MAO B cell death cascade in the prefrontal cortex of ethanol-preferring rats.

Brain cell loss has been reported in subjects with alcoholism. However, the molecular mechanisms are unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction with regards to ethanol exposure. We have recently reported that GAPDH protein expression was increased in the brains of rats fed with ethanol. Furthermore, GAPDH interacts with the transcriptional activator, transforming growth factor-beta-inducible early gene 2 (TIEG2), to augment TIEG2-mediated MAO B activation, resulting in neuronal cell damage due to ethanol exposure. The current study investigates whether the TIEG2-MAO B cascade is also active in the brains of rats fed with ethanol. Ten ethanol-preferring rats were fed with a liquid diet containing ethanol, with increasing amounts of ethanol up to a final concentration of 6.4% representing a final diet containing 36% of calories for 28 days. Ten control rats were fed the liquid diet without ethanol. The expression of TIEG2 protein, MAO B mRNA levels, MAO B catalytic activity, and the levels of anti-apoptotic protein Bcl 2 and apoptotic protein caspase 3 were determined in the prefrontal cortex of the rats. Ethanol significantly increased protein levels of TIEG2, active caspase 3, MAO B mRNA and enzyme activity, but significantly decreased Bcl 2 protein expression compared to control rats. In summary, ethanol increases the TIEG2-MAO B brain cell death cascade in rat brains, suggesting that the TIEG2-MAO B pathway is a novel pathway for brain cell damage resulting from ethanol exposure, and may contribute to chronic alcohol-induced brain damage.

Neonatal exposure to citalopram selectively alters the expression of the serotonin transporter in the hippocampus: dose-dependent effects.

Infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) late in pregnancy have been reported to exhibit signs of antidepressant withdrawal. Such evidence suggests that these drugs access the fetal brain in utero at biologically significant levels. Recent studies in rodents have revealed that early exposure to antidepressants can lead to long lasting abnormalities in adult behaviors, and result in robust decreases in the expression of a major serotonin synthetic enzyme (tryptophan hydroxylase) along the raphe midline. In the present investigation, we injected rat pups with citalopram (CTM: 5 mg/kg, 10 mg/kg, and 20 mg/kg) from postnatal Days 8-21, and examined serotonin transporter (SERT) labeling in the hippocampus, ventrobasal thalamic complex, and caudate-putamen when the subjects reached adulthood. Our data support the idea, that forebrain targets in receipt of innervation from the raphe midline are particularly vulnerable to the effects of CTM. SERT-immunoreactive fiber density was preferentially decreased throughout all sectors of the hippocampal formation, whereas the subcortical structures, each supplied by more lateral and rostral aspects of the raphe complex, respectively, were not significantly affected. Reductions in SERT staining were also found to be dose-dependent. These findings suggest that SSRIs may not only interfere with the establishment of chemically balanced circuits in the neonate but also impose selective impairment on higher cortical function and cognitive processes via more circumscribed (i.e., regionally specific) deficits in 5-HT action.

mu-Opioid receptor knockout mice are insensitive to methamphetamine-induced behavioral sensitization.

Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using mu-OR knockout mice, we examined the role of mu-OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild-type mice. METH-induced behavioral responses were attenuated in the mu-OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH-induced stereotypy in the mu-OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the mu-opioid system is involved in modulating the development of behavioral sensitization to METH. (c) 2010 Wiley-Liss, Inc.

Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study.

BACKGROUND: One of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies. Zinc, a non competitive NMDA receptor antagonist exhibits preclinical antidepressant efficacy. Moreover, a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression. METHODS: A placebo-controlled, double blind study of zinc supplementation in imipramine therapy was conducted in sixty, 18-55-year old, unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms. After a one week washout period, patients were randomized into two groups treated with imipramine (approximately 140 mg/day) and receiving once daily either placebo (n=30) or zinc supplementation (n=30, 25 mgZn/day) for 12 weeks. RESULTS: No significant differences in CGI, BDI, HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients. However, zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients. CONCLUSION: Zinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment, particularly in patients previously nonresponsive to antidepressant pharmacotherapies. These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance.

Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development.

Neonatal (postnatal days 8-21) exposure of rats to the selective serotonin reuptake inhibitor (SSRI), citalopram, results in persistent changes in behavior including decreased sexual activity in adult animals. We hypothesized that this effect was a consequence of abnormal stimulation of 5-HT(1A) and/or 5-HT(1B) receptors as a result of increased synaptic availability of serotonin during a critical period of development. We examined whether neonatal exposure to a 5-HT(1A) (8OH-DPAT) or a 5-HT(1B) (CGS 12066B) receptor agonist can mimic the effect of neonatal exposure to citalopram on adult sexual behavior. Results showed that neonatal treatment with 5-HT(1B) receptor agonist robustly impaired sexual behavior similar to the effect of citalopram, whereas exposure to 5-HT(1A) receptor agonist only moderately influenced male sexual activity in adult animals. These data support the hypothesis that stimulation of serotonin autoreceptors during development contributes to the adult sexual deficit in rats neonatally exposed to citalopram.

Motor functions but not learning and memory are impaired upon repeated exposure to sub-lethal doses of methyl parathion.

Our previous work showed that repeated exposure to methyl parathion (MP) caused a prolonged inhibition of acetylcholinesterase (AChE) activity (approximately 80%) and down-regulation of M(1) and M(2) muscarinic receptors (up to 38%) in rats at brain regions, including frontal cortex, striatum, hippocampus and thalamus. In the present neurobehavioral study, we found this repeated MP treatment had suppressant effects on rat's locomotor activity. However, we observed no evidence of long-term effects of MP on associative learning and memory. Our data demonstrated that repeated exposure to MP caused some functional deficits in CNS, but motor activity and associative learning/memory process might differ in the sensitivity to its toxic effect. The motor dysfunctions in MP-treated rats may be mediated via reciprocal balance between cholinergic and dopaminergic systems at striatum following cholinergic over-stimulation. Our findings also suggest that the CNS deficits induced by repeated exposure to MP or other organophosphate (OP) pesticides cannot be attributed entirely to the inhibition of AChE. To accurately assess the neuro-toxic risk by occupational exposure to sub-lethal doses of MP, novel biomarkers besides in vivo anticholinesterase potency are needed.

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat.

Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 +/- 3.6% in vehicle pups (n = 28) to 11.9 +/- 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2alpha measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 +/- 7 pg/g in the shams (n = 6), 175 +/- 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 +/- 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.