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Biomedical subjects

C B Nemeroff

Publications and source records attributed to C B Nemeroff.

At least 19 recordsLinked to original sources
PubMed2006

Novel treatments of schizophrenia: targeting the neurotensin system.

Evidence implicating neural circuits that utilize the neuropeptide transmitter neurotensin (NT) in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs has previously been reviewed. The majority of evidence, taken together, supports the development of NT receptor agonists as novel antipsychotic drugs. This review comprehensively describes the NT receptor subtypes, discusses the development of NT receptor agonists and the behavioral effects of currently available NT receptor agonists. The compilation of data suggests that NT receptor agonists may represent a novel class of antipsychotic drugs for the treatment of schizophrenia.

Animals↗
PubMed2003

Neurobiological effects of childhood abuse: implications for the pathophysiology of depression and anxiety.

Mood and anxiety disorders are highly prevalent psychiatric disorders, especially in women, and they are associated with significant morbidity and mortality. A considerable literature indicates that vulnerability to depression and anxiety disorders is markedly increased by childhood abuse, e.g., physical, sexual, and psychological abuse, as well as adulthood stressors, e.g., death of a spouse. Little is known about the developmental neurobiological mechanisms by which childhood abuse increases the susceptibility of women to the development of depression and anxiety disorders in adulthood. Recent research on the effects of adverse early life experiences on central nervous system (CNS) stress systems has provided a greater understanding of the link between childhood abuse and susceptibility to mood and anxiety disorders. Specifically, early life traumatic events, occurring during a period of neuronal plasticity, appear to permanently render neuroendocrine stress response systems supersensitive. These physiological maladaptations likely represent long-term risk factors for the development of psychopathology after exposure to additional stress.

Adrenocorticotropic Hormone↗
PubMed2003

The neurobiology of social anxiety disorder: the relevance of fear and anxiety.

OBJECTIVE: Social anxiety disorder (SAD) is a ubiquitous anxiety disorder. Despite being the third most common psychiatric disorder, little is known about the interaction between genetic predisposition and environmental factors in the development of SAD. The available literature on SAD has been compared with data on the genetics and environmental impact on the phenotypic expression of fear and anxiety, and its implicated neurobiology, in order to explore the neurobiology of SAD as understood through the neurochemical dysregulation expressed in fear and anxiety. METHOD: A systematic review of the literature was employed for the years from 1966 to 2001. RESULTS: SAD does indeed have much overlap with fear and anxiety. This is best demonstrated by the interactions of the noradrenergic and serotonergic systems with each other and the hypothalamic-pituitary-adrenal axis. CONCLUSION: SAD may well be understood as one potential outcome for predisposed individuals who are exposed to the proverbial 'second hit', or environmental insult, in childhood. Behavioral inhibition may be an early expression of this predisposition, with natural progression to SAD occurring via a disruption of neurochemical homeostasis. Through animal and human data it has become evident that fear and anxiety have shared, as well as distinct, neurochemical and neuroanatomical pathways. These similarities are expressed as symptoms and objective signs that are common to many individuals with social anxiety disorder.

Anxiety↗
PubMed2001

The role of neurotensin in the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.

It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather pathologic alterations of several interacting systems. Targeting of neuropeptide neuromodulator systems, capable of concomitantly regulating several transmitter systems, represents a promising approach for the development of increasingly effective and side effect-free antipsychotic drugs. Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia that specifically modulates neurotransmitter systems previously demonstrated to be dysregulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured revealed a subset of schizophrenic patients with decreased CSF NT concentrations that are restored by effective antipsychotic drug treatment. Considerable evidence also exists concordant with the involvement of NT systems in the mechanism of action of antipsychotic drugs. The behavioral and biochemical effects of centrally administered NT remarkably resemble those of systemically administered antipsychotic drugs, and antipsychotic drugs increase NT neurotransmission. This concatenation of findings led to the hypothesis that NT functions as an endogenous antipsychotic. Moreover, typical and atypical antipsychotic drugs differentially alter NT neurotransmission in nigrostriatal and mesolimbic dopamine (DA) terminal regions, and these effects are predictive of side effect liability and efficacy, respectively. This review summarizes the evidence in support of a role for the NT system in both the pathophysiology of schizophrenia and the mechanism of action of antipsychotic drugs.

Animals↗
PubMed2001

Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonin reuptake inhibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (K(i) = 1.1 and 1.4 nmol/L, respectively). Escitalopram was the most serotonin transporter-selective compound tested and was approximately 30-fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-Fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (K(i) = 64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed.

Animals↗
PubMed2001

Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates.

BACKGROUND: The authors previously reported elevated cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations in juvenile primates nursed by mothers undergoing experimentally imposed unpredictable foraging conditions in comparison to normally reared controls. The purpose of the present study was to determine if these changes would endure into young adulthood. METHODS: Cisternal CSF samples were obtained from those unpredictably reared young adult primates who had been previously studied as juveniles and age-matched ad libitum normally reared controls. Samples were assayed for CSF CRF. RESULTS: Concentrations of CSF CRF were significantly elevated in the unpredictably reared sample in comparison to the ad libitum-reared control group. A significant positive correlation was noted between juvenile and young adult CSF CRF values within the unpredictably reared cohort. CONCLUSIONS: Disturbances of maternal-infant attachment processes have an enduring impact on primate CRF function into young adulthood. The CRF elevations following unpredictable maternal foraging conditions appear traitlike in nature.

Age Factors↗
PubMed2001

The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies.

Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to subsequent stress as well as to the development of depression and anxiety. A number of preclinical studies suggest that early life stress induces long-lived hyper(re)activity of corticotropin-releasing factor (CRF) systems as well as alterations in other neurotransmitter systems, resulting in increased stress responsiveness. Many of the findings from these preclinical studies are comparable to findings in adult patients with mood and anxiety disorders. Emerging evidence from clinical studies suggests that exposure to early life stress is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. Current research is focused on strategies to prevent or reverse the detrimental effects of early life stress on the CNS. The identification of the neurobiological substrates of early adverse experience is of paramount importance for the development of novel treatments for children, adolescents, and adults.

Adrenocorticotropic Hormone↗
PubMed2001

Paroxetine for the prevention of depression induced by high-dose interferon alfa.

BACKGROUND: Depression commonly complicates treatment with the cytokine interferon alfa-2b. Laboratory animals pretreated with antidepressants have less severe depression-like symptoms after the administration of a cytokine. We sought to determine whether a similar strategy would be effective in humans. METHODS: In a double-blind study of 40 patients with malignant melanoma who were eligible for high-dose interferon alfa therapy, we randomly assigned 20 patients to receive the antidepressant paroxetine and 20 to receive placebo. The treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of interferon alfa therapy. RESULTS: During the first 12 weeks of interferon alfa therapy, symptoms consistent with a diagnosis of major depression developed in 2 of 18 patients in the paroxetine group (11 percent) and 9 of 20 patients in the placebo group (45 percent) (relative risk, 0.24; 95 percent confidence interval, 0.08 to 0.93). Severe depression necessitated the discontinuation of interferon alfa before 12 weeks in 1 of the 20 patients in the paroxetine group (5 percent), as compared with 7 patients in the placebo group (35 percent) (relative risk, 0.14; 95 percent confidence interval, 0.05 to 0.85). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In patients with malignant melanoma, pretreatment with paroxetine appears to be an effective strategy for minimizing depression induced by interferon alfa.

Adult↗
PubMed2001

Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.

To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs.

Acoustic Stimulation↗
PubMed2001

The effects of glutamate receptor agonists on neurotensin release using in vivo microdialysis.

In the present study, extracellular concentrations of neurotensin were measured from the striatum, nucleus accumbens and the medial prefrontal cortex in the awake, freely moving rat. Using a highly sensitive solid phase radioimmunoassay, basal concentrations of neurotensin were 2-5 pg/sample. In each region, glutamate receptor agonists, N-methyl-D-aspartate (NMDA) and kainic acid, increased neurotensin release 2-3-fold. Preincubation with the Na(+) channel blocker tetrodotoxin abolished the glutamate receptor agonist-induced increases except in the striatum following kainic acid infusion. These findings indicate that activation of glutamate receptors may indirectly stimulate neurotensin release.

Animals↗
PubMed2001

Effects of sodium valproate on corticotropin-releasing factor systems in rat brain.

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Animals↗
PubMed2001

Synthesis and characterization of fluorinated and iodinated pyrrolopyrimidines as PET/SPECT ligands for the CRF1 receptor.

Fluorine-18 labeled fluorobutyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-yl]ethylamine (FBPPA) and iodine-123 labeled butyl[2,5-dimethyl-7-(4-iodo-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]ethyl-amine (IBPPA) were synthesized in the development of a CRF receptor ligand. The methods of synthesis, in vitro binding assays, radiolabeling and in vivo tissue distribution in rats are described. Fluorine-18 labeled FBPPA was prepared with high specific activity (3 x 10(4) Ci/mmol) by nucleophilic displacement with an average radiochemical yield of 6% (EOB). Iodine-123 labeled IBPPA was prepared by electrophilic iododestannylation with good yield (60%) and high specific activity (3.3 x 10(3) Ci/mmol). The retention of FBPPA and IBPPA in the pituitary was good (1.16% i.d./g and 2.35% i.d./g respectively at 60 min). However, the accumulation of radioactivity in the brain for both radiotracers was very low at all time points of the study, which demonstrated the difficulties for these radiopharmaceuticals to penetrate the blood brain barrier (BBB).

Animals↗
PubMed2001

The evaluation and treatment of depression in primary care.

The evaluation and treatment of depressive disorders are vital functions for practicing primary care physicians. Depression is a prevalent, recurrent, highly treatable disorder that is debilitating and leads to significant psychosocial impairment. In view of the broadly available armamentarium of safe, newer medications, primary care physicians should be proficient in the treatment of these disorders. The following review will provide a synopsis of the current state of diagnosis, evaluation, and treatment of depression in the primary care setting. Appropriate treatment of depression can result in improvement in emotional, cognitive, and behavioral symptoms of depression and reduce psychosocial impairment, disability, and associated medical morbidity.

Adult↗
PubMed2001

Role of norepinephrine in the pathophysiology of neuropsychiatric disorders.

The concatenation of convergent lines of evidence from basic to clinical research continues to reveal that norepinephrine (NE) is a crucial regulator of a myriad of behaviors ranging from stress response to memory formation. Furthermore, many neuropsychiatric disorders involve neurocircuitry that is directly modulated by NE. This report summarizes the physiological roles of NE, as well as the main findings implicating a role for NE system dysfunction in mood and anxiety disorders, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, and Alzheimer's disease. In each of these disorders, there appears to be a complex dysregulation of NE function, with changes in locus ceruleus firing, NE availability, and both pre- and postsynaptic receptor regulation. Many symptoms of these disorders are attributable to abnormalities within distributed neural circuits regulated by NE. Appreciation of NE's role in modulating the neural circuitry mediating cognition and affect should help elucidate the pathophysiology of a variety of neuropsychiatric disorders and the development of novel treatments.

Journal Article↗