Anxiety Disorders: Neumaier JF

Mitchell ES, Neumaier JF. · University of Washington, Box 359911, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104, USA. · Pharmacol Ther. · Pubmed #16005519 No free full text.

Abstract: Over the past decade, there has been increasing interest in the role of serotonin 6 (5-HT6) receptors in higher cognitive processes such as memory. Polymorphisms of the 5-HT6 receptor have been implicated in syndromes that affect cognition, such as schizophrenia and dementia. Manipulation of 5-HT6 receptor activity alters the transmission of several neurotransmitters important in memory: acetylcholine and glutamate, as well as dopamine, ã-aminobutyric acid (GABA), epinephrine (E), and norepinephrine (NE). Several 5-HT6 antagonists have been developed, advancing the understanding of the relationship between 5-HT6 blockade and memory consolidation in diverse learning paradigms. There is also evidence that 5-HT6 receptor activity affects anxiety behaviors and may be involved in the pathophysiology of schizophrenia. Several clinically useful atypical antipsychotics and antidepressants have 5-HT6 affinity, but recently developed selective 5-HT6 receptor antagonists may present attractive, new therapeutic options for several types of disease states.

Clark MS, Neumaier JF. · Department of Psychiatry and Behavioral Sciences, Harborview Medical Center, University of Washington, Seattle, USA. · Psychopharmacol Bull. · Pubmed #12397864 links to  free full text

Abstract: 5-HT1B receptors are expressed throughout the mammalian central nervous system. These receptors are located in the axon terminals of both serotonergic and nonserotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. 5-HT1B receptors inhibit the release of a range of neurotransmitters, including serotonin, GABA, acetylcholine, and glutamate. These receptors have been difficult to study because of the diversity of their cellular localization and the absence of highly selective agonists and antagonists. There has been accumulating evidence, however, that 5-HT1B receptors modulate drug reinforcement, stress sensitivity, mood, anxiety, and aggression. The general results of a number of studies suggest that reduced 5-HT1B heteroreceptor activity may increase impulsive behaviors, whereas reduced 5-HT1B autoreceptor activity may have an antidepressant-like effect. This review focuses on the evidence from animal studies and human genetics that suggest that 5-HT1B receptors may be involved in the mechanism of action of antidepressants and may become important targets of drug therapy in the future.

Clark MS, McDevitt RA, Hoplight BJ, Neumaier JF. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. · Neuroscience. · Pubmed #17467184 links to  free full text

Abstract: Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1 ng/h), urocortin II (UCNII, 1 ng/h), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 min on each of 2 days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT1A, 5-HT1B, 5-HT transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression was examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on re-exposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT1A, SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress.

Clark MS, McDevitt RA, Neumaier JF. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA. · J Comp Neurol. · Pubmed #16917826 No free full text.

Abstract: Depression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States. Impaired serotonin neurotransmission appears to be a central mechanism inducing depressive and anxiety symptoms. Most serotonergic innervation of the forebrain arises from the median raphe nucleus (MRN) and dorsal raphe nucleus (DRN). The DRN displays a complex internal morphology, with distinct subregions varying across the anteroposterior (A-P) axis. However, many studies have considered the DRN as a whole or used easily confused terminology to describe position. Given the large differences in receptor expression, electrophysiological properties, and connectivity between various subregions of the DRN, it appears probable that they have distinct functional roles in the regulation of behavior. To foster uniform definitions of locations within these nuclei, we have quantitatively mapped gene expression in DRN and MRN for tryptophan hydroxylase-2 (Tph2), the serotonin transporter, as well as 5-HT1A and 5-HT1B receptors. These quantitative studies revealed differences in the density of expression of each gene in the ventromedial, dorsomedial, and dorsolateral subnuclei of the DRN, as well as distinct variation in expression across the A-P axis. These findings provide additional evidence that subregions of the DRN are heterogeneous and need to be considered independently. In addition, a fine scale map of Tph2 expression suggests definitions for categorical divisions of the DRN across the A-P axis. These are based on distinct morphological patterns of Tph2 expression and may be more reflective of physiology than the classic terminology dividing the DRN into equal thirds.

Mitchell ES, Hoplight BJ, Lear SP, Neumaier JF. · 1-University of Washington, Harborview Medical Center, Seattle, 98104, USA. · Neuropharmacology. · Pubmed #16298400 No free full text.

Abstract: Inhibition of 5-HT(6) receptors has been shown to improve memory consolidation, thus we tested whether a novel tryptamine analog with high affinity for 5-HT(6) receptors, BGC20-761 (5-methoxy-2-phenyl-N,N-dimethyltryptamine, PMDT), can enhance long-term memory. BGC20-761 (10 mg/kg i.p.) alone had no effect on social recognition in young rats, however, at doses of 5 mg/kg and 10 mg/kg i.p, BGC20-761 dose-dependently reversed a deficit of social recognition induced by scopolamine (0.4 mg/kg i.p.), an anticholinergic drug that impairs memory. BGC20-761 (10 mg/kg i.p.), scopolamine (0.2 mg/kg i.p.) or BGC20-761 + scopolamine had no effects on novel object discrimination in young rats (2 months). In mature rats (6 months), recognition of the novel object was improved following administration of BGC20-761. Scopolamine had no effect in object recognition. However, the addition of scopolamine disrupted the memory-enhancing effect of BGC20-761. Based on the high affinity of BGC20-761 for 5-HT(6) receptors, these cognitive enhancing effects are most likely mediated by 5-HT(6) receptor inhibition. The difference in effects of BGC20-761 in young vs. mature rats may reflect the status of memory consolidation in these different age ranges.

Kohen R, Neumaier JF, Hamblin MW, Edwards E. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA. · Biol Psychiatry. · Pubmed #12644357 No free full text.

Abstract: BACKGROUND: Affective disorders and the drugs used to treat them lead to changes in intracellular signaling. We used a genetic animal model to investigate to what extent changes in intracellular signal transduction confer a vulnerability to mood or anxiety disorders. METHODS: Levels of gene expression in a selectively bred strain of rats with a high vulnerability to develop congenitally learned helplessness (cLH), a strain highly resistant to the same behavior (cNLH) and outbred Sprague-Dawley (SD) control animals were compared using quantitative reverse transcription polymerase chain reaction. RESULTS: Congenitally learned helpless animals had a 24%-30% reduced expression of the cyclic adenosine monophosphate response element binding protein messenger ribonucleic acid (mRNA) in the hippocampus and a 40%-41% increased level of the antiapoptotic protein bcl-2 mRNA in the prefrontal cortex compared to cNLH and SD rats. Other significant changes included changes in the expression levels of the alpha catalytic subunit of protein kinase A, glycogen synthase kinase 3beta, and protein kinase C epsilon. CONCLUSIONS: Congenitally learned helpless animals show evidence of altered signal transduction and regulation of apoptosis compared to cNLH and SD control animals.