Faculty Bibliography

A previous study showed that two mouse models of behavioral depression, immune system activation and depletion of brain monoamines, are accompanied by marked reductions in stimulated neural activity in brain regions involved in motivated behavior. The present study tested whether this effect is common to other depression models by examining the effects of repeated forced swimming, chronic subordination stress or acute intraventricular galanin injection - three additional models - on baseline or stimulated c-fos expression in several brain regions known to be involved in motor or motivational processes (secondary motor, M2, anterior piriform cortex, APIR, posterior cingulate gyrus, CG, nucleus accumbens, NAC). Each of the depression models was found to reduce the fos response stimulated by exposure to a novel cage or a swim stress in all four of these brain areas but not to affect the response of a stress-sensitive region (paraventricular hypothalamus, PVH) that was included for control purposes. Baseline fos expression in these structures was either unaffected or affected in an opposite direction to the stimulated response. Pretreatment with either desmethylimipramine (DMI) or tranylcypromine (tranyl) attenuated these changes. It is concluded that the pattern of a reduced neural function of CNS motor/motivational regions with an increased function of stress areas is common to 5 models of behavioral depression in the mouse and is a potential experimental analog of the neural activity changes occurring in the clinical condition

Central alpha(1)-adrenoceptors are activated by norepinephrine (NE), epinephrine (EPI) and possibly dopamine (DA), and function in two fundamental and opposed types of behavior: (1) positively motivated exploratory and approach activities, and (2) stress reactions and behavioral inhibition. Brain microinjection studies have revealed that the positive-linked receptors are located in eight to nine brain regions spanning the neuraxis including the secondary motor cortex, piriform cortex, nucleus accumbens, preoptic area, lateral hypothalamic area, vermis cerebellum, locus coeruleus, dorsal raphe and possibly the C1 nucleus of the ventrolateral medulla, whereas the stress-linked receptors are present in at least three areas including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and bed nucleus of the stria terminalis. Recent studies utilizing c-fos expression and mitogen-activated protein kinase activation have shown that various diverse models of depression in mice produce decreases in positive region-neural activity elicited by motivating stimuli along with increases in neural activity of stress areas. Both types of change are attenuated by various antidepressant agents. This has suggested that the balance of the two networks determines whether an animal displays depressive behavior. A central unresolved question concerns how the alpha(1)-receptors in the positive-activity and stress systems are differentially activated during the appropriate behavioral conditions and to what extent this is related to differences in endogenous ligands or receptor subtype distributions.

The present experiments were undertaken to clarify the role of central alpha(1)-adrenoceptors in reward processes. Rats, trained to self-stimulate via electrodes in the medial forebrain bundle of the lateral hypothalamus, were administered alpha(1)-selective drugs near the locus coeruleus (LC), a site of a dense concentration of alpha(1)-receptors. Effects on reward potency were assessed from shifts in rate-frequency curves while effects on motor response capacity were judged from changes in the maximal rates of responding. It was found that local blockade of LC alpha(1)-receptors with terazosin produced a significant dose-dependent and site-dependent rightward shift of 0.08 log units and a significant decrease of 16.3% in the maximum response rate. Both effects were completely reversed by coadministration of the alpha(1)-agonist, phenylephrine and were not attributable to terazosin's weak action at alpha(2)-adrenoceptors. It is concluded that LC alpha(1)-adrenoceptors are involved both in reward/motivational processes and operant response elaboration which are postulated to work together to facilitate goal attainment.Neuropsychopharmacology advance online publication, 5 July 2006; doi:10.1038/sj.npp.1301145

BACKGROUND: Immune stimulation inhibits positively motivated behavior and induces depressive illness. To help clarify the mechanism of these effects, neural activity in response to a positive stimulus was examined in brain regions associated with positively motivated activity defined on the basis of prior behavioral studies of central alpha1-adrenoceptor action. METHODS: Mice pretreated with either lipopolysaccharide or, for comparison, reserpine were exposed to a motivating stimulus (fresh cage) and subsequently assayed for fos expression and mitogen-activated protein kinase (MAPK) phosphorylation, two measures associated with alpha1-adrenoceptor-dependent neural activity, in several positive-activity-related (motor, piriform, cingulate cortex, nucleus accumbens, locus coeruleus) and stress-related brain regions (paraventricular hypothalamus, bed nucleus stria terminalis). RESULTS: Both lipopolysaccharide and reserpine pretreatment abolished fresh cage-induced fos expression and MAPK activation in the positive activity-related brain regions but enhanced these measures in the stress-related areas. CONCLUSIONS: The results support the hypothesis that immune activation reduces alpha1-adrenoceptor-related signaling and neural activity in brain regions associated with positive activity while it increases these functions in stress-associated areas. It is suggested that neural activities of these two types of brain regions are mutually antagonistic and that a reciprocal shift toward the stress regions is a factor in the loss of positively motivated behaviors in sickness behavior and depressive illness

Dyskinesia is the most troublesome side effect in long-term treatment of both Parkinson's disease (PD) and schizophrenia. The 5-HT1A agonist and D3/D4 ligand sarizotan [Bartoszyk, G.D., van Amsterdam, C., Greiner, H.E., Rautenberg, W., Russ, H., Seyfried, C.A., 2004. Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J. Neural Transm. 111, 113-126.] is in clinical development for the treatment of PD-associated dyskinesia. Because 5-HT1A agonists are known to counteract antipsychotic-induced motor side effects, sarizotan was investigated for its effects in two rat models of tardive dyskinesia (TD). The acute administration of sarizotan (0.17-13.5 mg/kg i.p.) reduced episodes of SKF 38393-induced repetitive jaw movements (RJM) in rats with a maximal effect at 1.5 mg/kg. In a chronic study, sarizotan (0.04-9 mg/kg/day), administered in the drinking water for 7 weeks during withdrawal from chronic haloperidol treatment (1.5 mg/kg/day), dose-dependently reversed haloperidol-induced RJM, significant at the doses of 1.5 and 9 mg/kg. Agonism at 5-HT1A receptors may be mediating the inhibitory effect of sarizotan on RJM in rat models of tardive dyskinesia

RATIONALE: Central alpha(1)- and alpha(2)-adrenoceptors in a number of different brain regions are known to have opposing actions on gross behavioral activity, with the former stimulating and the latter inhibiting activity. Therefore, blockade of alpha(1)-receptors may induce inactivity by leading to unopposed alpha(2) activity. OBJECTIVE: The aim of this study was to test if central blockade of alpha(2)-receptor function restores behavioral activity in alpha(1)-receptor-blocked mice. METHODS: Dose-response studies were undertaken on the effects of alpha(1)- and alpha(2)-agonists and antagonists microinjected into the dorsal pons on gross behavioral activity in a novel cage test. RESULTS: The behavioral inactivity resulting from blockade of alpha(1)-receptors in the pons with the antagonist, terazosin, was reversed by either a low dose of an alpha(2)-antagonist, atipamezole, or a low dose of an alpha(2)-agonist, dexmedetomidine, but was exacerbated by a high dose of the alpha(2)-agonist. CONCLUSION: The results support the hypothesis that blockade of alpha(1)-receptors in the dorsal pons of mice produces inactivity by causing unopposed activity of alpha(2)-receptors. This condition may be relevant to inactive states seen after stress or during depressive illness

Previous studies have shown that central alpha1-adrenoceptor activity is necessary, acutely, for gross behavioral activity in response to novel surroundings and various psychostimulants. The present experiment tested whether it is also necessary for the hyperactivity produced by the peptide, orexin A, which is present in several central monoaminergic nuclei. Mice, pretreated intraventricularly with the alpha1-antagonist, terazosin, or the alpha2-antagonist, atipamezole, were given orexin A, intraventricularly (i.v.t.), and videotaped for gross movement and locomotion in the home cage between 30 and 60 min post-infusion. The alpha1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3 nmol dose and was near total at 30 nmol. The alpha2-antagonist, at 10 nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric alpha1-adrenoceptors, with 2,3-dichloro-alpha-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central alpha1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A

The question of whether or not the locus coeruleus (LC) participates in the control of motor activity has been controversial due to difficulties in demonstrating permanent motor deficits after neurotoxic lesions of this nucleus or of the dorsal noradrenergic bundle (DNB). In the present experiments it was shown in rats that acute local blockade (with terazosin) or stimulation (with phenylephrine) of LC alpha(1)-adrenoceptors respectively blocked or stimulated exploratory behavior in a novel cage and the home cage. Moreover, previous lesion of the DNB by i.p. DSP4 abolished the behavioral changes to local LC alpha(1)-receptor manipulation but did not affect motor activity in the novel or home cage by itself. These findings are consistent with the hypothesis that the intact LC does contribute to motor activity control, exerted in part by its alpha(1)-receptors; however, the permanent loss of this nucleus is compensated for by remaining CNS motor structures

MRI may be used for detecting cartilage invasion in patients with laryngeal carcinoma. However, the normal laryngeal ossification pattern has not been studied. Our purpose was to examine the normal age-related signal patterns in the cricoid, thyroid and arytenoid cartilages on T1-weighted images. Signal in the cartilages was assessed by two radiologists in a blinded fashion using three-point scales for intensity and symmetry. Statistical analysis consisted of logistic and monotonic regression. There was excellent interobserver agreement (>85%) for all categories. The cartilages predominantly ossify symmetrically and the extent of high signal from all three increases with age. The latter may help in detection of cartilage invasion by tumor in older patients. Normal symmetry may be helpful when comparing sides for tumor invasion