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Abstract: Central α1-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 α1-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. [Copyright &y& Elsevier]

The effects of chronic treatment with typical and atypical antipsychotics on acquisition, working memory, motor activity, and rat tardive dyskinesia (TD) were studied in 3- and 18-month-old Sprague–Dawley rats. Acquisition and working memory were studied in eight-arm radial mazes. TD liability of antipsychotic drugs (APD) was evaluated in rat model of TD in which spontaneous repetitive jaw movements (RJM) occur during withdrawal from neuroleptic treatment. Motor behavior was assessed using the traverse beam test. D1 and D2 receptor occupancy was determined in the rat brain during treatment with typical and atypical antipsychotics. Chronic administration of clozapine, haloperidol, and risperidone impaired acquisition of the eight-arm radial maze in both young and aging rats while olanzapine had no effect. Retention tests showed that aging rats made more errors than the adults and that the antipsychotics haloperidol and risperidone significantly impaired retention in both age groups. Evaluation of motor behavior revealed that typical and atypical antipsychotics used in comparable doses in young rats had no effect on motor behavior, whereas in aging rats performance was impaired by clozapine, haloperidol, and risperidone but not by olanzapine. RJM responses were increased during washout from haloperidol treatment in young and aging rats whereas olanzapine, clozapine, and risperidone had no effect. D2 receptor occupancy in haloperidol- and risperidone-treated rats was above 70% while olanzapine and clozapine receptor occupancy was below 70%, which is the threshold for the appearance of extrapyramidal syndrome (EPS) and TD. [Copyright &y& Elsevier]

The typical antipsychotic haloperidol and atypical antipsychotics olanzapine, quetiapine and risperidone were administered to pregnant Sprague–Dawley dams in the drinking water from Days 8 to 18 of gestation. When the offspring reached adulthood (2 months), spatial learning and short-term retention were examined using the radial arm maze. Results showed that prenatal administration of haloperidol, risperidone and quetiapine impaired learning but only haloperidol and risperidone disrupted short-term retention. [Copyright &y& Elsevier]

Abstract: Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24h after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8h, beginning immediately after TBI demonstrated significantly improved STM at 24h when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24h showed no improvement in STM. Mice treated with INO 10ppm for 8h exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24h after injury and persists for 2—3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion. [Copyright &y& Elsevier]

Abstract: The present study evaluated the extension of a new rat model of depression, repeated open-space swimming, which overcomes drawbacks of existing models, to mice. Mice were swum for 15 min daily in a large tank of tepid water for 4 days and thereafter at 4 day intervals for a period of 3 weeks. Some of the animals were provided with an active coping (escape) response. Variables measured included time floating, distance swum, immobility on a subsequent tail-suspension test, sucrose preference and brain cell proliferation (Ki67 immunohistochemistry) as well as responses to 2 antidepressant drugs, desmethylimipramine and fluoxetine, and 2 non-antidepressant drugs, haloperidol and diazepam. The repeated swims were found to increase time floating and tail-suspension immobility and to decrease distance swum, sucrose preference and brain cell proliferation. Both chronic antidepressant drugs as well as the active coping response attenuated the increased time floating while neither of the non-antidepressant drugs had this effect. The distance swum measure was found to be more variable. Chronic fluoxetine also reversed the increased tail-suspension immobility, reduced sucrose preference and reduced brain cell proliferation caused by the model. It is concluded that repeated open-space swim represents a useful new model of depression in the mouse. [Copyright &y& Elsevier]

Abstract: Functional neuroimaging studies of depressed patients have converged with functional brain mapping studies of depressed animals in showing that depression is accompanied by a hypoactivity of brain regions involved in positively motivated behavior together with a hyperactivity in regions involved in stress responses. Both sets of changes are reversed by diverse antidepressant treatments. It has been proposed that this neural pattern underlies the symptoms common to most forms of the depression, which are the loss of positively motivated behavior and increased stress. The paper discusses how this framework can organize diverse findings ranging from effects of monoamine neurotransmitters, cytokines, corticosteroids and neurotrophins on depression. The hypothesis leads to new insights concerning the relationship between the prolonged inactivity of the positive motivational network during a depressive episode and the loss of neurotrophic support, the potential antidepressant action of corticosteroid treatment, and to the key question of whether antidepressants act by inhibiting the activity of the stress network or by enhancing the activity of the positive motivational system. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Brain α1-adrenoceptors have been shown to be essential for motor activity and movement in mice using intraventricular injection of α1-antagonists. To facilitate subsequent neuroanatomical mapping of these receptors, the present study was undertaken to replicate these effects in the rat. Rats were administered the α1-antagonist, terazosin, in the absence and presence of the α1-agonist, phenylephrine, in the IVth ventricle and were tested for their motor activity responses to an environmental change. Terazosin was found to produce a dose-dependent, virtually complete cessation of behavioral activity that was reversed by coinfusion of phenylephrine. The results could not be explained by sedation. It is concluded that central α1-adrenoceptors are essential for behavioral activation in rats as in mice. [Copyright &y& Elsevier]

Abstract: Inhaled nitric oxide (iNO) has been shown to reduce ischemia/reperfusion (I/R) injury in several different organ systems including the brain. We investigated whether iNO was neuroprotective in a mouse model of transient focal ischemia. Male Swiss Webster mice underwent middle cerebral artery occlusion for 1h followed by reperfusion for 47h. Mice were divided into 5 concentration groups and administered nitric oxide (NO) at either 10, 20, 40, 60 or 80ppm. Each of the 5 concentration groups was subdivided into 4 duration groups which were treated with iNO for 5, 8, 16 or 24h beginning immediately after artery occlusion. Results showed both concentration and duration determined efficacy. At 10ppm only the 24hr duration group exhibited reduced infarct volume while at 20, 40 and 60ppm only 8 and 16h of exposure led to smaller infarctions. At these concentrations the dose response curves were strongly U shaped indicating a loss of benefit at long durations. At 80ppm, reduction in infarct volume was not observed at any duration. Additional experiments showed that 60ppm iNO could be transported from lung to brain and that iNO administered for 8h improved recovery from subarachnoid hemorrhage and reduced the inflammatory response accompanying ischemic stroke. Enhanced blood flow during reperfusion may be an important mediator of these effects. [Copyright &y& Elsevier]

Abstract: Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function. [Copyright &y& Elsevier]

Abstract: α1-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective α-agonist that has full efficacy at all brain α-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel-running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of α1- (terazosin) or α2- (atipamezole) receptors or of either the partial α1-agonist, phenylephrine, or full α2-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC α1-receptors consistent with the known greater density of α1- than α2-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the α1-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

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 α1-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 α1-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 α1-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. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that central α1-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 α1-antagonist, terazosin, or the α2-antagonist, atipamezole, were given orexin A, intraventricularly (ivt), and videotaped for gross movement and locomotion in the home cage between 30 and 60min post-infusion. The α1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3nmol dose and was near total at 30nmol. The α2-antagonist, at 10nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric α1-adrenoceptors, with 2,3-dichloro-α-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central α1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A. [Copyright &y& Elsevier]

Brain α1-adrenoceptors that participate in behavioral activation were mapped in the mouse brain by determining where microinjection of the α1-antagonist, terazosin, inhibited behavioral activity in a novel cage test. A total of 5 out of 23 tested regions were shown to be involved including the dorsal pons/locus coeruleus region (DP/LC), the dorsal raphe/periaqueductal gray area (DR/PAG), the vermis cerebellum (CER), the nucleus accumbens (ACC) and the medial preoptic area (MPOA). Injection in the 4th ventricle was also effective perhaps by acting on several of these regions simultaneously. A partial inhibition was obtained from the motor cortex. Coinjection of the α1/2-agonist, 6-fluoronorepinephrine (6FNE) but not the α2-agonist, dexmedetomidine (DMT) reversed the behavioral inhibition in all regions. It is hypothesized that brain motoric α1-receptors elicit behavioral activation by coordinately exciting several monoaminergic, motor and motivational systems. [Copyright &y& Elsevier]

Brain α1-adrenoceptors are known to be necessary for motor activity in rodents and have been shown to be altered by stress and corticosteroids but only in biochemical experiments. To determine if the behaviorally coupled receptors are also affected by stress, the present study examined the effect of stress and corticosteroids treatment on the motor activity response to modafinil, a putative α1-adrenoceptor agonist, which is unique in that it elicits extremely high levels of activity via these receptors. Mice were subjected to various schedules of restraint stress for 1–6 days and were subsequently tested for either modafinil-induced or dopaminergically induced behavioral activity in the home cage using videotape recording. In experiments on corticosteroid treatment, mice received exogenous corticosterone or dexamethasone in the drinking water before and during the stress and were tested for modafinil-induced activity as above. It was found that the stress significantly reduced the response to the drug by the third daily session. Motor responses to dopaminergic agents including apomorphine, amphetamine, dihydrexidine and quinpirole were either not altered or were increased at this time. Treatment of animals with corticosterone or dexamethasone prior to and during stress prevented the behavioral subsensitivity to modafinil. Corticosterone pretreatment markedly suppressed the plasma corticosterone response to the stress. The present results provide further support for the hypothesis that stress produces a selective desensitization or inhibition of motor-related brain α1-adrenoceptors and that this effect can be prevented by corticosteroid treatment. [Copyright &y& Elsevier]