Ketamine enhances structural plasticity in mouse mesencephalic and human iPSC-derived dopaminergic neurons via AMPAR-driven BDNF and mTOR signaling.

Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.

Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats.

Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.

Alpha1-adrenoceptors mediate dihydroxyphenylalanine-induced activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques.

The mechanisms underlying actions of dihydroxyphenylalanine (L-DOPA) in Parkinson's disease remain to be fully elucidated. Noradrenaline formed from L-DOPA may stimulate alpha(1)-adrenoceptors. We assessed the involvement of alpha(1)-adrenoceptors in actions of L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaques. In each animal, the minimal dose of L-DOPA required to alleviate parkinsonian symptoms was defined (12.5-25 mg/kg p.o.). The effects of coadministration of the alpha(1)-adrenoceptor antagonist prazosin ([4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone) on motor activity, parkinsonism, and dyskinesia were assessed. Antiparkinsonian benefit was accompanied by mild dyskinesia. L-DOPA also elicited hyperactivity, i.e., activity greater than that seen in normal animals. Coadministration of prazosin (0.16-0.63 mg/kg p.o.) with L-DOPA did not significantly affect either its antiparkinsonian actions or dyskinesia. However, prazosin significantly and dose-dependently attenuated L-DOPA-induced activity, reducing it to a level equivalent to that of normal animals. More specifically, during periods of pronounced L-DOPA-induced activity, prazosin attenuated the total and duration of activity by 80 and 76%, respectively. These actions of prazosin were expressed in the absence of sedation. Although activation of alpha(1)-adrenoceptors plays no major role in the antiparkinsonian and dyskinetic effects of L-DOPA per se, it does contribute to the induction of hyperactivity. alpha(1)-Adrenoceptors may be involved in pathological responses to L-DOPA treatment, including the dopamine dysregulation syndrome.

An immunocapture/scintillation proximity analysis of G alpha q/11 activation by native serotonin (5-HT)2A receptors in rat cortex: blockade by clozapine and mirtazapine.

Though transduction mechanisms recruited by heterologously expressed 5-HT(2A) receptors have been extensively studied, their interaction with specific subtypes of G-protein remains to be directly evaluated in cerebral tissue. Herein, as shown by an immunocapture/scintillation proximity analysis, 5-HT, the prototypical 5-HT(2A) agonist, DOI, and Ro60,0175 all enhanced [(35)S]GTPgammaS binding to G alpha q/11 in rat cortex with pEC(50) values of 6.22, 7.24 and 6.35, respectively. No activation of G o or G s/olf was seen at equivalent concentrations of DOI. Stimulation of G alpha q/11 by 5-HT (30 microM) and DOI (30 microM) was abolished by the selective 5-HT(2A) vs. 5-HT(2C)/5-HT(2B) antagonists, ketanserin (pK(B) values of 9.11 and 8.88, respectively) and MDL100,907 (9.82 and 9.68). By contrast, 5-HT-induced [(35)S]GTPgammaS binding to G alpha q/11 was only weakly inhibited by the preferential 5-HT(2C) receptor antagonists, RS102,221 (6.94) and SB242,084 (7.39), and the preferential 5-HT(2B) receptor antagonist, LY266,097 (6.66). The antipsychotic, clozapine, which had marked affinity for 5-HT(2A) receptors, blocked the recruitment of G alpha q/11 by 5-HT and DOI with pK(B) values of 8.54 and 8.14, respectively. Its actions were mimicked by the "atypical" antidepressant and 5-HT(2A) receptor antagonist, mirtazapine, which likewise blocked 5-HT and DOI-induced G alpha q/11 protein activation with pK(B) values of 7.90 and 7.76, respectively. In conclusion, by use of an immunocapture/scintillation proximity strategy, this study shows that native 5-HT(2A) receptors in rat frontal cortex specifically recruit G alpha q/11 and that this action is blocked by clozapine and mirtazapine. Quantification of 5-HT(2A) receptor-mediated G alpha q/11 activation in frontal cortex should prove instructive in characterizing the actions of diverse classes of psychotropic agent.

The PINK1 kinase-driven ubiquitin ligase Parkin promotes mitochondrial protein import through the presequence pathway in living cells.

Most of over a thousand mitochondrial proteins are encoded by nuclear genes and must be imported from the cytosol. Little is known about the cytosolic events regulating mitochondrial protein import, partly due to the lack of appropriate tools for its assessment in living cells. We engineered an inducible biosensor for monitoring the main presequence-mediated import pathway with a quantitative, luminescence-based readout. This tool was used to explore the regulation of mitochondrial import by the PINK1 kinase-driven Parkin ubiquitin ligase, which is dysfunctional in autosomal recessive Parkinson's disease. We show that mitochondrial import was stimulated by Parkin, but not by disease-causing Parkin variants. This effect was dependent on Parkin activation by PINK1 and accompanied by an increase in the abundance of K11 ubiquitin chains on mitochondria and by ubiquitylation of subunits of the translocase of outer mitochondrial membrane. Mitochondrial import efficiency was abnormally low in cells from patients with PINK1- and PARK2-linked Parkinson's disease and was restored by phosphomimetic ubiquitin in cells with residual Parkin activity. Altogether, these findings uncover a role of ubiquitylation in mitochondrial import regulation and suggest that loss of this regulatory loop may underlie the pathophysiology of Parkinson's disease, providing novel opportunities for therapeutic intervention.

Proposed clinical scale for the diagnosis of acute coronary syndrome in patients with an inconclusive electrocardiogram and myocardial injury biomarkers. / Propuesta de una escala clínica para el diagnóstico de síndrome coronario agudo en pacientes con electrocardiograma y biomarcadores de lesión miocárdica no concluyentes.

RATIONALE: Acute coronary syndrome (ACS) requires improved diagnostic accuracy through useful, safe and easy-to-apply tools. OBJECTIVES: To obtain an assessment scale for the diagnosis of ACS in patients with chest pain and nondiagnostic electrocardiogram and troponin concentrations. METHODS: A prospective cohort study included 286 patients treated in the emergency department for chest pain, with normal electrocardiogram and troponin levels. Using multiple logistic regression, we obtained the independent predictors for the diagnosis of ACS. The assessment scale's discriminative power was assessed with the area under the ROC curve. RESULTS: The diagnosis of ACS was confirmed in 103 patients (36%). The final predictive model included 3 endpoints: a history of coronary artery disease, hyperlipidaemia and a score≥6 points on the Geleijnse scale. The area under the ROC curve for the final model was 0.90 (95% confidence interval [95% CI] 0.85-0.93). A threshold of 5 points achieved a sensitivity of 76.7% (95% CI 68-84), a specificity of 91.8% (95% CI 87-95), a positive likelihood ratio of 9.36 (95% CI 5.70-15.40), a negative likelihood ratio of 0.25 (95% CI 18.00-36.00) and an overall diagnostic accuracy of 86.4% (95% CI 82-90). The predictive model was superior to the Geleijnse scale alone. CONCLUSIONS: The final scale showed good discriminative capacity for diagnosing ACS and could therefore be of interest for identifying ACS in emergency departments. Nevertheless, the scale needs to be validated in larger multicentre studies.

Dopamine D1 receptor coupling to Gs/olf and Gq in rat striatum and cortex: a scintillation proximity assay (SPA)/antibody-capture characterization of benzazepine agonists.

Cloned, human dopamine D(1) receptors recruit multiple effectors but the G-protein subtype(s) activated by cerebral populations remain poorly defined, a question addressed using a rapid immunocapture technique. In rat striatum, dopamine (DA) and four selective, benzazepine agonists at D(1) receptors concentration-dependently enhanced [(35)S]GTPgammaS binding to Galphas/olf. For all drugs, Galphaq was also recruited with similar potencies and efficacies. Comparable observations were made in the cortex wherein profiles of Galphas/olf vs Galphaq activation were also highly correlated. In contrast to Galphas/olf and Galphaq, Galphao and Galphai were activated neither in the striatum nor in the cortex, except for SKF82958. As compared to DA, both SKF81297 and SKF82958 were full agonists at Gs/olf and Gq in cortex and striatum, whereas SKF38393 behaved as a partial agonist. Likewise, the "atypical" agonist, SKF83959 only partially activated Galphaq and also Gs/olf in these two regions. In both striatum and cortex, the selective D(1) receptor antagonist, SCH23390, abolished the recruitment of Galphaq and Galphas by DA, and the action of DA was partially attenuated by SKF83959. These findings demonstrate that, in native CNS tissue, DA and other D(1) receptor agonists activate Galphas and Galphaq with similar potencies and efficacies, suggesting their recruitment via pharmacologically-indistinguishable populations of D(1) receptors, and show that SPA technology is well-adapted to study the coupling of native DA receptors.

Deconstructing vulnerability for psychosis: Meta-analysis of environmental risk factors for psychosis in subjects at ultra high-risk.

BACKGROUND: Subjects at ultra high-risk (UHR) for psychosis have an enhanced vulnerability to develop the disorder but the risk factors accounting for this accrued risk are undetermined. METHOD: Systematic review of associations between genetic or environmental risk factors for psychosis that are widely established in the literature and UHR state, based on comparisons to controls. RESULTS: Forty-four studies encompassing 170 independent datasets and 54 risk factors were included. There were no studies on association between genetic or epigenetic risk factors and the UHR state that met the inclusion criteria. UHR subjects were more likely to show obstetric complications, tobacco use, physical inactivity, childhood trauma/emotional abuse/physical neglect, high perceived stress, childhood and adolescent low functioning, affective comorbidities, male gender, single status, unemployment and low educational level as compared to controls. CONCLUSIONS: The increased vulnerability of UHR subjects can be related to environmental risk factors like childhood trauma, adverse life events and affective dysfunction. The role of genetic and epigenetic risk factors awaits clarification.

Diagnostic validity of hand gestures in chest pain of coronary origin. / Validez diagnóstica del lenguaje de las manos en el dolor torácico de origen coronario.

OBJECTIVES: To determine the frequency of 3 hand gestures by patients with chest pain and determine the diagnostic validity of the gestures in acute coronary syndrome. PATIENTS AND METHODS: A prospective study was conducted on 383 adult patients treated for chest pain in an emergency department. We observed certain hand gestures, previously referred to in the medical literature as characteristic of coronary pain (gesture 1: a clenched fist held over the sternal area or Levine's sign; gesture 2: open hand located over the same area; gesture 3: both hands placed in the centre of the chest), as well as other gestures. We analysed their association with the coronary origin of the pain. RESULTS: We confirmed the coronary origin of the pain in 164 (43%) patients (ACS group). The other 219 patients (57%) did not have a coronary origin for the pain (nonACS group). Eighty-nine percent of the patients identified their pain with one of the 3 classical gestures. The most frequent gesture was number 2, both overall (59%) and by group (60% ACS group; 57.5% nonACS group). There was no significant association between the type of gesture and the final diagnosis (P=.172). The greater specificity corresponded to Levine's sign (90%), followed by other gestures (86%) and gesture 3 (81%). CONCLUSIONS: Although 89% of the patients expressed their chest pain with one of the 3 manual gestures classically associated with coronary pain, none achieved sufficient diagnostic accuracy to be used as indicative of this type of pain.

Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors.

Mammalian circadian activity rhythms are generated by pacemaker cells in the suprachiasmatic nucleus (SCN). As revealed by the actions of diverse agonists, serotonergic input from raphe nuclei generally inhibits photic signaling in the suprachiasmatic nucleus. In contrast, the serotonin (5HT)1A partial agonist, 4-(benzodioxan-5-yl)1-(indan2-yl)piperazine (S 15535), was found to enhance the phase-shifting influence of light on hamster circadian rhythms [Gannon, Neuroscience 119 (2003) 567]. Herein, we extend this observation in showing that S 15535 (5.0 mg/kg, i.p.) markedly (275%) enhanced the light-induced phase shift in circadian activity rhythms: further, this action was dose-dependently abolished by the highly-selective 5HT1A receptor antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-2-pyridinyl-cyclohexane-carboxamide maleate) (0.1-0.5 mg/kg, i.p.). WAY 100,635, which was inactive alone, shares the antagonist actions of S 15535 at postsynaptic 5HT1A sites, yet blocks its effects at their presynaptic counterparts. Thus, 5HT1A autoreceptor activation must be involved in this effect of S 15535 which contrasts with the opposite, inhibitory influence upon phase shifts of the "full" agonist, 8-OH-DPAT, which acts by stimulation of postsynaptic 5HT1A receptors [Rea et al., J Neurosci 14 (1994) 3635]. Despite the occurrence of 5HT2A and 5HT2C receptors in the (rat) suprachiasmatic nucleus, their influence on circadian rhythms is unknown since actions of selective ligands have never been evaluated. This issue was investigated with the most selective agents currently available. However, the 5HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.25 and 0.5 mg/kg), and the 5HT2C agonist, alphaS-6-chloro-5-fluoro-a-methyl-1H-indole-1-ethanamine fumarate (Ro-60-0175) (1.0 and 5.0 mg/kg), failed to affect light-induced phase shifts in hamsters. Moreover, even over broad dose-ranges, the 5HT2A antagonist, (+)-(2,3-dimethoxy-phenyl)-[1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl]methanol (MDL 100,907) (0.1-1.0 mg/kg), and the 5HT2C antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl carbamoyl]indoline (SB 242,084) (1.0-10.0 mg/kg), were likewise inactive. In view of evidence that 5HT2A and 5HT2C sites functionally interact with 5HT1A receptors, we also examined the influence of these agents upon the actions of S 15535, but no significant alteration was seen in its enhancement of rhythms. In conclusion, S 15535 elicits a striking enhancement of light-induced phase shifts in circadian rhythms by specifically recruiting 5HT1A autoreceptors, which leads to suppression of serotonergic input to the suprachiasmatic nucleus. Surprisingly, no evidence for a role of 5HT2A or 5HT2C sites was found, though comparable functional studies remain to be undertaken in rats. Indeed, the present work underlines the importance of comparative studies of circadian rhythms in various species, as well as the need for further study of potential interactions among 5HT receptor subtypes in their control.

The induction of pain: an integrative review.

The highly disagreeable sensation of pain results from an extraordinarily complex and interactive series of mechanisms integrated at all levels of the neuroaxis, from the periphery, via the dorsal horn to higher cerebral structures. Pain is usually elicited by the activation of specific nociceptors ('nociceptive pain'). However, it may also result from injury to sensory fibres, or from damage to the CNS itself ('neuropathic pain'). Although acute and subchronic, nociceptive pain fulfils a warning role, chronic and/or severe nociceptive and neuropathic pain is maladaptive. Recent years have seen a progressive unravelling of the neuroanatomical circuits and cellular mechanisms underlying the induction of pain. In addition to familiar inflammatory mediators, such as prostaglandins and bradykinin, potentially-important, pronociceptive roles have been proposed for a variety of 'exotic' species, including protons, ATP, cytokines, neurotrophins (growth factors) and nitric oxide. Further, both in the periphery and in the CNS, non-neuronal glial and immunecompetent cells have been shown to play a modulatory role in the response to inflammation and injury, and in processes modifying nociception. In the dorsal horn of the spinal cord, wherein the primary processing of nociceptive information occurs, N-methyl-D-aspartate receptors are activated by glutamate released from nocisponsive afferent fibres. Their activation plays a key role in the induction of neuronal sensitization, a process underlying prolonged painful states. In addition, upon peripheral nerve injury, a reduction of inhibitory interneurone tone in the dorsal horn exacerbates sensitized states and further enhance nociception. As concerns the transfer of nociceptive information to the brain, several pathways other than the classical spinothalamic tract are of importance: for example, the postsynaptic dorsal column pathway. In discussing the roles of supraspinal structures in pain sensation, differences between its 'discriminative-sensory' and 'affective-cognitive' dimensions should be emphasized. The purpose of the present article is to provide a global account of mechanisms involved in the induction of pain. Particular attention is focused on cellular aspects and on the consequences of peripheral nerve injury. In the first part of the review, neuronal pathways for the transmission of nociceptive information from peripheral nerve terminals to the dorsal horn, and therefrom to higher centres, are outlined. This neuronal framework is then exploited for a consideration of peripheral, spinal and supraspinal mechanisms involved in the induction of pain by stimulation of peripheral nociceptors, by peripheral nerve injury and by damage to the CNS itself. Finally, a hypothesis is forwarded that neurotrophins may play an important role in central, adaptive mechanisms modulating nociception. An improved understanding of the origins of pain should facilitate the development of novel strategies for its more effective treatment.

Limited beneficial effects of piceatannol supplementation on obesity complications in the obese Zucker rat: gut microbiota, metabolic, endocrine, and cardiac aspects.

Resveratrol is beneficial in obese and diabetic rodents. However, its low bioavailability raises questions about its therapeutic relevance for treating or preventing obesity complications. In this context, many related natural polyphenols are being tested for their putative antidiabetic and anti-obesity effects. This prompted us to study the influence of piceatannol, a polyhydroxylated stilbene, on the prevention of obesity complications in Zucker obese rats. A 6-week supplementation was followed by the determination of various markers in plasma, liver, adipose tissue and heart, together with a large-scale analysis of gut microbiota composition. When given in doses of 15 or 45 mg/kg body weight/day, piceatannol did not reduce either hyperphagia or fat accumulation. It did not modify the profusion of the most abundant phyla in gut, though slight changes were observed in the abundance of several Lactobacillus, Clostridium, and Bacteroides species belonging to Firmicutes and Bacteroidetes. This was accompanied by a tendency to reduce plasma lipopolysaccharides by 30 %, and by a decrease of circulating non-esterified fatty acids, LDL-cholesterol, and lactate. While piceatannol tended to improve lipid handling, it did not mitigate hyperinsulinemia and cardiac hypertrophy. However, it increased cardiac expression of ephrin-B1, a membrane protein that contributes to maintaining cardiomyocyte architecture. Lastly, ascorbyl radical plasma levels and hydrogen peroxide release by adipose tissue were similar in control and treated groups. Thus, piceatannol did not exhibit strong slimming capacities but did limit several obesity complications.

Kappa-opioid receptors and analgesia.

Over the past decade, opioids have attracted great attention. One important reason for this is the need for novel, strong analgesics free of the abuse potential and side-effects of narcotics such as morphine. Because morphine acts at mu-opioid receptors, efforts have been made to characterize analgesia mediated by non-mu sites, in particular kappa-opioid receptors. There is now good evidence that kappa-receptors do indeed mediate analgesia. However, kappa-agonists display properties that could curtail their therapeutic exploitation. Since the first selective kappa-agonists are now entering clinical trials, this is an opportune moment for Mark Millan to review the pharmacology of drugs of this type in the control of nociception and their therapeutic potential as analgesics.

Gut microbiota: a key player in health and disease. A review focused on obesity.

Gut microbiota, its evolutive dynamics and influence on host through its protective, trophic and metabolic actions, has a key role in health and opens unique opportunities for the identification of new markers of the physiopathological state of each individual. Alterations in gut microbiota composition have been associated with plenty disorders. Of interest, the vast number of studies demonstrates the role of microbiota in obesity, a serious public health problem that has reached epidemic proportions in many developed and middle-income countries. The economic and health costs of this condition and its comorbidities such as fatty liver, insulin resistance/diabetes, or cardiovascular events are considerable. Therefore, every strategy designed to reduce obesity would imply important savings. Targeting microbiota, in order to restore/modulate the microbiota composition with antibiotics, probiotics, prebiotics, or even fecal transplants, is considered as a promising strategy for the development of new solutions for the treatment of obesity. However, there is still lot to do in this field in order to identify the exact composition of microbiota in "health" and the specific mechanisms that regulate the host-microbiotal crosstalk. In addition, it is important to note that changes not only in the gut microbiota profile (abundance) but also in its metabolism and functions need to be taken into account in the context of contribution in the physiopathology of obesity and related disorders.

N-methyl-D-aspartate receptor-coupled glycineB receptors in the pathogenesis and treatment of schizophrenia: a critical review.

Glutamatergic pathways, metabotropic receptors, and ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors are all implicated in the etiology and management of schizophrenia. As concerns NMDA receptors, open channel blockers (OCBs) such as phencyclidine (PCP) elicit psychotic symptoms in human subjects. This observation underpins biochemical studies indicating that a deficit in activity at NMDA receptors may be associated with psychotic states. Inasmuch as agonists at the NMDA recognition site are excitotoxic, drugs acting via the co-agonist, glycine(B) (GLY(B)) site are more promising clinical candidates as antipsychotic agents. Glycine (GLY) itself, a further endogenous agonist, D-Serine, and inhibitors of GLY reuptake are active in certain experimental models predictive of antipsychotic properties. Further, in controlled clinical trials, GLY and D-Serine enhance the ability of conventional neuroleptics such as haloperidol to improve cognitive and negative symptoms. Their actions are mimicked by the partial agonist, D-cycloserine (DCS). However, these agents exert little effect alone and may interfere with therapeutic actions of the atypical antipsychotic, clozapine. An important issue in the interpretation of drug actions at GLY(B) sites is their degree of occupation by endogenous GLY and D-Serine - although they are unlikely to be saturated. Further, distinct "subtypes" of GLY(B) site-bearing NMDA receptor may fulfill differential roles in psychotic states Finally, blockade of certain populations of NMDA receptor may be of use in the management of schizophrenia. This article reviews the complex role of GLY(B) sites/NMDA receptors and their endogenous ligands in the pathogenesis and treatment of psychotic states.

A non-beta-endorphinergic adenohypophyseal mechanism is essential for an analgetic response to stress.

The present paper examines the role of pituitary pools of beta-endorphin in mediating the elevation in nociceptive threshold produced by stress. A 5 min foot-shock stress, characterized as activating both central and pituitary systems of beta-endorphin (beta-EP) and eliciting a naloxone-attenuated elevation in tail-flick latency in rats, was employed. Both total hypophysectomy and selective ablation of the anterior lobe almost completely abolished stress-induced analgesia (SIA), whereas removal of the neuro-intermediate lobe alone proved ineffective. However, manipulation of the hypothalamus-pituitary-adrenal feedback system by administration of either the corticosteroid, dexamethasone, or the corticosteroid synthesis inhibitor, metyrapone, in neither case affected SIA. None of these surgical or pharmacological manoeuvres affected basal nociceptive threshold (BNT). These data indicate that although the integrity of the adenohypophysis is essential for the manifestation of SIA, an adenohypophyseal mechanism, probably involving neither ACTH nor beta-EP, is essential for the development of the analgesia which accompanies stress.

Evidence for an interrelationship between ventral noradrenergic bundle and CNS endorphins in the control of nociception in the rat.

The present paper examines the role of the ventral noradrenergic bundle (VB) in relation to endorphins in the control of nociception in the rat. Selective, bilateral destruction of the VB produced a substantial fall in hypothalamic levels of noradrenaline. On day 4 post-surgery, VB-lesioned rats displayed a pronounced elevation in basal nociceptive threshold. This proved to be reversible by the specific opioid antagonist, naloxone, evidential of its mediation by endorphins. It was, however, unaffected by dexamethasone, a suppressor of corticotrophic secretion of beta-endorphin, indicative that this pituitary pool of beta-endorphin was not responsible. On day 12, at which time the elevation in nociceptive threshold had disappeared, neither the time course nor the intensity of the antinociception elicited by acute stress or various doses of morphine was attenuated in VB-lesioned as compared to sham rats. These data are evidential that the VB may influence nociceptive thresholds via an interaction with a CNS endorphinergic network. They demonstrate, further, that the VB does not mediate a significant component of the antinociception generated by either morphine or stress.

Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent.

This study compared the antinociceptive properties of systemic administration of selective, non-peptidergic antagonists at neurokinin (NK1 and NK2) receptors to those of other classes of antinociceptive agent. (All doses are in mg/kg.) In mice, the NK1 antagonist, CP 99,994, preferentially (inhibitory dose50 (ID50) = 4.4) inhibited the late phase (LP) as compared to the early phase (EP) (16.1) of formalin-induced licking (FIL). A high dose (17.6) elicited ataxia in the rotarod test. Acetic acid-induced writhing was reduced at intermediate doses (10.0) whereas the tail-flick (TF) response to thermal and mechanical stimuli was inhibited only at high doses (22.7 and 17.7, respectively). Modulation of stimulus intensity did not modify the influence of CP 99,994 upon the response to heat. A similar pattern of data was acquired with RP 67,580, although this NK1 antagonist more potently inhibited writhing (2.8). In contrast, RP 68,651, the inactive isomer of RP 67,580, neither reduced the LP of FIL nor modified writhing indicating that these actions of RP 67,580 were stereospecific. Three further NK1 antagonists, SR 140,333, WIN 51,708 and WIN 62,577, likewise inhibited the LP of FIL and failed to modify the TF response at non-ataxic doses. Further, SR 140,333 (0.5) and WIN 51,708 (1.4) were potent ligands in the writhing procedure. The NK2 antagonist, SR 48,966, mimicked NK1 antagonists in preferentially inhibiting the LP (7.7) as compared to the EP (26.9) of FIL. Further, only at doses higher than those evoking ataxia (20.9) did SR 48,968 modify the TF response (36.5 and 32.0 for heat and pressure, respectively). However, it differed to NK1 antagonists in being inactive in the writhing test (> 40.0). In comparison to these NK1 and NK2 antagonists, the mu-opioid agonists (morphine and fentanyl) and kappa-opioid agonists (enadoline and U 69,593) equipotently inhibited all nociceptive responses at doses not provoking ataxia. While the glycine B receptor partial agonist, (+)-HA 966, selectively blocked the LP of FIL and did not evoke ataxia, the NMDA receptor channel blocker, (+)-MK 801, elicited antinociception only at doses close to those provoking ataxia. Finally, the NSAIDs, indomethacin and ibuprofen, the BK2 antagonist, Hoe 140 and the nitric oxide synthase (NOS) inhibitors, L-NAME and 7 nitroindazole, inhibited the LP (but not the EP) of FIL and (except for L-NAME) also reduced writhing: in contrast, they did not evoke ataxia and were inactive in the TF procedures.(ABSTRACT TRUNCATED AT 400 WORDS)

Motivational effects of opioids in an animal model of prolonged inflammatory pain: alteration in the effects of kappa- but not of mu-receptor agonists.

An unbiased preference conditioning procedure was used to characterize and compare the motivational effects of opioids in naive rats and those suffering from the prolonged pain associated with Freund's adjuvant (FA)-induced inflammation of one hind limb. The mu-opioid agonist morphine functioned as a reinforcer in naive animals, producing marked preferences for the drug-paired place. Similarly, rats injected with FA 7 days prior to conditioning exhibited a preference for the morphine place, and the magnitude of this effect did not differ between groups. Administration of the kappa-opioid receptor agonist U-69593 to naive rats produced dose-related place aversions. The aversive effect of this kappa-agonist was, however, abolished in FA-treated rats. Thus, regardless of the dose administered, U-69593 produced conditioning similar to that observed in response to saline. These data suggest that kappa-agonists may lack aversive effects in subjects experiencing prolonged noxious stimulation, and as such may be effective therapeutic agents in the management of chronic pain states.

Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat.

Inoculation of the right hind paw with Mycobacterium butyricum rapidly led to swelling and inflammation. The afflicted limb showed an enhanced sensitivity to noxious pressure (hyperalgesia) and a reduced sensitivity to noxious heat 24 h following treatment. Both naloxone and MR 2266 (which has greater activity at kappa-opioid receptors) further increased the sensitivity to pressure (that is, potentiated the hyperalgesia) but did not affect the response to heat. They did not affect the response of the uninflamed paw. At 1 week, only MR 2266 was effective. At both 24 h and 1 week, the inflamed paw showed pronounced supersensitivity to the antinociceptive action of morphine against noxious pressure. At both 24 h and (to a greater extent) 1 week, a rise in levels of immunoreactive (ir)-dynorphin (DYN) was seen in the ipsilateral dorsal horn of the lumbar spinal cord. There was no alteration in the contralateral dorsal horn or in either ventral horn. Furthermore, levels of ir-met-enkephalin (ME) and ir-leu-enkephalin (LE) were unaffected. There was no difference in the density of mu-, delta- or kappa-binding sites in any part of the lumbar cord, at either 24 h or 1 week, between ipsilateral and contralateral tissue. By 3 and 5 weeks postinoculation, the symptoms had spread to the contralateral hind limb and ir-DYN was elevated in the contralateral dorsal horn and the ipsilateral ventral horn. At 5 weeks, levels of ir-ME and ir-LE also were increased in the ipsilateral and contralateral dorsal horns, but not in the contralateral ventral horn. Furthermore, levels of ir-DYN were increased in the cervico-thoracic spinal cord, and rats displayed adrenal hypertrophy and a rise in plasma levels of ir-beta-endorphin (beta-EP). These data indicate: (1) Peripheral inflammation localized to a single limb selectively modifies levels of ir-DYN in ipsilateral dorsal horn. The effect is specific to DYN as compared to ME and LE. The density of mu-, delta-, or kappa-receptors in the lumbar spinal cord is unmodified. (2) The altered response to opioid agonists and antagonists shown by rats with an inflamed limb may be selective to the injured tissue. (3) Alterations in opioid systems associated with unilateral hind limb inflammation may not be exclusively chronic in nature: they appear very rapidly (within 24 h) of the induction of pain. With time, the contralateral limb becomes affected and, eventually, the effects resemble those seen with generalized polyarthritis.