Relationships Between a New Cultured Cell-Based Serum Anticholinergic Activity Assay and Anticholinergic Burden Scales or Cognitive Performance in Older Adults.

OBJECTIVES: Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both. DESIGN: The study was cross sectional in nature. SETTING: This was a five-centre study conducted in Toronto, Canada. PARTICIPANTS: Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD). MEASUREMENTS: The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery. RESULTS: Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis. CONCLUSIONS: These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden.

A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response.

The muscarinic acetylcholine receptor antagonist scopolamine elicits rapid antidepressant activity, but its underlying mechanism is not fully understood. In a chronic stress model, a single low-dose administration of scopolamine reversed depressive-like reactivity. This antidepressant-like effect was mediated via a muscarinic M1 receptor-SKC pathway because it was mimicked by intra-medial prefrontal cortex (intra-mPFC) infusions of scopolamine, of the M1 antagonist pirenzepine or of the SKC antagonist apamin, but not by the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. Extracellular and whole-cell recordings revealed that scopolamine and ketamine attenuate the SKC-mediated action potential hyperpolarization current and rapidly enhance mPFC neuronal excitability within the therapeutically relevant time window. The SKC agonist 1-EBIO abrogated scopolamine-induced antidepressant activity at a dose that completely suppressed burst firing activity. Scopolamine also induced a slow-onset activation of raphe serotonergic neurons, which in turn was dependent on mPFC-induced neuroplasticity or excitatory input, since mPFC transection abolished this effect. These early behavioral and mPFC activational effects of scopolamine did not appear to depend on prefrontocortical brain-derived neurotrophic factor and serotonin-1A activity, classically linked to SSRIs, and suggest a novel mechanism associated with antidepressant response onset through SKC-mediated regulation of activity-dependent plasticity.

In Vivo Brain Sampling Using a Microextraction Probe Reveals Metabolic Changes in Rodents after Deep Brain Stimulation.

Brain metabolomics is an emerging field that complements the more traditional approaches of neuroscience. However, typical brain metabolomics workflows require that animals be sacrificed and tend to involve tedious sample preparation steps. Microdialysis, the standard technique to study brain metabolites in vivo, is encumbered by significant limitations in the analysis of hydrophobic metabolites, which are prone to adsorption losses on microdialysis equipment. An alternative sampling method suitable for in vivo brain studies is solid-phase microextraction (SPME). In SPME, a small probe coated with a biocompatible polymer is employed to extract/enrich analytes from biological matrices. In this work, we report the use of SPME and liquid chromatography-mass spectrometry for untargeted in vivo analysis of rodent's brains after deep brain stimulation (DBS). First, metabolite changes occurring in brain hippocampi after application of 3 h of DBS to the animals' prefrontal cortex were monitored with the proposed approach. As SPME allows for nonlethal sampling, the same group of animals was sampled again after 8 days of daily DBS therapy. After acute DBS, we detected changes in a broad range of metabolites, including the amino acid citrulline, which may reflect changes in nitric oxide production, as well as various phospho- and glycosphingolipids. Measurements conducted after chronic DBS showed a decrease in hippocampal corticosterone, indicating that DBS may have a regulatory effect in the hypothalamic-pituitary-adrenal axis. Our findings demonstrate the potential of in vivo SPME as a tool of scientific and clinical interest capable of revealing changes in a wide range of metabolites in brain tissue.

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: involvement of the prefrontal cortex and dorsal raphe?

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature.

BACKGROUND: Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. METHODS: Here we applied 6h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5days. We investigated the "micro-lesion" effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. RESULTS: The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. CONCLUSIONS: Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.

Deep brain stimulation induces antiapoptotic and anti-inflammatory effects in epileptic rats.

BACKGROUND: Status epilepticus (SE) is a severe condition that may lead to hippocampal cell loss and epileptogenesis. Some of the mechanisms associated with SE-induced cell death are excitotoxicity, neuroinflammation, and apoptosis. OBJECTIVE: The objective of the present study is to test the hypothesis that DBS has anti-inflammatory and antiapoptotic effects when applied during SE. METHODS: Rats undergoing pilocarpine-induced SE were treated with anterior thalamic nucleus (AN) deep brain stimulation (DBS). Inflammatory changes and caspase 3 activity were measured within 1 week of treatment. RESULTS: In pilocarpine-treated rats, DBS countered the significant increase in hippocampal caspase 3 activity and interleukin-6 (IL-6) levels that follows SE but had no effect on tumor necrosis factor α (TNFα). CONCLUSIONS: DBS has anti-inflammatory and antiapoptotic effects when given to animals undergoing status.

Changes in dendritic spine density in the nucleus accumbens do not underlie ethanol sensitization.

Behavioral sensitization to various drugs of abuse has been shown to change dendritic spine density and/or morphology of nucleus accumbens (NAc) medium spiny neurons, an effect seen across drug classes. However, is it not known whether behavioral sensitization to ethanol (EtOH) is also associated with structural changes in this region. Here we compared dendritic spine density and morphology between mice showing High vs. Low levels of EtOH sensitization and found that high levels of EtOH sensitization were not associated with changes in dendritic spine density or spine type. Unexpectedly, however, a significant increase in the density of stubby-type spines was seen in mice that were resistant to sensitization. Since the presence of this spine type has been associated with long-term depression and cognitive/learning deficits this may explain why these mice fail to sensitize and why they show poor performance in conditioning tasks, as previously shown. A possible causal role for structural plasticity in behavioral sensitization to various drugs has been debated. In the case of EtOH sensitization, our results suggest that drug-induced changes in structural plasticity in the accumbens neurons may not be the cause of sensitized behavior.

Effects of high-frequency stimulation of the nucleus accumbens on the development and expression of ethanol sensitization in mice.

The behavioural effects of high-frequency electrical stimulation (HFS) are often similar to the effects of lesions, with the advantage of being reversible. The present study examined the effects of HFS of the nucleus accumbens (NAc), an area that has been shown to be important for sensitization to several psychostimulants, on the development and expression of EtOH sensitization. Male DBA/2 mice received five biweekly injections of EtOH (2.2 g/kg, intraperitoneally) or saline (SAL) immediately before assessments of locomotor activity (LMA). For some of the mice, each EtOH or SAL injection was preceded by 2 h of bilateral NAc HFS, whereas the remaining mice received no stimulation. Seven days after the last injection, LMA was again measured after the mice received a challenge dose of EtOH (1.8 g/kg, intraperitoneally) or SAL, either preceded or not preceded by 2 h of HFS. Mice receiving NAc HFS before EtOH injections during the sensitization period showed progressive increases in LMA that were not different from the LMA scores of EtOH-injected mice which had received no HFS. However, when the latter group was subsequently challenged after receiving HFS, a strong suppression of LMA was observed, in comparison with their own previous LMA scores (-72%) and compared with EtOH-sensitized groups challenged in the absence of HFS (-70%). A separate cohort of mice that were surgically implanted but not stimulated showed a robust EtOH sensitization response that did not differ from that of EtOH-treated mice without electrodes, demonstrating that HFS behavioural effects were not merely a result of the presence of electrodes in the NAc. These results suggest that NAc HFS may have different effects at different stages of the EtOH sensitization process, specifically suppressing expression, but not the development of EtOH sensitization. This pattern of distinct effects of NAc manipulations on different aspects of sensitization is similar to what has been reported for other drugs of abuse, suggesting a commonality of mechanisms. Our findings also suggest that the sensitization may provide a useful paradigm for the investigation of mechanisms of clinical effectiveness of HFS in humans.

Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits.

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity.

Changes in brain functional connectivity after chronic haloperidol in rats: a network analysis.

Although the effects of haloperidol (HAL) have been extensively examined in experimental animals at the cellular and brain regional levels, the effects of prolonged HAL treatment on functional connectivity in the brain have not yet been addressed. Here we used expression of the immediate early gene zif268 as a marker of neural activity to examine changes in brain regional interactivity after 12 wk of HAL treatment in rats. zif268 expression was measured by in situ hybridization in 83 brain regions of HAL- and vehicle (VEH)-treated controls and correlations among all brain regions were computed separately for the two treatment groups. The strongest correlations in each group were used for network construction. It was found that VEH and HAL networks were equally segregated and integrated, and that both networks display small world organization. Compared to the VEH network, the HAL network showed enhanced interactivity between the dorsolateral striatum and thalamus, and between different subdivisions of the thalamus. It will be of interest to determine the extent to which the observed changes in functional connectivity may be related to dyskinesias, to changes in motivated behaviours and/or to the therapeutic effects of chronic HAL. By identifying the connectivity features of a chronic HAL network in the absence of other manipulations, the current findings may provide a reference signature pattern to be targeted in future efforts to discriminate between the neural bases of different behavioural outcomes arising from chronic HAL treatment.

Contribution of decreased serotonin release to the antidyskinetic effects of deep brain stimulation in a rodent model of tardive dyskinesia: comparison of the subthalamic and entopeduncular nuclei.

Mechanisms whereby deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) reduces dyskinesias remain largely unknown. Using vacuous chewing movements (VCMs) induced by chronic haloperidol as a model of tardive dyskinesia (TD) in rats, we confirmed the antidyskinetic effects of DBS applied to the STN or entopeduncular nucleus (EPN, the rodent homolog of the GPi). We conducted a series of experiments to investigate the role of serotonin (5-HT) in these effects. We found that neurotoxic lesions of the dorsal raphe nuclei (DRN) significantly decreased HAL-induced VCMs. Acute 8-OH-DPAT administration, under conditions known to suppress raphe neuronal firing, also reduced VCMs. Immediate early gene mapping using zif268 in situ hybridization revealed that STN-DBS inhibited activity of DRN and MRN neurons. Microdialysis experiments indicated that STN-DBS decreased 5-HT release in the dorsolateral caudate-putamen, an area implicated in the etiology of HAL-induced VCMs. DBS applied to the EPN also suppressed VCMs but did not alter 5-HT release or raphe neuron activation. While these findings suggested a role for decreased 5-HT release in the mechanisms of STN DBS, further microdialysis experiments showed that when the 5-HT lowering effects of STN DBS were prevented by pretreatment with fluoxetine or fenfluramine, the ability of DBS to suppress VCMs remained unaltered. These results suggest that EPN- and STN-DBS have different effects on the 5-HT system. While decreasing 5-HT function is sufficient to suppress HAL-induced VCMs, 5-HT decrease is not necessary for the beneficial motor effects of DBS in this model.

The role of serotonin in the antidyskinetic effects of deep brain stimulation: focus on antipsychotic-induced motor symptoms.

Treatment with the classic antipsychotic drugs (APDs), such as haloperidol (HAL), is associated with both acute and chronic motor side effects. Acutely, these drugs may induce extrapyramidal symptoms, whereas a prolonged treatment may result in tardive dyskinesia (TD). Atypical antipsychotics have a lower incidence of motor side effects, which have been partially ascribed to the antagonism of serotonin (5-HT) receptors. Although there is currently no satisfactory pharmacotherapy for TD, deep brain stimulation (DBS) has emerged as a promising therapy. However, the mechanisms underlying its effects remain largely unknown. DBS has been shown to affect several neurotransmitter systems, including 5-HT. In this review, we outline the involvement of 5-HT in the development of HAL-induced catalepsy and TD. We also discuss the evidence for DBS-induced alterations in 5-HT function and the relevance of serotonergic alterations to the antidyskinetic effects of DBS. The evidence suggests that the serotonergic mechanisms may be involved in the acute and chronic motor side effects of APDs as well as in adverse psychiatric effects that have been reported following DBS. However, the current evidence suggests that 5-HT alterations do not play an important role in the effectiveness of DBS in models of dyskinesias induced by chronic APDs.

Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase.

Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an (18)F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [(18)F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [(18)F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [(18)F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [(18)F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [(18)F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

Pneumocephalus Secondary to Cerebral Air Embolism After Acute Bleeding in an Emphysema Bulla.

Pneumocephalus is the presence of air in the intracranial space and has multiple causes, including cerebral air embolism. Its presentation may range from asymptomatic to decrease mental status, coma, and seizures. We present a case of cerebral air embolism secondary to acute bleeding inside an emphysema bulla. A 69-year-old female was brought to the emergency room after suffering acute dyspnea, convulsions, and cardiac arrest during a commercial flight. The Head CT showed the presence of multiple small gas collections in the brain, and the Thoracic Angiotomography showed a thin-walled bulla surrounded with pulmonary venous vascular structures and signs of active bleeding. The patient had rapid neurological deterioration with evolution to brain death due to anoxic encephalopathy before the possibility of treatment with pulmonary lobectomy and hyperbaric oxygen therapy. It is important to identify the localization of pneumocephalus to determine its etiology and to deliver the best treatment. Cerebral air embolism may happen when air enters the arterial or venous system, which can cause brain damage due to capillary leak syndrome and local ischemia. Treatment of pneumocephalus includes treating the cause, bed rest, avoidance of Valsalva maneuvers, positive pressure, and hyperbaric oxygen therapy. Early recognition is essential to prevent complications such as irreversible brain lesions and to improve patient outcomes.

Ponatinib-Induced Pneumonitis with Severe Acute Respiratory Distress Syndrome.

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) that can effectively treat patients with acute lymphoblastic leukaemia (ALL), particularly those with Philadelphia chromosome-positive (Ph+ALL) subtype, who are resistant or have previously received other TKIs. We report a case of a 42-year-old female with Ph+ALL who was admitted to the intensive care unit with respiratory failure and severe acute respiratory distress syndrome (ARDS), while on treatment with ponatinib. Despite being treated with multiple antibiotics and antivirals, the patient's condition continued to worsen, and pulmonary complications secondary to TKI were suspected. After starting a steroid regimen, the patient's condition improved drastically with resolution of the pulmonary complications. While many adverse events (AEs) happen in the beginning stages of TKI treatment, certain toxicities may not arise until months after therapy initiation. Cardiovascular complications are the most common AE of ponatinib, including heart failure and arterial hypertension. Pulmonary complications may occur, and management includes drug cessation and individualised steroid therapy. In case of respiratory failure without signs of infection and no improvement with antimicrobial treatment, clinicians should consider the possibility of pulmonary toxicity associated with ponatinib. LEARNING POINTS: Although rarely reported, ponatinib may have pulmonary toxicity presenting as new onset of respiratory insufficiency.Management of pulmonary complications includes adjusting or discontinuation of ponatinib and simultaneous treatment with steroids.

Skimboarding: An Increasingly Recognized Cause of Life-Threatening Spinal Cord Injury.

Skimboarding is a sport that combines elements from aquatic and terrestrial sports and has gained popularity with increased riskier maneuvers. Spinal cord injuries associated with this sport have rarely been reported. Here we present a case of a previously healthy 44-year-old male with a life-threatening C2/C3 fracture and dislocation after a skimboarding fall. Traumatic facet dislocations in the cervical spine are usually consequent to high-energy transmission injuries, so it is difficult to explain the mechanism of injury in this clinical case. As this sport's practice continues to grow, our purpose is to emphasize that these injuries may occur with irreversible consequences as most of the damage occurs at the time of presentation, so the first step is to alert athletes and the community to prevent them.

Cell-based serum anticholinergic activity assay and working memory in cognitively healthy older adults before and after scopolamine: An exploratory study.

BACKGROUND: A new cell-based serum anticholinergic activity (cSAA) assay that measures anticholinergic activity specifically at muscarinic M1 receptors and eliminates many of the drawbacks of the existing assay was developed by our team. AIMS: We aimed to study the relationship between changes in working memory and executive function with changes in cSAA using the new assay in cognitively healthy older adults. METHODS: Cognitively healthy participants aged 50 years and above, received a single dose of 0.4 mg of intravenous scopolamine. Cognition and cSAA levels were measured before and 30 min after receiving scopolamine. Cognition was measured using the Cambridge Neuropsychological Test Automated Battery. RESULTS: Ten participants were recruited, and nine (mean age = 69.8, SD = 9.5, range 59-86 years) completed the study. Following scopolamine, participants experienced an increase in cSAA (cSAA pre = 0.90 ± 0.97 vs cSAA post = 12.0 ± 3.70 pmol/L; t-test (df = (8) = -9.5, p < 0.001). In addition, there was an association between change in cSAA and changes in working memory (Spearman's ρ = 0.68, p = 0.042) and executive function (Spearman's ρ = 0.72, p = 0.027). CONCLUSIONS: In our sample of cognitively healthy older adults, the new cSAA assay was able to quantify the scopolamine induced increase in anticholinergic load which correlated significantly with the observed decline in working memory and executive function.

N-mixture models provide informative crocodile (Crocodylus moreletii) abundance estimates in dynamic environments.

Estimates of animal abundance provide essential information for population ecological studies. However, the recording of individuals in the field can be challenging, and accurate estimates require analytical techniques which account for imperfect detection. Here, we quantify local abundances and overall population size of Morelet's crocodiles (Crocodylus moreletii) in the region of Calakmul (Campeche, Mexico), comparing traditional approaches for crocodylians (Minimum Population Size-MPS; King's Visible Fraction Method-VFM) with binomial N-mixture models based on Poisson, zero-inflated Poisson (ZIP) and negative binomial (NB) distributions. A total of 191 nocturnal spotlight surveys were conducted across 40 representative locations (hydrologically highly dynamic aquatic sites locally known as aguadas) over a period of 3 years (2017-2019). Local abundance estimates revealed a median of 1 both through MPS (min-max: 0-89; first and third quartiles, Q1-Q3: 0-7) and VFM (0-112; Q1-Q3: 0-9) non-hatchling C. moreletii for each aguada, respectively. The ZIP based N-mixture approach shown overall superior confidence over Poisson and NB, and revealed a median of 6 ± 3 individuals (min = 0; max = 120 ± 18; Q1 = 0; Q3 = 18 ± 4) jointly with higher detectabilities in drying aguadas with low and intermediate vegetation cover. Extrapolating these inferences across all waterbodies in the study area yielded an estimated ~10,000 (7,000-11,000) C. moreletii present, highlighting Calakmul as an important region for this species. Because covariates enable insights into population responses to local environmental conditions, N-mixture models applied to spotlight count data result in particularly insightful estimates of crocodylian detection and abundance.

Antidepressant activity of pharmacological and genetic deactivation of the small-conductance calcium-activated potassium channel subtype-3.

RATIONALE: The voltage-insensitive, small-conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization and is implicated in the pathophysiology of depressive disorders. OBJECTIVE: We ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model and whether it can serve as a molecular target of antidepressant action. METHODS: We assessed the depressive-like behavioral phenotype of CUS-exposed rats and performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knockout mice and selective SK3 channel negative allosteric modulators (NAMs). RESULTS: We found that [125I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity. CONCLUSIONS: Taken together, these findings link depression-related neural and behavioral pathophysiology with abnormal SK channel functioning and suggest that this can be reversed by the selective inhibition of SK3 channels.

Partial agonists in schizophrenia--why some work and others do not: insights from preclinical animal models.

While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success.