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Leucanthemum vulgare, a perennial forb native to Eurasia, has become invasive in several other parts of the world. Since there is a lack of methods suitable for sustainable management of this plant across invaded landscapes, a biological control project has been initiated in North America and Australia. We evaluated the potential of the root‐feeding weevil Cyphocleonus trisulcatus as a biological control agent for L. vulgare in North America by investigating its impact on L. vulgare and studying its larval host range under no‐choice, multiple‐choice cage and open‐field conditions. Our impact experiment revealed that larval feeding by C. trisulcatus can severely damage and even kill plants. No‐choice tests conducted with 41 non‐target species showed that C. trisulcatus can develop on five closely related species. In a multiple‐choice cage test established with three of these species, the medicinal plant Matricaria chamomilla and the native North American M. occidentalis were also attacked, but to a lower degree than L. vulgare. An open‐field test conducted with four varieties of the ornamental Shasta daisy (Leucanthemum × superbum and L. × maximum) revealed similar attack on Shasta daisy as on L. vulgare. Due to the popularity of Shasta daisies, we suggest that C. trisulcatus, despite its potential to suppress L. vulgare populations, is not a suitable biological control agent for North America. However, C. trisulcatus may still be a potential biological control agent for L. vulgare in regions where Shasta daisy is less popular, such as Australia. Further host‐range tests with species native to Australia as well as with additional species important for the horticultural industry in Australia are currently under way. [ABSTRACT FROM AUTHOR]

Background: Cerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10-/- mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration. Methods: The neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy. Results: IL-10-/- mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/−) numbers in IL-10-/- compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45−, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma. Conclusions: These studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10-/- animals. [ABSTRACT FROM AUTHOR]

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors. [ABSTRACT FROM AUTHOR]

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT2C receptor (5-HT2C) is essential in normal physiology, whereas aberrant 5-HT2C function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT2C interacts with specific protein partners, but the impact of such interactions on 5-HT2C function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT2C and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT2C-mediated biology but not that of the closely homologous 5-HT2AR. A peptide derived from the third intracellular loop of the human 5-HT2C [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT2C-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT2C signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT2C allostery and therapeutics for 5-HT2C-mediated disorders. [ABSTRACT FROM AUTHOR]

The serotonin 5-HT2C receptor (5-HT2CR) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT2CR is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of c-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT2CR within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT2CR upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT2CR innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which .50% also contained 5-HT2CR immunoreactivity. Thus, we demonstrate for the first time that the 5-HT2CR colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT2CR may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 1504–1515. The action of serotonin (5-HT) at the 5-HT2C receptor (5-HT2CR) in cerebral cortex is emerging as a candidate modulator of neural processes that mediate core phenotypic facets of several psychiatric and neurological disorders. However, our understanding of the neurobiology of the cortical 5-HT2CR protein complex is currently limited. The goal of the present study was to explore the subcellular localization of the 5-HT2CR in synaptosomes and the post-synaptic density, an electron-dense thickening specialized for post-synaptic signaling and neuronal plasticity. Utilizing multiples tissues (brain, peripheral tissues), protein fractions (synaptosomal, post-synaptic density), and controls (peptide neutralization, 5-HT2CR stably-expressing cells), we established the selectivity of two commercially available 5-HT2CR antibodies and employed the antibodies in western blot and immunoprecipitation studies of prefrontal cortex (PFC) and motor cortex, two regions implicated in cognitive, emotional and motor dysfunction. For the first time, we demonstrated the expression of the 5-HT2CR in post-synaptic density-enriched fractions from both PFC and motor cortex. Co-immunoprecipitation studies revealed the presence of post-synaptic density-95 within the 5-HT2CR protein complex expressed in PFC and motor cortex. Taken together, these data support the hypothesis that the 5-HT2CR is localized within the post-synaptic thickening of synapses and is therefore positioned to directly modulate synaptic plasticity in cortical neurons. [ABSTRACT FROM AUTHOR]

The 5-HT 2A receptor (5-HT 2A R) and 5-HT 2C R are localized to the same neurons within the medial prefrontal cortex (mPFC), which regulates executive function, decision-making, and reward-guided learning and memory processes. The 5-HT 2A R and 5-HT 2C R coimmunoprecipitate in the mPFC of male Sprague-Dawley rats, while in vitro studies demonstrate the presence of a physical interaction between the 5-HT 2A R and 5-HT 2C R. The purpose of this study was to identify mPFC subregions in which the 5-HT 2A R and 5-HT 2C R physically interact ex vivo in the male Sprague-Dawley rat. We established the expression patterns of 5-HT 2A R and 5-HT 2C R in layers I-VI of the anterior cingulate cortex (ACC), prelimbic (PL), and infralimbic (IL) subregions using double-label fluorescence immunohistochemistry in male rats. We then employed the proximity ligation assay (PLA) to test the hypothesis that the 5-HT 2A R and 5-HT 2C R form a close, physical association within these mPFC subregions. Our results demonstrate subregion- and layer-specific expression of the 5-HT 2A R and 5-HT 2C R proteins using immunofluorescence and single recognition PLA, and a spatially close (within 40 nm) interaction between the 5-HT 2A R and 5-HT 2C R that occurs along a dorsal-ventral gradient in the rat mPFC.

Binge eating disorder (BED) is characterized by dysfunctional hedonic food intake and reward-related processes. Activation of the serotonin (5-HT) 5-HT 2C receptor (5-HT 2C R) suppresses both food intake and reward-related behaviors and is thus poised to regulate BED. This study assessed the effects of 5-HT 2C R activation via the selective 5-HT 2C R agonist WAY163909 on binge eating-related behaviors in adult male Sprague-Dawley rats. Low doses of WAY163909 (1.0, 2.0 mg/kg) suppressed high-fat food (HFF) binge intake, but not standard food non-binge intake. WAY163909 (1.0 mg/kg) also attenuated operant responding for self-administered HFF pellets on fixed and progressive ratio schedules of reinforcement, indicating that 5-HT 2C R activation suppresses the reinforcing and motivational properties of HFF, respectively. These findings suggest that activation of the 5-HT 2C R may be effective at suppressing binge eating in patients with BED via suppression of the reinforcing and motivational properties of HFF. This work supports future studies targeting the 5-HT 2C R in the treatment of BED.