Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions.

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward.

Impact of Fkbp5 × early life adversity × sex in humanised mice on multidimensional stress responses and circadian rhythmicity.

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation.

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents.

-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is an established cellular model underlying learning and memory, and involves intracellular signaling mediated by the second messenger cyclic guanosine monophosphate (cGMP). As phosphodiesterase (PDE)9A selectively hydrolyses cGMP in areas of the brain related to cognition, PDE9A inhibitors may improve cognitive function by enhancing NMDA receptor-dependent LTP. This study aimed to pharmacologically characterize BI 409306, a novel PDE9A inhibitor, using in vitro assays and in vivo determination of cGMP levels in the brain.

Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator.

The NMDA (N-methyl-D-aspartate)-receptor is fundamentally involved in cognitive functions. Recent studies demonstrated a functional interaction between the metabotropic glutamate receptor 5 (mGlu(5) receptor) and the NMDA-receptor in neurons. In rat hippocampal slices, it was shown that activation of mGlu(5) receptor by a positive modulator in the presence of a subthreshold agonist concentration potentiated NMDA-receptor mediated currents and phosphorylation of intracellular signalling proteins.

Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson's disease: A pharmacokinetic-pharmacodynamic study using in vivo microdialysis in rats.

Short-acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providing continuous dopaminergic stimulation may achieve higher therapeutic benefit for example by alleviating nocturnal disturbances as well as early morning akinesia. In the present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet minipumps, whereas subcutaneous PPX injections were used to mimic PPX immediate release (IR) in male Wistar rats.

The role of glycogen synthase kinase-3beta in schizophrenia.

Glycogen synthase kinase (GSK)-3beta is recognized as a ubiquitous multifunctional enzyme involved in the modulation of many aspects of neuronal function. Inhibitory control of GSK-3beta has been identified to be crucial for the phosphoinositide 3'-kinase (PI3K)-protein kinase B (Akt)-mediated cell survival. Several lines of evidence converge in implicating abnormal GSK-3beta activity in the pathogenesis of schizophrenia.

The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats.

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.

Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on ethanol discrimination in the rat.

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine.

Effect of chronic intermittent restraint stress on hippocampal expression of marker proteins for synaptic plasticity and progenitor cell proliferation in rats.

Chronic restraint stress may change hippocampal mRNA levels of markers for synaptic plasticity such as synaptophysin, growth-associated protein 43 (GAP-43), and brain-derived neurotrophic factor (BDNF). In order to examine the relation between that stressor and those biochemical markers on protein level as well as the Ki-67 protein, a marker of progenitor cell proliferation, we subjected rats to chronic intermittent restraint stress for 6 h per day for 14 days excluding the weekends. This stress intensity caused a significant increase in adrenal gland weight and decrease in body weight gain.

Intravenous self-administration of morphine and cocaine: a comparative study.

The aim of the present study was to estimate differences between patterns of morphine and cocaine use in Sprague-Dawley rats. This was done by first developing a set of conditions under which both drugs would be consistently self-administered over time. Subsequently rats were studied in groups of three, with only one rat actively self-administering morphine or cocaine while others two receiving yoked injections of either the drug or saline.

Different pattern of brain c-Fos expression following re-exposure to ethanol or sucrose self-administration environment.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behavior and lead to relapse to heavy drinking. The aim of the present study was to identify brain regions activated by alcohol (ethanol)-related stimuli in Wistar rats trained to lever press for 8% ethanol solution in operant self-administration cages. Ethanol self-administration was stabilized in a maintenance phase, which lasted for 30 days.

Taste function in methadone-maintained opioid-dependent men.

It has been shown repeatedly that opioid dependence is associated with increased consumption of refined sugars. It is possible that this association results from altered taste reactivity in opioid-dependent subjects. Thus, in the present study, we compared taste responses to sweet, bitter, sour and salty solutions in methadone-maintained opioid-dependent men and healthy control subjects.