Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D and D receptors.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors.

Infections Up to 76 Days After Stroke Increase Disability and Death.

Early infection after stroke is associated with a poor outcome. We aimed to determine whether delayed infections (up to 76 days post-stroke) are associated with poor outcome at 90 days. Data came from the international Efficacy of Nitric Oxide Stroke (ENOS, ISRCTN99414122) trial.

Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay.

Previous in vivo electrophysiological studies suggest that the anterior cingulate cortex (ACgx) is an important substrate of novel object recognition (NOR) memory. However, intervention studies are needed to confirm this conclusion and permanent lesion studies cannot distinguish effects on encoding and retrieval. The interval between encoding and retrieval tests may also be a critical determinant of the role of the ACgx.

Contribution of serotonin and dopamine to changes in core body temperature and locomotor activity in rats following repeated administration of mephedrone.

The psychoactive effects of mephedrone are commonly compared with those of 3,4-methylenedioxymethamphetamine, but because of a shorter duration of action, users often employ repeated administration to maintain its psychoactive effects. This study examined the effects of repeated mephedrone administration on locomotor activity, body temperature and striatal dopamine and 5-hydroxytryptamine (5-HT) levels and the role of dopaminergic and serotonergic neurons in these responses. Adult male Lister hooded rats received three injections of vehicle (1 ml/kg, i.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits.

Subconvulsive hippocampal neural disinhibition, that is reduced GABAergic inhibition, has been implicated in neuropsychiatric disorders characterized by attentional and memory deficits, including schizophrenia and age-related cognitive decline. Considering that neural disinhibition may disrupt both intra-hippocampal processing and processing in hippocampal projection sites, we hypothesized that hippocampal disinhibition disrupts hippocampus-dependent memory performance and, based on strong hippocampo-prefrontal connectivity, also prefrontal-dependent attention. In support of this hypothesis, we report that acute hippocampal disinhibition by microinfusion of the GABA-A receptor antagonist picrotoxin in rats impaired hippocampus-dependent everyday-type rapid place learning performance on the watermaze delayed-matching-to-place test and prefrontal-dependent attentional performance on the 5-choice-serial-reaction-time test, which does not normally require the hippocampus.

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia.

Background: Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.

Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats.

Administration of caffeine with 3,4-methylenedioxymethamphetamine (MDMA) alters the pharmacological properties of MDMA in rats. The current study examined whether caffeine alters the behavioural and neurochemical effects of mephedrone, which has similar psychoactive effects to MDMA. Rats received either saline, mephedrone (10 mg/kg), caffeine (10 mg/kg) or combined caffeine and mephedrone intraperitoneally twice weekly on consecutive days for three weeks.

Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex.

Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.

Too little and too much: hypoactivation and disinhibition of medial prefrontal cortex cause attentional deficits.

Attentional deficits are core symptoms of schizophrenia, contributing strongly to disability. Prefrontal dysfunction has emerged as a candidate mechanism, with clinical evidence for prefrontal hypoactivation and disinhibition (reduced GABAergic inhibition), possibly reflecting different patient subpopulations. Here, we tested in rats whether imbalanced prefrontal neural activity impairs attention.

The antimalarial drug quinine interferes with serotonin biosynthesis and action.

The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells.

Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of 'schizophrenia-like' behaviour in the rat.

Rationale: Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies.

Objectives: This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone.

Methods: Forty-two male Lister-hooded rat pups received the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.

Lentiviral delivery of a vesicular glutamate transporter 1 (VGLUT1)-targeting short hairpin RNA vector into the mouse hippocampus impairs cognition.

Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects.

In vivo neurometabolic profiling to characterize the effects of social isolation and ketamine-induced NMDA antagonism: a rodent study at 7.0 T.

Continued efforts are undertaken to develop animal models of schizophrenia with translational value in the quest for much needed novel drugs. Existing models mimic specific neurobiological aspects of schizophrenia, but not its full complexity. Here, we used proton magnetic resonance spectroscopy ((1)H-MRS) to assess the metabolic profile in the prefrontal cortex (PFC) of two established models, rearing in social isolation and acute N-methyl-D-aspartate receptor (NMDA-R) antagonism and their combination.

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats.

Rationale: Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia.

Objective: This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model.

Method: Forty-five male Lister hooded rats were housed in groups of 3-4 (n = 16) or singly (n = 29) for 4 weeks immediately after weaning on postnatal day (PND) 22-24.

Behavioural and neurochemical comparison of chronic intermittent cathinone, mephedrone and MDMA administration to the rat.

The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats.

5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia.

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT(6) receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT(6) receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR.

S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: II. A behavioral, neurochemical, and electrophysiological characterization.

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.

Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex.

Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) receptor antagonist, S33084 (0.

Exposure to maternal consumption of cafeteria diet during the lactation period programmes feeding behaviour in the rat.

Lactational overfeeding programmes obesity in the adult rat, and also impacts on adult emotional behaviour. The present study investigated the impact of exposing the lactating female to a hypercaloric diet on structural aspects of feeding behaviour in the adult offspring as measured by the behavioural satiety sequence (BSS). Lactating Wistar rats were fed a hypercaloric cafeteria diet (CD) in addition to chow.

Influence of social isolation in the rat on serotonergic function and memory--relevance to models of schizophrenia and the role of 5-HT₆ receptors.

There is increasing awareness of the importance that early environmental factors have on brain development and their role in the neurobiology of neurodevelopmental disorders including schizophrenia. The isolation reared rat attempts to model adverse effects that human social isolation (absence of social contact) can have on normal brain development. The isolation reared rat also models aspects of schizophrenia including the development of persistent learning and memory deficits.

Blockade of dopamine D₃ but not D₂ receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment.

Dopamine D₃ receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D₃ vs. D₂ receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia.

The dopamine D3 receptor antagonist, S33138, counters cognitive impairment in a range of rodent and primate procedures.

Although dopamine D(3) receptor antagonists have been shown to enhance frontocortical cholinergic transmission and improve cognitive performance in rodents, data are limited and their effects have never been examined in primates. Accordingly, we characterized the actions of the D(3) receptor antagonist, S33138, in rats and rhesus monkeys using a suite of procedures in which cognitive performance was disrupted by several contrasting manipulations. S33138 dose-dependently (0.

Acute concomitant effects of MDMA binge dosing on extracellular 5-HT, locomotion and body temperature and the long-term effect on novel object discrimination in rats.

Rationale: 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an acute release of 5-HT in the brain, together with increased locomotion and hyperthermia.

Objective: This study examined whether the acute functional changes of locomotor activity and body temperature are related to enhanced 5-HT release induced by MDMA.

Methods: We concomitantly measured changes in extraneuronal 5-HT by in vivo brain microdialysis and used radiotelemetry to measure locomotion and body temperature to establish whether any positive correlations occur between these three parameters.

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat.

Rationale: Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia.

Objective: This study evaluated the potent, selective mGluR2/3 agonist, LY379268, on the behavioural deficits induced by rearing rat pups in social isolation from weaning, a neurodevelopmental model of schizophrenia, to investigate its antipsychotic potential.