ABSTRACT
ABSTRACT: More than half of US veterans seek care outside of the Veterans Health Administration. Physical and mental healthcare needs can be complicated by experiences during military service. Community clinicians can deliver more holistic and comprehensive care to veterans through understanding the unique needs of the veteran population.
Subject(s)
Veterans , Delivery of Health Care , Humans , United StatesABSTRACT
Research on mammals and turtles has suggested that acetylcholine is involved in attention in these groups. Two experiments investigated the ability of painted turtles (Chrysemys picta) to ignore irrelevant stimuli when the basal forebrain acetylcholine system was compromised. In experiment 1, turtles given lesions of the basal magnocellular cholinergic nucleus (NBM) or sham lesions were tested on a go/no go discrimination between horizontal and vertical stripes with or without irrelevant inserts in the box. The irrelevant inserts were blue and white checked walls and green carpet on the floor. The group with lesions of the NBM and no irrelevant inserts had no difficulty learning the task, but the lesioned group with irrelevant inserts was impaired on the discrimination. The sham-lesioned group was not impaired by the presence of irrelevant inserts. In experiment 2, turtles were given either the acetylcholine muscarinic receptor blocker scopolamine or saline and tested on the same task. The turtles given scopolamine had no difficulty learning the task in the absence of irrelevant inserts, but they were severely impaired when irrelevant inserts were present. The irrelevant inserts did not affect the learning of control turtles given saline. These findings provide evidence that acetylcholine enhances turtles' ability to orient to relevant stimuli and suggest that its role in learning and memory may be to allow animals to orient to the stimuli relevant to a task and to ignore irrelevant stimuli.
Subject(s)
Acetylcholine/physiology , Attention/physiology , Basal Forebrain , Behavior, Animal/physiology , Learning/physiology , Muscarinic Antagonists/pharmacology , Psychomotor Performance/physiology , Turtles/physiology , Acetylcholine/metabolism , Animals , Attention/drug effects , Basal Forebrain/drug effects , Basal Forebrain/metabolism , Basal Forebrain/physiopathology , Behavior, Animal/drug effects , Female , Learning/drug effects , Male , Psychomotor Performance/drug effects , Scopolamine/pharmacology , Turtles/metabolismABSTRACT
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
Subject(s)
Attention/drug effects , Cognition Disorders/drug therapy , Cognition/drug effects , Indans/pharmacology , Memory/drug effects , Oxazoles/pharmacology , Pyrimidines/pharmacology , Receptors, AMPA/chemistry , Schizophrenia/drug therapy , Allosteric Site , Amphetamines/pharmacology , Animals , Calcium/metabolism , Cerebral Cortex/metabolism , Cyclic AMP/metabolism , Dizocilpine Maleate/chemistry , Dizocilpine Maleate/pharmacology , Electroconvulsive Therapy , HEK293 Cells , Humans , Indans/therapeutic use , Male , Maze Learning , Memory, Short-Term/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxazoles/therapeutic use , Phenotype , Pyrimidines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30 mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30 mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3-30 mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments.
