Reduced expression of synapsin II in a chronic phencyclidine preclinical rat model of schizophrenia.

Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)-a N-methyl-D-aspartate (NMDA) receptor antagonist-induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well-known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini-pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper-locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre-pulse inhibition (p < 0.0001) in comparison to saline-treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer-term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.

Differential Expression of Synapsin I and II upon Treatment by Lithium and Valproic Acid in Various Brain Regions.

Introduction: Due to the heterogeneity of psychiatric illnesses and overlapping mechanisms, patients with psychosis are differentially responsive to pharmaceutical drugs. In addition to having therapeutic effects for schizophrenia and bipolar disorder, antipsychotics and mood stabilizers have many clinical applications and are used unconventionally due to their direct and indirect effects on neurotransmitters. Synapsins, a family of neuronal phosphoproteins, play a key regulatory role in neurotransmitter release at synapses. In this study, we investigated the effects of mood stabilizers, lithium, and valproic acid on synapsin gene expression in the rat brain. Methods: Intraperitoneal injections of saline, lithium, and valproic acid were administered to male Sprague Dawley rats twice daily for 14 d, corresponding to their treatment group. Following decapitation and brain tissue isolation, mRNA was extracted from various brain regions including the hippocampus, striatum, prefrontal cortex, and frontal cortex. Results: Biochemical analysis revealed that lithium significantly increased gene expression of synapsin I in the striatum, synapsin IIa in the hippocampus and prefrontal cortex, and synapsin IIb in the hippocampus and striatum. Valproic acid significantly increased synapsin IIa in the hippocampus and prefrontal cortex, as well as synapsin IIb in the hippocampus and striatum. Conclusion: These significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics and provide deeper insight on the involvement of synaptic proteins in treating neuropsychiatric illnesses.

Systemic reactions to subcutaneous allergen immunotherapy: real-world cause and effect modelling.

BACKGROUND: Subcutaneous immunotherapy (SCIT) is an effective treatment for allergic rhinoconjunctivitis. However, adverse events, including life-threatening systemic reactions, may occur. The purpose of this project is to identify risk factors for systemic reactions to SCIT and to provide practice-based solutions using a quality improvement (QI) framework. METHODS: A QI initiative was performed in a hospital-based, Canadian Allergy clinic administering SCIT in a 12-month period. RESULTS: A total of 4242 injections of SCIT were performed over a period of 12 months. Of these, 10 injections resulted in a systemic reaction requiring epinephrine administration (i.e., an incidence of 1 in 424 injections, or 0.24%). Eight patients had at least one documented risk factor for a systemic reaction, and six had multiple risk factors. Major risk factors included seasonal exacerbation of allergic rhinitis, uncontrolled asthma, and an error in route of administration. All reactions occurred with the highest allergen extract concentration. CONCLUSION: This QI initiative highlights the need for improved patient and health care practitioner education and pre-administration screening. We suggest several considerations for SCIT administration: provide patients with written information on safety; screen patients before injections, including a review of treatment plan adherence and asthma control; adjust dosing to slow down buildup of the most concentrated immunotherapy extract, particularly in high risk patients; and apply additional safety measures in patients with multiple risk factors.

The Effect of PAOPA, a Novel Allosteric Modulator of Dopamine D2 Receptors, on Signaling Proteins Following Sub-Chronic Administration in Rats.

BACKGROUND: Allosteric modulators of G-protein coupled receptors regulate receptor activity by binding to sites other than the active site and have emerged as a new and highly desirable class of drugs. PAOPA (3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide), a peptidomimetic analog of L-prolyl-L-leucyl-glycinamide, is a potent dopamine D2 receptor allosteric modulator. PAOPA has shown therapeutic effects in pre-clinical models of schizophrenia and extrapyramidal dysfunction. OBJECTIVE: In this study, we sought to examine the biomolecular underpinnings of PAOPA's therapeutic outcomes in pre-clinical models of schizophrenia. METHODS: Following sub-chronic (daily for 7 days) administration of PAOPA, we assessed levels of dopamine D2 receptors, receptor kinases (GRK2 (G protein-coupled receptor kinase 2) and Arrestin- 3), and phosphorylated mitogen-activated protein kinase (MAPKs), namely, extracellular signal- regulated kinases (ERK1/2) in the hippocampus, medial pre-frontal cortex, nucleus accumbens, pre-frontal cortex, and dorsal striatum via protein quantification. RESULTS: Following 7 days of daily PAOPA treatment, we observed decreased GRK2 and increased dopamine D2 receptor expression in the dorsal striatum. These findings potentially underscore the therapeutic mechanism of action of PAOPA for the positive-like symptoms of schizophrenia in pre-clinical animal models. Additionally, we observed a decline in GRK2 in the hippocampus and an increase in phosphorylated ERK1 in the pre-frontal cortex, suggesting a role of PAOPA in treating cognitive and/or affective dysfunction in pre-clinical models. CONCLUSION: While further studies are required to elucidate the mechanism of action of PAOPA, this study discusses prior investigations and develops an early framework to describe the therapeutic mechanism of action of PAOPA.

The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia.

PAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson's disease and haloperidol-induced extrapyramidal movement disorders. PAOPA's unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA's therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for 7 days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioral tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioral paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioral indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA's prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP-while phenotypically similar-are mechanistically different and that PAOPA's effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia.