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Ji-Yong Kang, Jayashree Chadchankar, Thuy N Vien, Michelle I Mighdoll, Thomas M Hyde, Robert J Mather, Tarek Z Deeb, Menelas N Pangalos, Nicholas J Brandon, John Dunlop, Stephen J Moss
The behavioral and anatomical deficits seen in Fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. While modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill-defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein coupled receptors constructed from R1a and R2 or R1b and R2 subunits...
February 17, 2017: Journal of Biological Chemistry
C R Kasten, A M Frazee, S L Boehm
Although United States smoking rates have been on the decline over the past few decades, cigarette smoking still poses a critical health and economic threat. Very few treatment options for smoking exist, and many of them do not lead to long-term abstinence. Preclinical models are necessary for understanding the effects of nicotine and developing treatments. Current self-administration models of nicotine intake may require surgical procedures and often result in low levels of intake. Further, they do not lend themselves to investigating treatments...
September 2016: Pharmacology, Biochemistry, and Behavior
Irene Lorrai, Paola Maccioni, Gian Luigi Gessa, Giancarlo Colombo
Racemic baclofen [(±)-baclofen] has repeatedly been reported to suppress several -alcohol-motivated behaviors, including alcohol drinking and alcohol -self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(-)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats...
2016: Frontiers in Psychiatry
Yujiro Hayashi, Daisuke Sakamoto, Daichi Okamura
An efficient asymmetric total synthesis of (S)-baclofen was accomplished via a one-pot operation from commercially available materials using sequential reactions, such as aldol condensation of acetaldehyde, diphenylprolinol silyl ether mediated asymmetric Michael reaction of nitromethane, Kraus-Pinnick oxidation, and Raney Ni reduction. Highly enantioenriched baclofen was obtained in one pot with a good yield over four reactions.
January 4, 2016: Organic Letters
Tsuyoshi Mita, Yuki Higuchi, Yoshihiro Sato
Various allylic alcohols were carboxylated in the presence of a catalytic amount of PdCl2 and PPh3 using ZnEt2 as a stoichiometric transmetalation agent under a CO2 atmosphere (1 atm). This carboxylation proceeded in a highly regioselective manner to afford branched carboxylic acids predominantly. The β,γ-unsaturated carboxylic acid thus obtained was successfully converted into an optically active γ-butyrolactone, a known intermediate of (R)-baclofen.
November 9, 2015: Chemistry: a European Journal
Deborah S Raithel, Kirsten H Ohler, Isabel Porto, Alma R Bicknese, Donna M Kraus
Paroxysmal sympathetic hyperactivity (PSH) is a life-threatening condition characterized by hyperadrenergic activity and autonomic dysfunction. Also termed autonomic storms, PSH can occur after a variety of cerebral insults, most commonly traumatic brain injury. Limited pediatric literature is available, especially in patients with brain injury from hypoxia. No consensus exists for the terminology, diagnostic criteria, or treatment algorithm for PSH. Thus, the optimal management, including medication selection and dosing, remains unclear...
July 2015: Journal of Pediatric Pharmacology and Therapeutics: JPPT: the Official Journal of PPAG
I V Belozertseva, O A Dravolina, M A Tur, S R Kuvarzin, É É Zvartau
AIM: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds. MATERIAL AND METHODS: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al. (1978). Subcutaneous injections of different doses of morphine (10-60 mg/kg) induced a dose-dependent SR with maximum response obtained 15-30 min after the morphine administration...
2015: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Gregory B Bissonette, Matthew R Roesch
Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward...
October 2015: European Journal of Neuroscience
Elliott Kyung Lee, Alan Bruce Douglass
Narcolepsy is a disabling sleep disorder characterized by daytime hypersomnolence. Those with cataplexy have spells of muscle weakness precipitated by strong emotions, especially laughter or surprise. Cataplexy treatments include antidepressants or a GABA-B agonist, gamma hydroxybutyrate (GHB). GHB is the most effective treatment for cataplexy, but is expensive and can have significant side effects. A recent report of a murine model of narcolepsy-cataplexy suggests R-baclofen has potential efficacy against cataplexy...
2015: Nature and Science of Sleep
Liga Zvejniece, Edijs Vavers, Baiba Svalbe, Grigory Veinberg, Kristina Rizhanova, Vilnis Liepins, Ivars Kalvinsh, Maija Dambrova
Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R-phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABAB receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the α2-δ subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP...
October 2015: Pharmacology, Biochemistry, and Behavior
Jing Wang, Deb Kumar Mojumder, Jun Yan, An Xie, Robert F Standaert, Haohua Qian, David R Pepperberg, Laura J Frishman
All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABACR (GABA(A)-ρ), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABACR versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABACR(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABACR antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABAAR antagonist, SR95531; GABABR antagonist, CGP, and agonist, baclofen...
October 2015: Experimental Eye Research
Amer Dastgir, Nathan J Ranalli, Theresa L MacGregor, Philipp R Aldana
The authors report an unusual case of intrathecal baclofen withdrawal due to the perforation and subsequent leakage of a baclofen pump catheter in a patient with spastic cerebral palsy. A 15-year-old boy underwent an uncomplicated placement of an intrathecal baclofen pump for the treatment of spasticity due to cerebral palsy. After excellent control of symptoms for 3 years, the patient presented to the emergency department with increasing tremors following a refill of his baclofen pump. Initial evaluation consisted of radiographs of the pump and catheter, which appeared normal, and a successful aspiration of CSF from the pump's side port...
September 2015: Journal of Neurosurgery. Pediatrics
Kristen R Nichols, Chad A Knoderer, Nicholas G Jackson, John J Manaloor, John C Christenson
A 13-year-old female experienced a recurrence of baclofen pump-related central nervous system (CNS) infection caused by Achromobacter, despite absence of retained foreign material. Due to the failure of meropenem (120 mg/kg/d in divided doses every 8 hours and infused over 30 minutes) in the initial infection, the dose was infused over 4 hours during the recurrence. Meropenem is an antibiotic for which efficacy is time dependent, and 4-hour versus 30-minute infusions have been shown to prolong the time the concentration of the antibiotic exceeds the minimum inhibitory concentration (MIC) of the organism at the site of infection (T>MIC)...
August 2015: Journal of Pharmacy Practice
Monica Blichowski, Alexander Shephard, Jessica Armstrong, Liqing Shen, Miguel A Cortez, James H Eubanks, O Carter Snead
OBJECTIVE: Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans...
July 2015: Epilepsia
F Migliorini, A B Porcaro, R Baldassarre, W Artibani
Recurrent ischaemic priapism also known as stuttering priapism is an uncommon form of ischaemic priapism, and its treatment is not yet clearly defined. If left untreated, it may evolve into classic form of acute ischaemic priapism and lead to erectile dysfunction due to fibrosis of corpora cavernosa. Several drugs have been proposed with variable results and only supported with level three or four of evidence. Hormonal therapy such as cyproterone acetate, oestrogen, bicalutamide or Lh-Rh agonist are often effective but can cause side effects such as hypogonadal state and infertility...
March 2016: Andrologia
J Alsiö, S R O Nilsson, F Gastambide, R A H Wang, S A Dam, A C Mar, M Tricklebank, T W Robbins
RATIONALE: Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. OBJECTIVES: The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms...
November 2015: Psychopharmacology
Justin R Davanzo, Elias Rizk
This is a case report illustrating an overdose of baclofen in a 10-year-old boy due to a likely malfunction of a SynchroMed II pump. This ultimately necessitated a pump replacement. One-year follow-up showed no further incidents of baclofen overdose, with multiple pump refills.
August 2015: Journal of Neurosurgery. Pediatrics
F Javier Rubio, Qing-Rong Liu, Xuan Li, Fabio C Cruz, Rodrigo M Leão, Brandon L Warren, Sarita Kambhampati, Klil R Babin, Kylie B McPherson, Raffaello Cimbro, Jennifer M Bossert, Yavin Shaham, Bruce T Hope
Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum...
April 8, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Shunying Jin, Michael L Merchant, Jeffrey D Ritzenthaler, Kenneth R McLeish, Eleanor D Lederer, Edilson Torres-Gonzalez, Mostafa Fraig, Michelle T Barati, Alex B Lentsch, Jesse Roman, Jon B Klein, Madhavi J Rane
Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI...
2015: PloS One
Mary Miller Phillips, Natasa Miljkovic, Marlyn Ramos-Lamboy, John J Moossy, John Horton, Alhaji M Buhari, Michael C Munin
OBJECTIVE: To report our clinical experience using continuous intrathecal baclofen (ITB) trials prior to permanent pump implantation. DESIGN: Retrospective chart review. SETTING: An inpatient neurosurgery unit and outpatient physical medicine and rehabilitation clinics. PARTICIPANTS: Fifty-seven patients with refractory spasticity who underwent a continuous ITB trial during the years 2006-2012. METHODS: Patients underwent placement of a temporary intrathecal catheter that was connected to an external pump...
October 2015: PM & R: the Journal of Injury, Function, and Rehabilitation
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