Huy Quang Nguyen

The 5-HT6 receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus

Preclinical evidence has suggested a possible role for the 5-HT6 receptor in the treatment of cognitive dysfunction. However, currently there is little neurochemical evidence suggesting the mechanism(s) which may be involved. Using the selective 5-HT6 antagonist SB-271046 and in vivo microdialysis, we have evaluated the effects of this compound on the modulation of basal neurotransmitter release within multiple brain regions of the freely moving rat. SB-271046 produced no change in basal levels of dopamine (DA), norepinephrine (NE) or 5-HT in the striatum, frontal cortex, dorsal hippocampus or nucleus accumbens. Similarly, this compound had no effect on excitatory neurotransmission in the striatum or nucleus accumbens. Conversely, SB-271046 produced 3- and 2-fold increases in extracellular glutamate levels in both frontal cortex and dorsal hippocampus, respectively. These effects were completely attenuated by infusion of tetrodotoxin but unaffected by the muscarinic antagonist, atropine. Here we demonstrate for the first time the selective enhancement of excitatory neurotransmission by SB-271046 in those brain regions implicated in cognitive and memory function, and provide mechanistic evidence in support of a possible therapeutic role for 5-HT6 receptor antagonists in the treatment of cognitive and memory dysfunction.

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity.

Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7–30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3–3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7–17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3–3 mg/kg i.p.; 1–17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT2B/2C receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1–10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

In vivo effects of the 5‐HT6 antagonist SB‐271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5‐HT, glutamate and aspartate

Although the 5‐HT6 receptor subtype was identified some 5 years ago, very little is known about its function within the brain. Here we demonstrate, for the first time, the neurochemical effects of a selective 5‐HT6 receptor ligand. Using in vivo microdialysis in the freely moving rat, we evaluated the effects of the selective 5‐HT6 receptor antagonist SB‐271046 by simultaneous measurement of 5‐hydroxytryptamine (5‐HT), dopamine (DA), noradrenaline (NA), glutamate and aspartate from the striatum and frontal cortex. SB‐271046 did not alter basal levels of 5‐HT, DA and NA in either brain region. Similarly, there was no change basal levels of either of the excitatory amino acids within the striatum. In contrast, administration of SB‐271046 (10 mg kg−1 s.c.) produced a significant (P<0.05), tetrodotoxin‐dependent, increase in extracellular levels of both glutamate and aspartate within the frontal cortex, reaching maximum values of 375.4±82.3 and 215.3±62.1% of preinjection values, respectively.

Global weak solutions for generalized SQG in bounded domains

We prove the existence of global

Local and global strong solutions for SQG in bounded domains

L^2

Onsager's Conjecture and Anomalous Dissipation on Domains with Boundary

weak solutions for a family of generalized inviscid surface-quasi geostrophic (SQG) equations in bounded domains of the plane. In these equations, the active scalar is transported by a velocity field which is determined by the scalar through a more singular nonlocal operator compared to the SQG equation. The result is obtained by establishing appropriate commutator representations for the weak formulation together with good bounds for them in bounded domains.

Remarks on the Emergence of Weak Euler Solutions in the Vanishing Viscosity Limit

Abstract We prove local well-posedness for the inviscid surface quasigeostrophic (SQG) equation in bounded domains of R 2 . When fractional Dirichlet Laplacian dissipation is added, global existence of strong solutions is obtained for small data for critical and supercritical cases. Global existence of strong solutions with arbitrary data is obtained in the subcritical cases.

Potentiation of amphetamine-induced changes in dopamine and 5-HT by a 5-HT6 receptor antagonist

We give a localized regularity condition for energy conservation of weak solutions of the Euler equations on a domain

Global Weak Solutions for SQG in Bounded Domains

\Omega\subset \mathbb{R}^d

Sharp Strichartz estimates for water waves systems

,