Neuropsychopharmacology (2010) 35, 929-937; doi:10 1038/npp 2009

Neuropsychopharmacology (2010) 35, 929-937; doi:10.1038/npp.2009.195; published online 2 December 2009″
“3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha 7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits

in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, VX-770 solubility dmso and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After

the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye SP600125 in vivo movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha 7-nicotinic receptors on inhibitory interneurons in Protein kinase N1 the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful

in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia. Neuropsychopharmacology (2010) 35, 938-942; doi:10.1038/npp.2009.196; published online 2 December 2009″
“The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine.

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