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Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia. [ABSTRACT FROM AUTHOR]

Increased postcontrast enhancement in contrast-enhanced magnetic resonance imaging (CE-MRI) of the central nervous system (CNS) is a predictor of human immunodeficiency virus (HIV) dementia severity in HIV-infected subjects. The present study confirms this earlier finding in a mildly impaired patient cohort, and demonstrates that the increased postcontrast enhancement is correlated with increased cerebrospinal fluid (CSF) levels of monocyte chemoattractant protein (MCP)-1, an inflammatory chemokine, and increased CNS levels of mI, a microglial marker. These results suggest that early CNS inflammation may underlie the microvascular changes observed, and may be a factor in the development of HIV dementia. [ABSTRACT FROM AUTHOR]

We report a patient with rapidly accelerating HIV dementia accompanied by seizures and an unusual movement disorder despite highly potent antiretroviral therapy. This clinical constellation was associated with the non-parenteral use of methamphetamine and cocaine. Fractional enhancement time on post contrast magnetic resonance imaging studies revealed a progressive breakdown of the blood brain barrier particularly in the basal ganglia. The movement disorder but not the dementia responded to a combination of dopamine replacement and anticholinergic therapy. While the movement disorder may have been unmasked by concomitant anticonvulsant therapy, we suggest in this instance, that prior drug abuse synergized with HIV to cause a domino effect on cerebral function. Careful attention and analysis to histories of remote non-injecting drug abuse may help substantiate our hypothesis. [ABSTRACT FROM AUTHOR]

The article cites a research study on the regulation of insulin for dealing with diabetes and obesity. It is said that the number of people suffering from diabetes and obesity have increased dramatically over the past few years despite efforts to therapeutically target homeostatic mechanisms. Insulin regulate both homeostatic and reward-based high-fat feeding.