Milameline (CI-979/RU35926): A Muscarinic Receptor Agonist with Cognition-Activating Properties: Biochemical and In Vivo Characterization 1

ABSTRACT Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM 1 -hM 5 ) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM 1 and hM 3 CHO cells and inhibited forskolin-activated cAMP accumulation in hM 2 and hM 4 CHO cells. Additionally, it decreased K ϩ -stimulated release of [ 3 H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to ϳ30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of lowvoltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors. Muscarinic receptors have been characterized according to their pharmacological sensitivity and high affinity for specific antagonists Five subtypes of muscarinic receptors (M 1 -M 5 ) have been demonstrated to be distinct gene products on the basis of molecular characterization. These receptors were shown to share a high level of sequence homology and belong to the super family of G protein-coupled receptors possessing seven transmembrane-spanning domains There are several clinical disorders with impaired cognitive function that may benefit from drugs that improve memory and learning. The largest population would be individuals suffering from Alzheimer's disease (AD), an age-related neurodegenerative disorder presenting progressive loss of cognitive function and characterized by brain neurofibrillary tangles and amyloid-containing plaques. Several neurotransmitters have been shown to be altered during the course of the disease, the most consistent pathological findings being the loss of forebrain cholinergic neurons, as evidenced by a decrease in choline acetyltransferase activit

Changes in ImPACT Cognitive Subtest Networks Following Sport-Related Concussion

Objective: High school athletes are administered ImPACT at the start of the academic year or sport season and again after suspected concussion. Concussion management involves the comparison of baseline and post-injury cognitive scores with declines in scores providing evidence for concussive injury. A network framework may provide additional information about post-concussive cognitive changes and expand characterization of sport-related concussion (SRC) recovery. Design: Retrospective cohort study. Setting: High school. Participants: High school athletes (n = 1553) were administered ImPACT at baseline (T1), post-SRC (T2 = 72 h of injury), and prior to return to play (T3 = within two weeks post-injury). Independent Variables: ImPACT cognitive subtest scores. Main Outcome Measures: Cognitive networks were calculated and compared over three time points. Centrality indices were calculated to determine the relative importance of cognitive variables within networks. Results: Network connectivity increased from T1 to T2 and remained hyperconnected at T3. There was evidence of network reorganization between T1 and T3. Processing speed was central within each network, and visual memory and impulsivity became more central over time. Conclusions: The results suggest potential evidence of cognitive network change over time. Centrality findings suggest research specific to visual memory and impulse control difficulties during the post-concussion recovery period is warranted. Network analysis may provide additional information about cognitive recovery following SRC and could potentially serve as an effective means of monitoring persisting cognitive symptoms after concussion

Modulation of serotonergic neurotransmission by short- and long-term treatments with sigma ligands

1. Sigma receptors were first described in 1976 as opiate receptors but were later determined to be a distinct class of receptors with two subtypes, sigma(1) and sigma(2). Although the endogenous ligand is yet to be elucidated, the sigma(1) receptor has recently been cloned. 2. Behavioural models used to test potential antidepressants have shown sigma ligands to produce antidepressant effects but their mechanism of action is unknown. 3. The goal of the present study was to assess the effects of various sigma(1) ligands on the firing activity of serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) using extracellular in vivo recordings in anaesthetized rats. 4. The sigma(1) ligands (+)-pentazocine and 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP) (2 mg kg(−1) day(−1)) increased markedly 5-HT firing activity after 2 days of treatment and maintained the same increased firing rate after long-term (21 days) treatments. Furthermore, the increased firing rate produced by 2 and 21 day treatments with (+)-pentazocine was prevented by the co-administration of N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-thylamine (NE-100) (10 mg kg(−1) day(−1)) a selective sigma(1) antagonist, confirming the sigma(1) receptor's modulation of these effects. In contrast, the sigma(1) ligands (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-1-ethyl-but-3-en-1-ylamine hydrochloride (JO-1784) and 2-(4-morpholinoethyl 1-phenyl-cyclohexane-1-carboxylate hydrochloride (PRE-084) had no effect. 5. Following a 21-day treatment with (+)-pentazocine there was a marked reduction in the number of neurons found per track. This decrease was not seen after chronic treatment with 4-IBP and may represent a depolarization block. 6. These results suggest a modulation of serotonergic neurotransmission by some sigma receptors and provide a potential mechanism for the ‘antidepressant effects' reported and provide evidence toward sigma(1) ligands as potential antidepressants with a rapid onset of action