BACKGROUND Strong evidence supports the concept that conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. However, there is no evidence that nitrogen, which only exhibits narcotic potency at increased pressure, may act by a similar mechanism. METHODS We compared the inhibitory a...

OBJECTIVE Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors w...

The dopamine receptors have been classified into two groups, the D1like and D2-like dopamine receptors, respectively, based on molecular biology and pharmacological studies. The D1-like dopamine receptors comprise the D1 and D5 dopamine receptors and the D2-like dopamine receptors include the D2, D3 and D4 dopamine receptors. The gene structures of these two classes of receptors are dissimilar ...

Chronic interruption of the nigrostriatal dopaminergic pathway leads to sensitized dopaminergic responses in striatum. We attempted to explore the mechanism(s) underlying this dopaminergic supersensitivity by assessing dopamine receptor signaling and receptor-G protein coupling in unilateral 6-hydroxydopamine-lesioned rats. Dopamine-stimulated adenylyl cyclase activity as well as dopamine-activ...

Recombinant human dopamine D4.4 receptor-mediated G protein activation was characterized in membranes of transfected mammalian (Chinese hamster ovary) cells by the use of [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding. An initial series of experiments defined the conditions (3 microM GDP, 100 mM NaCl, 3 mM MgCl2) under which optimal stimulation (2.2-fold increase in specific ...

Migraine is a common, disabling problem with three phases: premonitory, main headache attack, and postdrome. The headache phase is thought to involve activation of trigeminal neurons, whereas the premonitory and postdrome phases may involve dopaminergic mechanisms. In animal studies, dopamine has been found to cause vasodilation of cranial arteries at very low doses. Using intravital microscopy...

Parkinson's disease (PD) is characterized by both motor and nonmotor deficits. Among cardinal symptoms of this disorder, tremor the least responsive to dopamine replacement therapy often undertreated. Zuranolone (SAGE-217) an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABAA) receptor–positive allosteric modulator (PAM) that has been investigated for its safety eff...

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget strategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an effort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through biological and computational studies of 5-HT2A and D2 receptors, we identified the re...

A circadian oscillator is located within the eye of Xenopus laevis. This oscillator regulates retinal melatonin synthesis, stimulating it at night. The primary goal of the studies reported here was to define input pathways to this circadian oscillator as a step toward identification of circadian clock mechanisms. A flow-through superfusion culture system was developed to monitor circadian rhyth...

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D(2) receptor. We measured in vivo occupancy of striatal D(2) receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D(2) receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of i...