Quantitative assessment of dopamine D2 antagonist activity using invertebrate (Planaria) locomotion as a functional endpoint.

INTRODUCTION: Dopaminergic ligands, including drugs of abuse, modulate the locomotor activity of planarians and induce characteristic abnormal patterns of motility at high doses. It has been presumed that the effect is related to dopamine receptors based on ligand specificity and effects on second messenger levels. However, to date, the measured changes have been mostly qualitative in nature and it is not completely clear that the effect is related to stereospecific receptor mechanisms. METHODS: The present study addressed these issues by devising a convenient and sensitive metric (locomotor velocity, pLMV) and applied the method to test Planaria enantiomer-sensitivity to a dopamine D2-receptor antagonist. RESULTS: pLMV was remarkably constant over the observation period and established a stable baseline against which to study and quantitate pharmacologic intervention. Further, S(-)-sulpiride at low doses (10(-10) to 10(-8) M) attenuated pLMV in a dose-dependent manner, but R(+)-sulpiride was only 1/25th as potent. DISCUSSION: The new methodology thus provides a method for quantifying actions of D2 ligands in a simple in vivo system.

Insulin receptors and insulin action in the brain: review and clinical implications.

Insulin receptors are known to be located on nerve cells in mammalian brain. The binding of insulin to dimerized receptors stimulates specialized transporter proteins that mediate the facilitated influx of glucose. However, neurons possess other mechanisms by which they obtain glucose, including transporters that are not insulin-dependent. Further, insulin receptors are unevenly distributed throughout the brain (with particularly high density in choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex). Such factors imply that insulin, and insulin receptors, might have functions within the central nervous system in addition to those related to the supply of glucose. Indeed, invertebrate insulin-related peptides are synthesized in brain and serve as neurotransmitters or neuromodulators. The present review summarizes the structure, distribution and function of mammalian brain insulin receptors and the possible implications for central nervous system disorders. It is proposed that this is an under-studied subject of investigation.

Energy-dependent UV light-induced disruption of (-)sulpiride antagonism of dopamine.

The dopamine D2 receptor antagonist sulpiride decreases the spontaneous locomotor activity of Planaria in an enantiomeric-selective and dose-dependent manner. We now report that (-)sulpiride (0.1 microM)-induced decrease of planarian locomotor activity is significantly (P<0.05) attenuated by low-energy (366 nm) ultraviolet (UV) light and to a greater extent by high-energy (254 nm) UV light. The phenomenon offers a novel approach for studying dopamine D2 receptor transduction processes in a simple in vivo model.