The mechanism by which dopamine induces or facilitates neurohypophysial hormone release is not completely understood. Because oxytocin- and vasopressin-secreting supraoptic neurons are under the control of a prominent GABAergic inhibition, we investigated the possibility that dopamine exerts its action by modulating GABA-mediated transmission. Whole cell voltage-clamp recordings of supraoptic n...

Adenosine receptors modulate dopaminergic function by regulating dopamine release in presynaptic neurons and intracellular signaling in postsynaptic striatal neurons. To investigate how adenosine impinges on the action of dopamine in feeding and locomotion, genetically altered, dopamine-deficient mice were treated with adenosine receptor antagonists. Acute administration of the nonselective ade...

The present study was performed to assess the role of excitatory amino acid and dopamine receptors on associative functions of the prefrontal cortex (PFC) of the rat. Spatial delayed alternation was used as a PFC-sensitive cognitive task. In addition, in vivo microdialysis was used to assess the release of dopamine in the PFC. The noncompetitive NMDA antagonists ketamine (10-30 mg/kg) and MK-80...

Methamphetamine is a potent psychomotor stimulant and a major drug of abuse. There is currently no effective medication available for treatment for methamphetamine addiction. The present study investigated the role of the dopamine D3 receptor on IV methamphetamine self-administration and its effect on methamphetamine induced neurochemical changes. Acute administration of the putative D3 recepto...

Several dopamine agonists, administered i.m., produced persistent, excessive and non-localized scratching in squirrel monkeys (Saimiri sciureus). Studies were conducted with a series of drugs to determine the pharmacological mechanisms responsible for this effect. All of the dopamine D2 agonists studied produced dose-related increases in scratching, whereas several dopamine D1 receptor agonists...

The dorsal striatum participates in motor function and stimulus-response or "habit" learning. Acetylcholine (ACh) is a prominent neurotransmitter in the striatum and exerts part of its actions through nicotinic cholinergic receptors. Activation of these receptors has been associated with the enhancement of learning and certainly is instrumental in habitual use of nicotine. Nicotinic receptors h...

A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacopho...

Dopamine D(2) receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D(2) antagonist in the striatum. Firs...

Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine ...

In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalen...