Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral...

Area of Science:

• Neuroscience
• Pharmacology
• Adrenergic Receptor Research

Background:

• Norepinephrine (NE) release in the brain is regulated by presynaptic alpha-2 adrenoceptors.
• Alpha-2 adrenoceptor antagonists can modulate neurotransmitter release.
• CH-38083 is a selective alpha-2 adrenoceptor antagonist with an alloberbane skeleton.

Purpose of the Study:

• To investigate the stereospecificity of CH-38083 enantiomers at presynaptic alpha-2 adrenoceptors.
• To determine how CH-38083 enantiomers affect electrically induced norepinephrine release.
• To compare the effects of CH-38083 enantiomers with racemic CH-38083 and idazoxan.

Main Methods:

• Rat cerebral cortex slices were loaded with [3H]norepinephrine ([3H]NE).
• Superfusion experiments measured [3H]NE release at rest and during electrical stimulation.
• Concentration-dependent effects of CH-38083 enantiomers, racemic CH-38083, idazoxan, and prazosin were assessed.

Main Results:

• Both (-)- and (+)-CH-38083 enantiomers increased [3H]NE release in a concentration-dependent manner, similar to racemic CH-38083 and idazoxan.
• The enantiomers of CH-38083 were equipotent in facilitating stimulation-evoked [3H]NE release.
• CH-38083 enantiomers antagonized the inhibitory effect of exogenous NE on [3H]NE release with different potencies, suggesting stereospecificity for occupied receptors.

Conclusions:

• Presynaptic alpha-2 adrenoceptors available for released NE do not exhibit stereospecificity towards CH-38083 enantiomers.
• Presynaptic alpha-2 adrenoceptors occupied by exogenous NE show greater sensitivity to the (-)-isomer of CH-38083.
• Prazosin, an alpha-1 antagonist, differentiated between alpha-2 adrenoceptor subtypes, indicating complex regulatory mechanisms.