Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum.
BACKGROUND
Acute systemic administration of salvinorin A, a naturally occurring kappa-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow.


OBJECTIVE
Conventional and quantitative microdialysis techniques were used to determine whether salvinorin A infusion into the dorsal striatum (DSTR) decreases DA overflow by altering DA uptake or release. The influence of repeated salvinorin A administration on basal DA dynamics and cocaine-evoked alterations in DA overflow and locomotion was also assessed.


METHODS
Salvinorin A was administered via the dialysis probe (0; 20-200 nM) or via intraperitoneal (i.p.) injection (1.0 or 3.2 mg/kg per day x 5 days). The effects of a challenge dose of cocaine were examined 48 h after repeated salvinorin treatment.


RESULTS
Retrodialysis of salvinorin A produced a dose-related, KOPr antagonist reversible, decrease in DA levels. Extracellular DA levels were decreased whereas DA extraction fraction, which provides an estimate of DA uptake, was unaltered. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced.


CONCLUSIONS
These data demonstrate that acute, but not repeated, salvinorin A administration decreases mesostriatal neurotransmission and that activation of DSTR KOPr is sufficient for this effect. Differences in the interaction of salvinorin and synthetic KOPr agonists with cocaine suggest that the pharmacology of these agents may differ.
Gehrke
Brenda J
BJ
Integrative Neuroscience Section, NIH/NIDA Intramural Research Program, Baltimore, MD 21224, USA. gehrkeb@nida.nih.gov
Chefer
Vladimir I
VI
Shippenberg
Toni S
TS
D000818:Animals; D001931:Brain Mapping; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006213:Hallucinogens / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D045785:Diterpenes, Clerodane; D006213:Hallucinogens; D017473:Receptors, Opioid, kappa; D003042:Cocaine; C090499:salvinorin A; D004298:Dopamine