Salvinorin A (SA) is a potent and highly selective kappa-opioid receptor (KOR) agonist with rapid kinetics and commensurate behavioral effects; however, brain regions associated with these effects have not been determined.
Freely moving adult male rats were given SA intraperitoneally during uptake and trapping of the brain metabolic radiotracer, 2-deoxy-2-[F-18]fluoro-d-glucose (FDG), followed by image acquisition in a dedicated animal positron emission tomography (PET) system. Age-matched control animals received vehicle treatment. Animal behavior during FDG uptake was recorded digitally and later analyzed for locomotion. Group differences in regional FDG uptake normalized to whole brain were determined using Statistical Parametric Mapping (SPM) and verified by region of interest (ROI) analysis.
SA-treated animals demonstrated significant increases in FDG uptake compared to controls in several brain regions associated with the distribution of KOR such as the periaqueductal grey, bed nucleus of the stria terminalis and the cerebellar vermis, as well as in the hypothalamus. Significant bilateral activations were also observed in the auditory, sensory, and frontal cortices. Regional decreases in metabolic demand were observed bilaterally in the dorsolateral striatum and hippocampus. Locomotor activity did not differ between SA and vehicle during FDG uptake.
We have provided the first extensive maps of cerebral metabolic activation due to the potent κ-opioid agonist, salvinorin A. A major finding from our small animal PET studies using FDG was that neural circuits affected by SA may not be limited to direct activation or inhibition of kappa-receptor-expressing cells. Instead, salvinorin A may trigger brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output.
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This work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the U.S. Department of Energy and supported by its Office of Biological and Environmental Research. J.M.H. was supported by an NIH Postdoctoral Fellowship (1F32EB008320-01) and through the Goldhaber Distinguished Fellowship program at BNL. The authors are grateful to Dr. Stephen Dewey, David Alexoff, and Dr. Martine Mirrione for helpful discussions and insights.
Significance: Salvinorin A is the major psychoactive compound from Salvia divinorum and is a potent kappa-opioid receptor agonist. Owing to its hallucinogenic properties, abuse liability, and medicinal potential as a kappa-agonist there has been a growing effort to characterize its physiological effects in rodents. Our manuscript describes our efforts to further inform how salvinorin A leads to behavioral (and physiological) changes in rodents. We have determined the regional differences (relative to controls) in glucose utilization in the brains of freely behaving rats after acute administration of salvinorin A. Using FDG, we have mapped brain regions that are activated or deactivated as a result of the kappa agonist. We feel there will be an increasing need to systematically understand how affinity, pharmacokinetics, and distribution influence behavior through regional changes in brain activation. Our studies highlight the potential of FDG with small animal PET to accomplish this.
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Hooker, J.M., Patel, V., Kothari, S. et al. Metabolic Changes in the Rodent Brain after Acute Administration of Salvinorin A. Mol Imaging Biol 11, 137–143 (2009). https://doi.org/10.1007/s11307-008-0192-x
- Salvinorin A
- Kappa opioid
- Positron emission tomography