Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum

Abstract

Rationale-Acute systemic administration of salvinorin A, a naturally occurring κ-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow.Objectives-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. 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. Materials and methods-SalvinorinConclusions-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.

Kappa opioid receptors regulate cocaine effects on nucleus accumbens dopamine through phosphorylation of dopamine transporter at the threonine 53 site

“…We further showed that KOR activation did not change NAc DA uptake in this preparation. This is in line with other published striatal slice work 47,48 , as well as in vivo reports employing microdialysis 17 and FSCV 49 . However, it is important to note that these findings conflict with data from cell expression systems 14 , striatal synaptosomes 15,16 , and in vivo experiments 10,16 , which suggest KOR activation increases DA uptake.…”

Kappa opioid receptors regulate cocaine effects on nucleus accumbens dopamine through phosphorylation of dopamine transporter at the threonine 53 site

“…We further showed that KOR activation did not change NAc DA uptake in this preparation. This is in line with other published striatal slice work 47,48 , as well as in vivo reports employing microdialysis 17 and FSCV 49 . However, it is important to note that these findings conflict with data from cell expression systems 14 , striatal synaptosomes 15,16 , and in vivo experiments 10,16 , which suggest KOR activation increases DA uptake.…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…The maximum CPP response observed with the 40 g/kg dose was reduced by the CB 1 receptor inverse-agonist rimonabant as well as norBNI. In contrast to other studies (Zhang et al, 2005;Gehrke et al, 2008), 40 g/kg salvinorin A increased extracellular DA by ϳ150% of baseline for 140 min in the shell of the nucleus accumbens. Consistent with the salvinorin A-induced increase in extracellular DA observed in this study, intracerebroventricular salvinorin A supported self-administration behavior, an effect that was attenuated by either rimonabant or norBNI.…”

“…decreased extracellular DA but not 5-HT. Gehrke et al, (2008) extended these findings. This study showed that administration of salvinorin A (1.0 and 3.2 mg/kg i.p.)…”

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…Further evidence to support this is a recent study by Ebner et al (2010) who showed that Sal A (2 mg/kg) decreased phasic DA release in the rat NAcb 5–135 min post injection without increasing DA reuptake, with max effects seen at 15 min. A lower dose of Sal A (0.25 mg/kg) did not alter DA release in the NAcb (Ebner, Roitman, Potter, Rachlin, & Chartoff, 2010), which is in contrast to the study in mice by Gehrke et al (2008). However, species differences and the route of Sal A administration (local versus systemic administration) are likely explanations for the difference seen in these studies.…”

Kappa opioid receptors regulate cocaine effects on nucleus accumbens dopamine through phosphorylation of dopamine transporter at the threonine 53 site

“…We further showed that KOR activation did not change NAc DA uptake in this preparation. This is in line with other published striatal slice work 47,48 , as well as in vivo reports employing microdialysis 17 and FSCV 49 . However, it is important to note that these findings conflict with data from cell expression systems 14 , striatal synaptosomes 15,16 , and in vivo experiments 10,16 , which suggest KOR activation increases DA uptake.…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…The maximum CPP response observed with the 40 g/kg dose was reduced by the CB 1 receptor inverse-agonist rimonabant as well as norBNI. In contrast to other studies (Zhang et al, 2005;Gehrke et al, 2008), 40 g/kg salvinorin A increased extracellular DA by ϳ150% of baseline for 140 min in the shell of the nucleus accumbens. Consistent with the salvinorin A-induced increase in extracellular DA observed in this study, intracerebroventricular salvinorin A supported self-administration behavior, an effect that was attenuated by either rimonabant or norBNI.…”

“…decreased extracellular DA but not 5-HT. Gehrke et al, (2008) extended these findings. This study showed that administration of salvinorin A (1.0 and 3.2 mg/kg i.p.)…”

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…Further evidence to support this is a recent study by Ebner et al (2010) who showed that Sal A (2 mg/kg) decreased phasic DA release in the rat NAcb 5–135 min post injection without increasing DA reuptake, with max effects seen at 15 min. A lower dose of Sal A (0.25 mg/kg) did not alter DA release in the NAcb (Ebner, Roitman, Potter, Rachlin, & Chartoff, 2010), which is in contrast to the study in mice by Gehrke et al (2008). However, species differences and the route of Sal A administration (local versus systemic administration) are likely explanations for the difference seen in these studies.…”

Kappa opioid receptors regulate cocaine effects on nucleus accumbens dopamine through phosphorylation of dopamine transporter at the threonine 53 site

“…We further showed that KOR activation did not change NAc DA uptake in this preparation. This is in line with other published striatal slice work 47,48 , as well as in vivo reports employing microdialysis 17 and FSCV 49 . However, it is important to note that these findings conflict with data from cell expression systems 14 , striatal synaptosomes 15,16 , and in vivo experiments 10,16 , which suggest KOR activation increases DA uptake.…”

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

“…The maximum CPP response observed with the 40 g/kg dose was reduced by the CB 1 receptor inverse-agonist rimonabant as well as norBNI. In contrast to other studies (Zhang et al, 2005;Gehrke et al, 2008), 40 g/kg salvinorin A increased extracellular DA by ϳ150% of baseline for 140 min in the shell of the nucleus accumbens. Consistent with the salvinorin A-induced increase in extracellular DA observed in this study, intracerebroventricular salvinorin A supported self-administration behavior, an effect that was attenuated by either rimonabant or norBNI.…”

“…decreased extracellular DA but not 5-HT. Gehrke et al, (2008) extended these findings. This study showed that administration of salvinorin A (1.0 and 3.2 mg/kg i.p.)…”

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…Further evidence to support this is a recent study by Ebner et al (2010) who showed that Sal A (2 mg/kg) decreased phasic DA release in the rat NAcb 5–135 min post injection without increasing DA reuptake, with max effects seen at 15 min. A lower dose of Sal A (0.25 mg/kg) did not alter DA release in the NAcb (Ebner, Roitman, Potter, Rachlin, & Chartoff, 2010), which is in contrast to the study in mice by Gehrke et al (2008). However, species differences and the route of Sal A administration (local versus systemic administration) are likely explanations for the difference seen in these studies.…”