Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens - PubMed (original) (raw)
Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens
Stephanie R Ebner et al. Psychopharmacology (Berl). 2010 Jun.
Abstract
Rationale: Kappa opioid receptors (KORs) have been implicated in depressive-like states associated with chronic administration of drugs of abuse and stress. Although KOR agonists decrease dopamine in the nucleus accumbens (NAc), KOR modulation of phasic dopamine release in the core and shell subregions of the NAc-which have distinct roles in reward processing-remains poorly understood.
Objectives: Studies were designed to examine whether the time course of effects of KOR activation on phasic dopamine release in the NAc core or shell are similar to effects on motivated behavior.
Methods: The effect of systemic administration of the KOR agonist salvinorin A (salvA)-at a dose (2.0 mg/kg) previously determined to have depressive-like effects-was measured on electrically evoked phasic dopamine release in the NAc core or shell of awake and behaving rats using fast scan cyclic voltammetry. In parallel, the effects of salvA on intracranial self-stimulation (ICSS) and sucrose-reinforced responding were assessed. For comparison, a threshold dose of salvA (0.25 mg/kg) was also tested.
Results: The active, but not threshold, dose of salvA significantly decreased phasic dopamine release without affecting dopamine reuptake in the NAc core and shell. SalvA increased ICSS thresholds and significantly lowered breakpoint on the progressive ratio schedule, indicating a decrease in motivation. The time course of the KOR-mediated decrease in dopamine in the core was qualitatively similar to the effects on motivated behavior.
Conclusions: These data suggest that the effects of KOR activation on motivation are due, in part, to inhibition of phasic dopamine signaling in the NAc core.
Figures
Fig. 1
A representative example of salvA (2.0 mg/kg) effects on electrically evoked phasic dopamine. a) Electrical stimulation of the VTA evokes a phasic increase of dopamine in the NAc core prior to injection (baseline). Top: Background-subtracted color plot indicates changes in dopamine concentration in response to stimulation (time=0; 24 pulses, 60 Hz, 120 μA, 4 ms/phase, monophasic). Time is the abscissa, the electrode potential is the ordinate, and current changes are encoded in color. Dopamine concentration [identified by its oxidation (~0.6 V; green) and reduction (~−0.2 V; blue on the negative going scan) features] increased in response to the stimulation. Bottom: dopamine concentration as a function of time is extracted from the color plot above. Inset: Current changes due to the presence of dopamine at the electrode surface are confirmed by plotting current as a function of electrode potential (cyclic voltammogram). b) The same stimulation train evokes a smaller change in dopamine concentration 15 min and c) 180 min post-salvA (2.0 mg/kg) injection. Data in b and c were plotted and analyzed as in a
Fig. 2
SalvA decreases phasic dopamine concentration evoked by electrical stimulation of the VTA. a) Time course of salvA effects on the peak concentration of dopamine in the NAc core evoked by electrical stimulation. Compared to vehicle (_n_=6 rats), salvA (2.0 mg/kg; _n_=6 rats) significantly decreased evoked dopamine concentration in the NAc core from 5–135, but not 60, min post-injection. Compared to vehicle, salvA (0.25 mg/kg; _n_=6 rats) had no effect on peak dopamine concentration. b) Time course of salvA effects on the peak concentration of dopamine in the NAc shell evoked by electrical stimulation. Compared to vehicle (_n_=6 rats), salvA (2.0 mg/kg; _n_=6 rats) significantly decreased evoked dopamine concentration in the NAc shell from 5 to 25 min with the exception of 10-min post-injection. Compared to vehicle, salvA (0.25 mg/kg; _n_=5 rats) had no effect on peak dopamine concentration. In both graphs, each point represents the mean (+sem) percent change from pre-injection baseline. *p<0.01 compared to vehicle at each time point, Fisher's protected t tests
Fig. 3
SalvA does not affect the rate of dopamine reuptake in the NAc. The descending portions of dopamine concentration curves in the NAc core a) and shell b) evoked at baseline and 15, 60, and 180-min post-salvA (2.0 mg/kg) injection are overlaid. Comparisons of the descending curves of concentration-matched, electrically evoked dopamine indicate that dopamine reuptake rates are not different. In both graphs, each point represents the mean (+sem) dopamine concentration evoked by stimulation of the VTA (_n_=6 rats). ANOVAs (stimulation time × decay time) revealed no main effects
Fig. 4
Effects of salvA on ICSS thresholds. Rats were treated systemically with vehicle or salvA (0.25, 2.0 mg/kg, IP) and immediately placed in the ICSS chambers for 12 rate-frequency determinations over the course of the 180-min test session. (a, b, and c) Rate of bar pressing (per 50 s) as a function of stimulation frequency for a representative rat at indicated times after vehicle (a), salvA (0.25 mg/kg) (b), or salvA (2.0 mg/kg) (c) injection. Time course of drug effects on thresholds (d) and maximal rates of responding (e). Each point in d and e represents the mean (+sem) percent change from pre-injection baseline thresholds. SalvA (2.0 mg/kg) significantly increased thresholds for 105 min and decreased maximal rates of responding for 45 min compared to vehicle (_N_=9 rats). *p<0.05, **p<0.01 compared to vehicle at each time point, Fisher's protected t tests
Fig. 5
Effects of salvA on the number of ratios completed for sucrose pellets prior to 15 min of inactivity (breakpoint). a) Compared to vehicle and salvA (0.25 mg/kg), salvA (2.0 mg/kg) significantly lowered breakpoint in the PR schedule. b) There were no significant differences in FR5 breakpoints across salvA dose. In both graphs, each bar represents the mean (+sem) breakpoint during the session (_n_=10 rats). *p<0.05 compared to vehicle and salvA (0.25 mg/kg), Tukey's Honestly Significant Difference tests
Fig. 6
Effects of salvA on cumulative active lever responding for sucrose pellets. a) Compared to vehicle, salvA (2.0 mg/kg) significantly decreased active lever responding in the PR schedule between 10 and 150 min post-injection—but not at 115 or 140 min. b) Compared to vehicle, salvA (2.0 mg/kg) significantly decreased active lever responding in the FR5 schedule between 20 and 40-min post-injection. In both graphs, each point represents the mean (+sem) number of cumulative lever presses made on the active lever (_n_=10 rats). *p<0.05 compared to vehicle at each time point, Tukey's Honestly Significant Difference tests
References
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