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Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.

Cohen A, Whitfield TW, Kreifeldt M, Koebel P, Kieffer BL, Contet C, George O, Koob GF - PLoS ONE (2014)

Bottom Line: The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects.Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days.These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

View Article: PubMed Central - PubMed

Affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

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Prodynorphin (Pdyn) knockdown in the NAcc does not alter anxiety-like behavior.A) Time in the open arms of the elevated plus maze, a measure of anxiety-like behavior. B) Time in the closed arms of the elevated plus maze. The Groups did not differ in the number of entries into the open arms (C) or the closed arms (D) of the elevated plus maze, suggesting that the results were not affected by differences in locomotor activity. N = 10.
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pone-0097216-g004: Prodynorphin (Pdyn) knockdown in the NAcc does not alter anxiety-like behavior.A) Time in the open arms of the elevated plus maze, a measure of anxiety-like behavior. B) Time in the closed arms of the elevated plus maze. The Groups did not differ in the number of entries into the open arms (C) or the closed arms (D) of the elevated plus maze, suggesting that the results were not affected by differences in locomotor activity. N = 10.

Mentions: Anxiety-like behavior was similar between shPdyn and shScr rats, reflected by a similar amount of time spent in the open arms of the elevated plus maze (P>0.05; Fig 4). Note that the groups did not differ also in the time spent in the closed arm entries (P>0.05) or open arm entries (P>0.05), suggesting that the results were not affected by differences in locomotion. However, shPdyn rats demonstrated reduced depression-like behavior in the forced swim test (FST), as reflected by lower percent of time spent floating (t19 = 2.74, P<0.01; Fig 5A), and increased percent of time spent swimming (t19 = 3.94, P<0.01; Fig 5B). Interestingly, climbing behavior was reduced in the shPdyn rats (t19 = 3.07, P<0.01; Fig 5C). Notably, on the forced-swim pretest, the groups did not differ in the % of time spent swimming (shPdyn: 76.41±2.99%, shScr: 73.16±4.68%, P>0.05), floating (shPdyn: 6.37±1.49%, shScr: 8.4±2.96%, P>0.05) or climbing (shPdyn: 14.4±1.95%, shScr: 16.39±4.27%, P>0.05).


Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization.

Cohen A, Whitfield TW, Kreifeldt M, Koebel P, Kieffer BL, Contet C, George O, Koob GF - PLoS ONE (2014)

Prodynorphin (Pdyn) knockdown in the NAcc does not alter anxiety-like behavior.A) Time in the open arms of the elevated plus maze, a measure of anxiety-like behavior. B) Time in the closed arms of the elevated plus maze. The Groups did not differ in the number of entries into the open arms (C) or the closed arms (D) of the elevated plus maze, suggesting that the results were not affected by differences in locomotor activity. N = 10.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016270&req=5

pone-0097216-g004: Prodynorphin (Pdyn) knockdown in the NAcc does not alter anxiety-like behavior.A) Time in the open arms of the elevated plus maze, a measure of anxiety-like behavior. B) Time in the closed arms of the elevated plus maze. The Groups did not differ in the number of entries into the open arms (C) or the closed arms (D) of the elevated plus maze, suggesting that the results were not affected by differences in locomotor activity. N = 10.
Mentions: Anxiety-like behavior was similar between shPdyn and shScr rats, reflected by a similar amount of time spent in the open arms of the elevated plus maze (P>0.05; Fig 4). Note that the groups did not differ also in the time spent in the closed arm entries (P>0.05) or open arm entries (P>0.05), suggesting that the results were not affected by differences in locomotion. However, shPdyn rats demonstrated reduced depression-like behavior in the forced swim test (FST), as reflected by lower percent of time spent floating (t19 = 2.74, P<0.01; Fig 5A), and increased percent of time spent swimming (t19 = 3.94, P<0.01; Fig 5B). Interestingly, climbing behavior was reduced in the shPdyn rats (t19 = 3.07, P<0.01; Fig 5C). Notably, on the forced-swim pretest, the groups did not differ in the % of time spent swimming (shPdyn: 76.41±2.99%, shScr: 73.16±4.68%, P>0.05), floating (shPdyn: 6.37±1.49%, shScr: 8.4±2.96%, P>0.05) or climbing (shPdyn: 14.4±1.95%, shScr: 16.39±4.27%, P>0.05).

Bottom Line: The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects.Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days.These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

View Article: PubMed Central - PubMed

Affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
Dynorphins, endogenous opioid peptides that arise from the precursor protein prodynorphin (Pdyn), are hypothesized to be involved in the regulation of mood states and the neuroplasticity associated with addiction. The current study tested the hypothesis that dynorphin in the nucleus accumbens (NAcc) mediates such effects. More specifically, we examined whether knockdown of Pdyn within the NAcc in rats would alter the expression of depressive-like and anxiety-like behavior, as well as cocaine locomotor sensitization. Wistar rats were injected with adeno-associated viral (AAV) vectors encoding either a Pdyn-specific short hairpin RNA (AAV-shPdyn) or a scrambled shRNA (AAV-shScr) as control. Four weeks later, rats were tested for anxiety-like behavior in the elevated plus maze test and depressive-like behavior in the forced swim test (FST). Finally, rats received one daily injection of saline or cocaine (20 mg/kg, i.p.), followed by assessment of locomotion for 4 consecutive days. Following 3 days of abstinence, the rats completed 2 additional daily cocaine/saline locomotor trials. Pdyn knockdown in the NAcc led to a significant reduction in depressive-like behavior in the FST, but had no effect on anxiety-like behavior in the elevated plus maze. Pdyn knockdown did not alter baseline locomotor behavior, the locomotor response to acute cocaine, or the initial sensitization of the locomotor response to cocaine over the first 4 cocaine treatment days. However, following 3 days abstinence the locomotor response to the cocaine challenge returned to their original levels in the AAV-shPdyn rats while remaining heightened in the AAV-shScr rats. These results suggest that dynorphin in a very specific area of the nucleus accumbens contributes to depressive-like states and may be involved in neuroadaptations in the NAcc that contribute to the development of cocaine addiction as a persistent and lasting condition.

Show MeSH
Related in: MedlinePlus