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Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation.

de Jong JW, Roelofs TJ, Mol FM, Hillen AE, Meijboom KE, Luijendijk MC, van der Eerden HA, Garner KM, Vanderschuren LJ, Adan RA - Neuropsychopharmacology (2015)

Bottom Line: They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion.This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking.We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

View Article: PubMed Central - PubMed

Affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

ABSTRACT
Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

No MeSH data available.


Related in: MedlinePlus

Sucrose self-administration under FR and PR schedules of reinforcement, extinction, and reinstatement. (a) FR5 responding (1 h session) was increased after surgery with no difference between D2R knockdown and controls. (b) PR responding (average of six sessions) approximately doubled in D2R knockdown animals after surgery whereas PR responding in control animals was unaltered. (c) D2R knockdown and control animals made a comparable, minimal amount of inactive lever presses during PR sessions. There was no difference between experimental groups. (d) Rats were exposed to 10 (1 h) extinction sessions, in which active lever presses were not reinforced. Extinction of responding occurred in a comparable manner in D2R knockdown and control animals. (e) The non-contingent delivery of three sucrose pellets induced significant reinstatement of sucrose seeking in both groups. ‘Extinction' represents the number of active lever presses in extinction session 10. Data are presented as means+SEM *p<0.05, **p<0.01, ****p<0.0001.
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fig3: Sucrose self-administration under FR and PR schedules of reinforcement, extinction, and reinstatement. (a) FR5 responding (1 h session) was increased after surgery with no difference between D2R knockdown and controls. (b) PR responding (average of six sessions) approximately doubled in D2R knockdown animals after surgery whereas PR responding in control animals was unaltered. (c) D2R knockdown and control animals made a comparable, minimal amount of inactive lever presses during PR sessions. There was no difference between experimental groups. (d) Rats were exposed to 10 (1 h) extinction sessions, in which active lever presses were not reinforced. Extinction of responding occurred in a comparable manner in D2R knockdown and control animals. (e) The non-contingent delivery of three sucrose pellets induced significant reinstatement of sucrose seeking in both groups. ‘Extinction' represents the number of active lever presses in extinction session 10. Data are presented as means+SEM *p<0.05, **p<0.01, ****p<0.0001.

Mentions: To investigate the effect of VTA D2R knockdown on sucrose self-administration, rats (n=23) were tested on FR and PR for sucrose before and after virus injection. We found an increase in FR responding in both groups after surgery (F(1, 19) surgery=32.58, P=0.0001), which may reflect increased sucrose appetite in older and therefore heavier animals. We did not observe a difference in FR responding between the groups (F(1, 19) knockdown=0.922, P=0.349; data from two animals were excluded because of a malfunctioning operant chamber) (Figure 3a). However, D2R knockdown animals made approximately twice as many responses under a PR schedule of reinforcement (F(1, 21) surgery × knockdown=8.929, P=0.007) (Figure 3b). VTA D2R knockdown did not affect inactive lever presses (F(1, 21) surgery × knockdown=1.388, P=0.253) (Figure 3c). Next, we assessed responding under extinction and sucrose-primed reinstatement. We did not observe a difference between the two groups, neither under extinction (F(1, 21) knockdown=0.0760, P=0.785) (Figure 3d) nor during sucrose-primed reinstatement (F(1, 21) reinstatement=5.304, P=0.032; F(1,21) knockdown=0.167, P=0.687) (Figure 3e).


Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation.

de Jong JW, Roelofs TJ, Mol FM, Hillen AE, Meijboom KE, Luijendijk MC, van der Eerden HA, Garner KM, Vanderschuren LJ, Adan RA - Neuropsychopharmacology (2015)

Sucrose self-administration under FR and PR schedules of reinforcement, extinction, and reinstatement. (a) FR5 responding (1 h session) was increased after surgery with no difference between D2R knockdown and controls. (b) PR responding (average of six sessions) approximately doubled in D2R knockdown animals after surgery whereas PR responding in control animals was unaltered. (c) D2R knockdown and control animals made a comparable, minimal amount of inactive lever presses during PR sessions. There was no difference between experimental groups. (d) Rats were exposed to 10 (1 h) extinction sessions, in which active lever presses were not reinforced. Extinction of responding occurred in a comparable manner in D2R knockdown and control animals. (e) The non-contingent delivery of three sucrose pellets induced significant reinstatement of sucrose seeking in both groups. ‘Extinction' represents the number of active lever presses in extinction session 10. Data are presented as means+SEM *p<0.05, **p<0.01, ****p<0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4613606&req=5

fig3: Sucrose self-administration under FR and PR schedules of reinforcement, extinction, and reinstatement. (a) FR5 responding (1 h session) was increased after surgery with no difference between D2R knockdown and controls. (b) PR responding (average of six sessions) approximately doubled in D2R knockdown animals after surgery whereas PR responding in control animals was unaltered. (c) D2R knockdown and control animals made a comparable, minimal amount of inactive lever presses during PR sessions. There was no difference between experimental groups. (d) Rats were exposed to 10 (1 h) extinction sessions, in which active lever presses were not reinforced. Extinction of responding occurred in a comparable manner in D2R knockdown and control animals. (e) The non-contingent delivery of three sucrose pellets induced significant reinstatement of sucrose seeking in both groups. ‘Extinction' represents the number of active lever presses in extinction session 10. Data are presented as means+SEM *p<0.05, **p<0.01, ****p<0.0001.
Mentions: To investigate the effect of VTA D2R knockdown on sucrose self-administration, rats (n=23) were tested on FR and PR for sucrose before and after virus injection. We found an increase in FR responding in both groups after surgery (F(1, 19) surgery=32.58, P=0.0001), which may reflect increased sucrose appetite in older and therefore heavier animals. We did not observe a difference in FR responding between the groups (F(1, 19) knockdown=0.922, P=0.349; data from two animals were excluded because of a malfunctioning operant chamber) (Figure 3a). However, D2R knockdown animals made approximately twice as many responses under a PR schedule of reinforcement (F(1, 21) surgery × knockdown=8.929, P=0.007) (Figure 3b). VTA D2R knockdown did not affect inactive lever presses (F(1, 21) surgery × knockdown=1.388, P=0.253) (Figure 3c). Next, we assessed responding under extinction and sucrose-primed reinstatement. We did not observe a difference between the two groups, neither under extinction (F(1, 21) knockdown=0.0760, P=0.785) (Figure 3d) nor during sucrose-primed reinstatement (F(1, 21) reinstatement=5.304, P=0.032; F(1,21) knockdown=0.167, P=0.687) (Figure 3e).

Bottom Line: They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion.This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking.We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

View Article: PubMed Central - PubMed

Affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

ABSTRACT
Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

No MeSH data available.


Related in: MedlinePlus