Pumping the brakes: rostromedial tegmental inhibition of compulsive cocaine seeking

Abstract

Addiction is marked by aberrant decision-making and an inability to suppress inappropriate and often dangerous behaviors. We previously demonstrated that inactivation of the rostromedial tegmental nucleus (RMTg) in rats causes persistent food seeking despite impending aversive footshock, an effect strikingly similar to the punishment resistance observed in people with a history of protracted drug use [1]. Here, we extend these studies to demonstrate chemogenetic silencing of RMTg axonal projections to the ventral tegmental area (VTA) (RMTg→VTA pathway) causes rats to endure significantly more footshock to receive cocaine infusions. To further test whether activation of this circuit is sufficient to suppress reward seeking in the absence of an overtly aversive stimulus, we used temporally specific optogenetic stimulation of the RMTg→VTA pathway as a "punisher" in place of footshock following lever pressing for either food or cocaine reward. While optical stimulation of the RMTg→VTA pathway robustly suppressed lever pressing for food, we found that stimulation of this circuit had only modest effects on suppressing responding for cocaine infusions. Even though optical RMTg→VTA stimulation was not particularly effective at reducing ongoing cocaine use, this experience nevertheless had long-lasting consequences, as reinstatement of drug seeking in response to cocaine-associated cues was profoundly suppressed when tested nearly two weeks later. These results suggest the RMTg may serve as a useful target for producing enduring reductions in drug craving, particularly during periods of abstinence from drug use.

Figure 1.

Chemogenetic inhibition of the RMTg→VTA pathway causes punishment resistance in lever pressing for cocaine. A) Rats received bilateral injections of inhibitory Gi DREADDs into the RMTg (upper left panel) and intracranial cannulae were implanted bilaterally above RMTg terminals in the VTA. B) Schematic of the punishment task where lever pressing for cocaine was punished by footshock that increased in intensity as the session progressed. (C-D) Individual data and (E) group means in shock breakpoint from rats expressing control vector or Gi DREADDs after pretreatment with either CNO (1mM) or vehicle (0.5% DMSO). F) Rats expressing Gi DREADDs showed a 65% increase in shock breakpoint after CNO versus vehicle sessions. Panel C: t(6)=−2.626, *p=0.039; Panel D: t(5)=0.542, p=0.611; Panel E: Drug (F1,11=2.437, p=0.147), Virus (F1,11=0.936, p=0.354); Drug × Virus (F1,11=5.188, p=0.044); n=6–7 per group; *p<0.05;

Figure 2.

Optical RMTg→VTA stimulation suppressed lever pressing for food reward. A) Rats received bilateral injection of virus encoding channelrhodopsin-2 (ChR2) or control vector in the RMTg (left), and optical fibers were implanted above axon terminals in the VTA (right). B) Contingent foot shock exposure (Exp) sessions 1–4; 0.5mA, 500ms duration) delivered immediately after successful completion of the FR significantly reduced the total number of trials completed compared to their pre-shock baseline and to 500ms optical RMTg→VTA stimulation. In contrast, 500ms optical stimulation did not affect responding for food. C) After repeated footshock sessions, rats exhibited increased latency to complete food seeking trials when analyzed over the first 10 trials of each exposure session. D) Longer duration optical stimulation (30sec duration), however, robustly reduced the total number of food seeking trials ChR2 rats completed compared to mCherry controls. E) Rats receiving 30sec light exposure demonstrated increased latency to complete food seeking trials when analyzed over the first 10 trials of each test session. (Panel B: Session (F7,77 = 14.092, p<0.001); Condition (F1,15 = 206.389, p<0.001); Session × Condition (F7,88=12.304, p<0.001). (Panel C: Session (F4,32=3.076, p=0.03), Condition (F1,8=11.397, p=0.01), Session × Condition (F4,32=2.913, p=0.037). (Panel D: Session (F7,70=18.219, p<0.001); Virus (F1,10=22.747, p<0.001); Session × Virus (F7,70=18.219, p<0.001). *ǂ p<0.05 vs all other groups, *p<0.05 vs Baseline and L1. Panel E: Session (F3,27= 3.370; p=0.033), Virus (F1,9= 13.290; p= 0.005), Session × Virus (F1,9= 3.590; p=0.026). n=5–7 per group; *p<0.05 vs control.

Figure 3.

Optical RMTg→VTA stimulation suppressed lever pressing but had only negligible effects on cocaine intake. Rats were trained to self-administer cocaine prior to receiving an additional 4 light-paired sessions in which lever pressing yielded light and tone cues, infusion of cocaine, and two minutes of optical stimulation (20mW/side, 50Hz with 5ms light duration). A) Schematic of trial in light-paired session. B) Rats in both the ChR2 and control groups rapidly acquired stable rates of cocaine self-administration that was nearly identical by the end of training. C) In light sessions 1–4, control rats displayed a significant increase in lever presses occurring during the extended intertrial interval in light-paired sessions. D) The number of earned cocaine infusions during light-paired sessions was relatively unaffected by optical stimulation, as both ChR2-expressing and control rats did not differ in the rate of infusions during light vs baseline (S8–10) sessions; however, a modest but statistically significant difference in infusions was found when comparing across groups during light-paired sessions. Panel B: Session (F2.86, 62.8= 4.239; p=0.01), Virus (F3,22= 33.209; p<0.001), Session × Virus (F8.56, 62.8 = 4.553; p<0.001). By S3 both ChR2 and control rats were significantly discriminating between active vs inactive lever (p<0.05). n=6–7 per group; *p<0.05 control active lever vs ChR2 active lever.

Figure 4.

Cue-induced reinstatement was significantly attenuated by prior stimulation of the RMTg→VTA pathway during cocaine self-administration, while extinction rates were similar between groups (A-B). Neither reinstatement lever presses nor infusions correlated with previous self-administration lever presses or infusions (C-D). Panel A: Session (F2.75,30.30= 9.624, p<0.001), Virus (F1,11= 6.89, p=0.024), Session × Virus (F2.75,30.30= 2.348, p=.097; Panel B: Group (F3,22=3.845, p=0.024), n=6–7 per group; *p<0.05 vs all other groups.