Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

Abstract

Aim: Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats.

Methods: Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming.

Results: Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities.

Conclusion: Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.

Figure 1

Diagrams of coronal sections of the rat brain showing the location of the microinjector (NAc shell, NAc core and striatum).

Figure 2

Acquisition of heroin self-administration. Number of infusions and active and inactive nose-poke responses during the consecutive 14 d of heroin self-administration training. The rats were trained under an FR1 reinforcement schedule, and the dose of heroin was 0.1 mg per kg for the first 2 d, 0.05 mg per kg for the next 4 d, and 0.025 mg per kg for the last 8 d. Mean±SEM.

Figure 3

Effects of MPEP microinfusion into the NAc shell on heroin-seeking. The rats were microinjected with vehicle or MPEP (5, 15, or 50 nmol per side) 10 min before test. (A) Microinfusion of MPEP into the NAc shell attenuated heroin-seeking behavior induced by context. (B)Microinfusion of MPEP into the NAc shell attenuated heroin-seeking behavior induced by heroin priming. (C) MPEP microinfusions into the NAc shell attenuated heroin-seeking behavior induced by cues. (D) MPEP microinfusions into the NAc shell attenuated heroin-seeking behavior induced by heroin priming with cues. Mean±SEM of number of active or inactive responses during testing. ^bP<0.05 compared with the vehicle group.

Figure 4

Effects of MPEP microinfusions into the NAc core on heroin seeking. The rats were pre-treated with vehicle or MPEP (15 or 50 nmol per side) 10 min before the test. (A) Microinfusion of MPEP into the NAc core had no effect on cue-induced heroin-seeking compared with the vehicle or anatomical control groups. (B) Microinfusion of MPEP into the NAc core had no effect on heroin seeking behavior induced by heroin priming with cues. Mean±SEM of number of active or inactive responses during the drug seeking testing.

Figure 5

Effects of MPEP microinfusions into the NAc shell or core on locomotor activity after withdrawal. The rats were put in chambers for 1 h of habituation and then microinfused with MPEP (vehicle, 15 or 50 nmol per side) into the NAc shell, NAc core or striatum. The total distance (mean±SEM) was recorded for an additional 1 h. There was no difference in the total distance among the groups.

Figure 6

Effects of MPEP microinfusion into the NAc shell on the elevated plus maze test after withdrawal. (A) The percentage of open arms entries. (B) The percentage of time spent in open arms. One group of rats that had similar experiences and a time frame without heroin exposure was used as the normal control. The other heroin withdrawn rats (n=6 per group) were microinfused with MPEP (vehicle, 15 or 50 nmol per side) into the NAc shell and then placed in the elevated plus maze for a 5 min test. Mean±SEM. ^bP<0.05 compared with the normal control. ^eP<0.05 compared with the vehicle group.