Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion

Abstract

Rationale: Ethanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood. We have previously shown that the lateral habenula (LHb), a region critical for aversive conditioning, plays an important role in ethanol-directed behaviors. However, the neurocircuitry through which LHb exerts its actions is unknown.

Objective: In the present study, we investigate a role for the rostromedial tegmental nucleus (RMTg), a major LHb projection target, in regulating ethanol-directed behaviors.

Methods: Rats received either sham or RMTg lesions and were studied during voluntary ethanol consumption; operant ethanol self-administration, extinction, and yohimbine-induced reinstatement of ethanol-seeking; and ethanol-induced conditioned taste aversion (CTA).

Results: RMTg lesions increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA.

Conclusions: The RMTg plays an important role in regulating voluntary ethanol consumption, possibly by mediating ethanol-induced aversive conditioning.

Keywords: Aversion; Ethanol; Lateral habenula (LHb); Reward; Rostromedial tegmental nucleus (RMTg).

Fig. 1

RMTg lesion increases voluntary consumption in an intermittent ethanol access (IEA) paradigm. a RMTg-lesioned rats voluntarily consumed significantly more 20 % ethanol as compared to sham-lesioned animals. Open symbols represent data for sham-lesioned rats, and closed circles represent data for RMTg-lesioned rats in this and all subsequent figures unless otherwise mentioned. Symbols depict mean ± SEM. b RMTg-lesioned rats had a higher preference for ethanol relative to sham-lesioned animals. c Water intake decreased progressively in both groups. There were no significant differences between sham- and RMTg-lesioned rats. d Total fluid intake did not differ between sham- and RMTg-lesioned rats. e Blood ethanol concentration (BEC) was significantly correlated with ethanol intake in the first 30 min for both sham- and RMTg-lesioned rats. Gray line shows linear fit for sham-lesioned rats, and black line shows linear fit for RMTg-lesioned rats. f BEC for RMTg-lesioned after voluntary intake was significantly higher than that measured for sham-lesioned animals

Fig. 2

RMTg lesions do not alter saccharin preference or quinine aversion. RMTg lesion did not alter a aversion to quinine or b preference for saccharin

Fig. 3

RMTg lesions do not alter operant self-administration of ethanol, extinction of operant responding, or yohimbine-induced reinstatement of ethanol-seeking. a RMTg lesion did not significantly change operant responding for 20 % ethanol, b the rate of operant extinction, c the mean number of extinction sessions required to reach the extinction criterion, d Yohimbine caused robust reinstatement in both sham- and RMTg-lesioned rats. Asterisk indicates the main effect of drug

Fig. 4

RMTg lesions accelerate extinction of CTA. a Sham-lesioned rats are shown as squares, and RMTg-lesioned rats are shown as circles. Open and closed symbols indicate treatment with ethanol and saline (vehicle), respectively. Trials 1–4 are acquisition trials and trials 5–14 are extinction trials. Arrows (x axis) indicate the trials in which saccharin access was paired with ethanol injection. Asterisks indicate significant differences between sham- and RMTg-lesioned groups who received ethanol injection (p < 0.05). b RMTg lesion reduced the latency to initiate lick during extinction trials. Bar graph shows the average latency to initiate lick (seconds) for trials 6–14. RMTg-lesioned rats had significantly lower latency to initiate lick compared to sham-lesioned rats

Fig. 5

RMTg lesion placements. a Representative photomicrograph of RMTg lesion. The upper and middle panels show sections from a sham-lesioned rat while the lower panel demonstrates a section from a RMTg-lesioned rat. Note the considerably reduced NeuN staining in the RMTg-lesioned rat. b Excitotoxic lesion sites for 6 representative rats are overlaid such that the areas with the darkest shading have the maximum damage. Damage was restricted to RMTg in most cases; however, there was some damage to adjacent areas including the median raphe and interpeduncular nucleus in some rats. The anterior-posterior coordinates relative to bregma are shown to the right of each coronal section (scp superior cerebellar peduncle, Pn pontine nuclei)