The Rostromedial Tegmental Nucleus Modulates Behavioral Inhibition Following Cocaine Self-Administration in Rats

Abstract

Recent findings suggest that the mesolimbic dopamine neurons, known to promote cocaine-seeking behavior, are strongly inhibited by a newly characterized region of the midbrain known as the rostromedial tegmental nucleus (RMTg). The RMTg appears to be involved in generating reward-prediction error signals and inhibition of motivated behaviors, suggesting its potential involvement in the extinction of cocaine seeking as well. Therefore, to address this question, male Sprague-Dawley rats underwent surgeries for implantation of catheters and cannulas targeted at the RMTg. After cocaine self-administration, rats underwent modified extinction training. Pre-or post-training intra-RMTg microinjections of the allosteric AMPA receptor potentiator PEPA during the first 5 days of extinction training appeared to enhance the retention of the extinction learning. Following the extinction training, rats underwent cue-induced reinstatement or an 'inactivation-alone' extinction tests. RMTg inactivation before a cue-induced reinstatement session or inactivation alone before a standard extinction session increased overall lever pressing. To determine whether these effects generalized to other motivated behaviors, additional experiments examining food-seeking behavior were also conducted. The results from the food-seeking experiments indicate that PEPA microinjections into the RMTg did not influence the extinction of food seeking and that, at least in rats that had not been given PEPA during the extinction learning experiments, RMTg inactivation had no effect on lever pressing during the cue-induced reinstatement or inactivation-alone tests. These findings suggest that the RMTg provides general behavioral inhibition and is potentially involved in learning to extinguish cocaine-seeking behavior in rats.

Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

“…This finding indicates that RMTg GABA neurons may normally play an inhibitory role over locomotion (Huff and LaLumiere, 2015). Dopamine cells are implicated in many aspects of motivated behavior (Barrot et al, 2012) and locomotor activity (Beninger, 1983).…”

Pharmacological Manipulation of the Rostromedial Tegmental Nucleus Changes Voluntary and Operant Ethanol Self-Administration in Rats

“…Most of the neurons in the RMTg received a strong glutamatergic input from the LHb (Balcita‐Pedicino et al., ; Hong et al., ; Jhou et al., ; Kaufling et al., ; Stamatakis and Stuber, ). AMPA receptors belong to the ionotropic glutamate receptor family and are mainly found on the postsynaptic membrane on dendritic spines and produce relatively fast actions in many brain areas (Chater and Goda, ), including the RMTg (Huff and LaLumiere, ; Jhou et al., ). It has been shown that local injection of AMPA (300 nl, 0.3 mM) activated the RMTg in rats (Jhou et al., ).…”

“…Stereotaxic surgery was performed on rats as described (Li et al., ). Briefly, a bilateral guide cannula (1.2 mm width, 26 gauge; Plastics One, Wallingford, CT) was inserted dorsally into the RMTg (A/P: −7.4 mm from Bregma and D/V: −7.5 mm from skull surface) based on previous work (Huff and LaLumiere, ; Jhou et al., ; Kaufling et al., ). Before microinjection, animals were taken from the colony, brought to the experimental room, and handled for 5 min/d until the experimental day.…”

Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice

“…Recent studies found that RMTg lesion or inactivation of RMTg terminals in the VTA led to profound resistance to punishment, inducing rats to continue responding for rewards despite also receiving strong aversive outcomes (Vento et al 2017). Finally, RMTg has been implicated in suppression of drug seeking, as RMTg inhibition increased reinstatement of extinguished cocaine seeking (Huff and LaLumiere 2015) and ethanol seeking (Sheth et al 2016), and increased ethanol consumption (Fu et al 2016). …”