Il nucleo rostromediale del tegmento: caratterizzazione elettrofisiologica e ruolo nella neurobiologia delle sostanze d'abuso

Recent findings have underlined that the rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area, is an important site involved in aversion processes (Jhou et al., 2009a;2009b). RMTg contains GABAergic neurons responding to noxious stimuli, that are densely innervated by the lateral habenula (LHb) and provide a major inhibitory projection to reward-encoding dopamine (DA) midbrain neurons (Jhou et al., 2009a, 2009b). Perseverance of drug seeking in spite of negative and unpleasant consequences is one of the key features of drug addiction, possibly mediated by response suppression within neural pathways mediating aversion. Here, utilizing single unit extracellular recordings in anesthetized rats, we first investigated whether addicting drugs (morphine, the cannabinoid agonist WIN55212-2, cocaine and nicotine) affect RMTg neuron activity. We discovered that 73.2% of putative RMTg GABAergic neurons were excited by aversive stimuli (paw pinch). Moreover, LHb electrical stimulation activated 46.3% of RMTg neurons at short latency (5.5±0.3 ms). When addictive compounds were injected, only cells responding both to LHb activation and paw pinch were selected. Morphine, WIN55212-2 (WIN) and cocaine inhibited RMTg neuron firing rate in vivo. In contrast, nicotine strongly excited RMTg firing rate. In the follow-up study we investigated whether the previous drugs of abuse affect RMTg-evoked inhibition of DA neurons. To this aim, we studied acute effects of morphine, WIN, cocaine, and nicotine on the inhibitory effects induced on DA cells by RMTg stimulation. The electrical stimulation of the RMTg induced a complete suppression of spontaneous activity in 53.3% of the DA neurons examined, lasting on average 82.5±6.1 ms. The duration of inhibition was inversely correlated (r= -0.71, p<0.0001) to the discharge rate of DA neurons, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA neurons. Both morphine and WIN depressed this RMTg-induced inhibition of DA neurons in vivo. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results suggest that drugs of abuse profoundly influence both RMTg neuron activity and synaptic responses of DA neurons evoked by RMTg activation. These newly characterized neurons, as important inhibitory afferents to midbrain DA cells, might take place in the complex interplay between the neural circuits mediating aversion and reward. 1.Jhou TC et al. (2009a). The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61: 786-800. 2.Jhou TC et al. (2009b). The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 513: 566-596.