ABSTRACT
Title
Drugs of abuse modulate spontaneous activity of neurons in the rat rostromedial tegmental nucleus and their inhibitory actions on midbrain dopamine cells
Authors
Lecca S.1, Melis M.1, Luchicchi A.1, Muntoni A.L.2, and Pistis M.1,2,3
1B.B.Brodie Department of Neuroscience ,2CNR Neuroscience Institute-Cagliari, 3Center of Excellence for the Neurobiology of Addiction, University of Cagliari, Italy
1B.B.Brodie Department of Neuroscience ,2CNR Neuroscience Institute-Cagliari, 3Center of Excellence for the Neurobiology of Addiction, University of Cagliari, Italy
Abstract
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 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. Consistently, we discovered that morphine and the cannabinoid agonist WIN55212-2 (WIN) inhibited both RMTg neuron firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude (Lecca et al., 2011).
In this follow-up study we investigated whether addicting drugs also depress 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. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to identify DA cells and characterize their RMTg-evoked inhibition.
The electrical stimulation of the RMTg induced a complete suppression of spontaneous activity in 53.3% of the DA neurons examined (n=60), lasting on average 85.0±9.0 ms. The duration of inhibition was inversely correlated (r= -0.67, 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 (29 % and 54% of baseline, respectively; n=7, p<0.0001) and inhibitory postsynaptic currents (IPSCs) evoked by RMTg stimulation in brain slices (40 % and 50% of baseline, respectively; n=5, p<0.01). 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.
3. Lecca S et al., (2011). Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells. Neuropsychopharmacology 36:589-602
In this follow-up study we investigated whether addicting drugs also depress 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. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to identify DA cells and characterize their RMTg-evoked inhibition.
The electrical stimulation of the RMTg induced a complete suppression of spontaneous activity in 53.3% of the DA neurons examined (n=60), lasting on average 85.0±9.0 ms. The duration of inhibition was inversely correlated (r= -0.67, 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 (29 % and 54% of baseline, respectively; n=7, p<0.0001) and inhibitory postsynaptic currents (IPSCs) evoked by RMTg stimulation in brain slices (40 % and 50% of baseline, respectively; n=5, p<0.01). 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.
3. Lecca S et al., (2011). Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells. Neuropsychopharmacology 36:589-602