Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions

Abstract

A new mesopontine structure exerting a strong influence on dopamine systems has recently been defined: the tail of the ventral tegmental area/rostromedial tegmental nucleus (tVTA/RMTg). This review presents a neuroanatomical, physiological, and behavioral overview of some of the recent and ongoing research on this brain region and its relationship with dopamine systems. The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. The inhibitory influence of tVTA/RMTg on dopamine neurons is supported by both neuroanatomical and electrophysiology data. The latter studies also reveal the tVTA/RMTg as a substrate for morphine and cannabinoid action on dopamine cells. In primates, the tVTA/RMTg has been implicated in reward prediction error signals, through a basal ganglia-lateral habenula-tVTA/RMTg-dopamine-basal ganglia circuit. In rodents, the tVTA/RMTg has been shown to play a critical role in aversive behaviors, particularly those involving behavioral inhibition, such as freezing and avoidance. These findings highlight the functional importance of the tVTA/RMTg as a major GABA brake for dopamine systems.

Figure 1.

The tVTA/RMTg. The schema represents the rat tVTA/RMTg (in green) and lists its main afferent and efferent connections. Most afferent structures also innervate the VTA directly.

Figure 2.

The tVTA/RMTg as a GABA brake for the dopamine system. The schema represents the tVTA/RMTg, its main glutamatergic input (lateral habenula, LHb), and its output to the nearby dopamine systems. Opiates and cannabinoids would recruit dopamine cells (DA) by blocking the GABA brake exerted by neurons of the tVTA/RMTg onto dopamine cells. CB1, cannabinoid receptors 1; MOR, μ-Opioid receptors.

Figure 3.

The tVTA/RMTg as part of the reward prediction error circuit. A, Responses of representative GPb, lateral habenula (LHb), tVTA/RMTg, and dopamine neurons (DA) to the visual target onset in the 1DR task (Hong et al., 2011). The averaged activity of each neuron, expressed as a spike (spk) density function, is shown separately for the reward trials (red) and no-reward trials (blue) as the response to the onset of the target. B, Neuroanatomical schematic of the reward prediction error circuit in the monkey. CC, Corpus callosum; GPb, borders of the globus pallidus internal segment; IC, inferior colliculus; PN, pontine nuclei; SC, superior colliculus; STR, striatum.