Rostromedial tegmental nucleus explained

The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic nucleus which functions as a "master brake" for the midbrain dopamine system.^{[1] [2]} This region was discovered by the researchers, M. Barrot, J.Kaufling and T. Jhou. It is poorly differentiated from the rest of the ventral tegmental area (VTA) and possesses robust functional and structural links to the dopamine pathways. Notably, both acute and chronic exposure to psychostimulants have been shown to induce FosB and ΔFosB expression in the RMTg; no other drug type has been shown to induce these proteins in the RMTg.

Inputs

The RMTg receives incoming projections from the following structures:

• Medial prefrontal cortex
• Cingulate cortex
• Preoptic area
• Lateral hypothalamus
• Lateral habenula
• Superior colliculus
• Periaqueductal gray
• Dorsal raphe
• Laterodorsal tegmental nucleus
• Substantia nigra
• Nucleus accumbens
• Pontine tegmentum
• Ventral pallidum

Outputs

GABA projections from the RMTg include:

• RMTg → Raphe nuclei
• RMTg → Preoptic area
• RMTg → Lateral hypothalamus
• RMTg → Substantia nigra
• RMTg → VTA
• RMTg → Periaqueductal gray
• RMTg → Pontine tegmentum

Clinical significance

The RMTg plays a "crucial role" in the regulation of dopaminergic neuronal activity in the central nervous system by endogenous opioids and opiate drugs. The GABAergic neurons that project from the RMTg to the midbrain dopaminergic nuclei (i.e., the ventral tegmental area and substantia nigra pars compacta) express μ-opioid receptors. Current evidence suggests that exogenous opiates (e.g., morphine and heroin) excite the dopamine pathways originating in the VTA by activating the μ-opioid receptors in neurons projecting from the RMTg; opioid activation of these neurons leads to disinhibition of the GABAergic brake on dopamine networks. Since RMTg projections to the VTA are the primary inhibitor of the dopaminergic pathways that are implicated in addiction (e.g., the mesolimbic pathway), the RMTg plays a significant role in the development of opiate addictions.^[3]

Psychostimulants have been shown to increase expression of the FosB and ΔFosB in the RMTg; the effects of stimulant-induced increases in ΔFosB expression in the RMTg are not known.

Notes and References

1. Bourdy R, Barrot M . A new control center for dopaminergic systems: pulling the VTA by the tail . Trends Neurosci. . 35 . 11 . 681–690 . November 2012 . 22824232 . 10.1016/j.tins.2012.06.007 . In light of the crucial role of the tVTA in the opiate control of dopamine activity ...
   In the context of addiction, the tVTA is a target for psychostimulant-induced plasticity [1,6,23] and is also essential for morphine action on dopamine neurons [19]. This latter finding suggests that the classical disinhibition model may need to be revisited in light of the GABAergic control that the tVTA exerts on dopamine systems. ...
   The tVTA is rich in inhibitory GABA neurons expressing μ-opioid receptors and sends extensive projections toward midbrain dopamine cells. It is proposed as a major brake for dopamine systems. ...
   The tVTA was initially described in rats as a bilateral cluster of GABA neurons within the posterior VTA, dorsolateral to the interpeduncular nucleus, and expressing FosB/ΔFosB after psychostimulant administration [1]. However, the Fos staining showed that this group of cells extends caudally beyond the defined borders of the VTA [1], shifting dorsally to become embedded within the superior cerebellar peduncle [2]. Around the same time as the tVTA was described, a region caudal to the rat VTA and lateral to the median raphe was proposed to influence passive aversive responses [24]. This region belongs to the reticular formation and was later designated as RMTg [3]. The RMTg extends rostrally, shifting ventrally to become embedded within the posterior VTA. A similar region has also been observed in primates [18] and in mice [25]. There is now agreement that the tVTA and RMTg are two faces of the same structure..
2. Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC . Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions . J. Neurosci. . 32 . 41 . 14094–14101 . October 2012 . 23055478 . 3513755 . 10.1523/JNEUROSCI.3370-12.2012 . The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. ...
   Indeed, tVTA/RMTg cells express high levels of mu-opioid receptors (Jhou et al., 2009a, 2012; Jalabert et al., 2011), and in vivo, ex vivo and optogenetic electrophysiological approaches demonstrated that morphine excites dopamine neurons by targeting receptors localized to tVTA/RMTg cell bodies as well as its terminals within the VTA (Jalabert et al., 2011; Lecca et al., 2011; Matsui and Williams, 2011; Lecca et al., 2012). ... Recent research on the tVTA/RMTg started from observations related to psychostimulant induction of FosB/ΔFosB (Perrotti et al., 2005) and to the control of aversive responses (Jhou, 2005). The rat tVTA/RMTg showed a neuroanatomically delimited increase in the expression of Fos-related proteins following exposure to psychostimulants (Scammel et al., 2000; Perrotti et al., 2005; Geisler et al., 2008; Jhou et al., 2009a; Kaufling et al., 2009, 2010a, 2010b; Rottlant et al., 2010; Zahm et al., 2010; Cornish et al., 2012). This induction was observed with both acute and chronic exposure to psychostimulants, and with both self-administration and non-contingent administration. There is a strong selectivity of this molecular response, as the Fos-related induction was never observed with non-psychostimulant drugs (Perrotti et al., 2005; Kaufling et al., 2010b)..
3. Web site: Morphine addiction - Homo sapiens (human) . KEGG . Kanehisa Laboratories . 11 September 2014 . 18 June 2013 . Ventral tegmental area (VTA)
   Rostromedial tegmental nucleus (RMTg)
   Nucleus accumbens (NAc)
   Ventral Pallidum(VP).