ΔFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment

“There are two major neuronal cell types in the VTA, dopamine and GABA (Swanson, 1982).”

“Chronic administration of cocaine also leads to long-term activity changes in GABA neurons in the VTA or the RMTg, which are the main targets of the LH”

“It receives afferents from many forebrain and brainstem structures (Jhou et al, 2009b), consists primarily of GABA cells (Perrotti et al, 2005; Olson and Nestler, 2007; Kaufling et al, 2009), and has extensive projections to the entire SNc–VTA complex (Figure 1; Colussi-Mas et al, 2007; Ferreira et…”

“…enigmatic ‘‘ball-like nuclei’’ (Olson and Nestler, 2007) in the posterior VTA that exhibit psychostimulant-induced Fos expression (Scammell et al., 2000; Perrotti et al., 2005), high levels of GAD67 (Olson and Nestler, 2007), and projections to other dopaminergic neurons (Ferreira et al., 2008).”

“D and shown in several previous publications following various experimental treatments (Scammell et al., 2000; Perrotti et al., 2005; Geisler et al., 2008).”

“…al., 2009; Kim, 2009), (2) its prominent projection to DA-rich areas (Jhou et al., 2009a; Kaufling et al., 2009; Balcita-Pedicino et al., 2011), and (3) its GABAergic nature (Perrotti et al., 2005; Olson and Nestler, 2007; Jhou et al., 2009a,b; Kaufling et al., 2009; Balcita-Pedicino et al., 2011).”

“Although investigators originally postulated that the DA released from the VTA mediates only the hedonic or pleasurable effects of natural reinforcers and drugs in the NAc, evidence indicates that DA can signal events of opposite hedonic valence based on novelty or salience.”

“Finally, repeated psychostimulant exposure increases expression of 1FosB in PFC pyramidal neurons and NAc dMSNs (Perrotti et al., 2005), which contributes to an increase in dendritic branching that persists for at least 30 days of abstinence (Robinson and Kolb, 1997, 2004; Russo et al., 2010).”

“…substantial innervation from the LHb (Herkenham & Nauta, 1979; Araki et al., 1988; Jhou et al., 2009), contains almost exclusively GABA neurons (Perrotti et al., 2005; Olson & Nestler, 2007) and projects extensively to the entire nigra-VTA complex (Ferreira et al., 2008; Jhou et al., 2009).”

“As expected, given the dominant GABA phenotype of RMTg neurons (Perrotti et al., 2005; Olson and Nestler, 2007; Jhou et al., 2009b; Kaufling et al., 2009), the majority of LHb axons synapsing in this region contacted dendrites immunoreactive for GABA.”

“…psychostimulant abuse in humans (Sinha, 2008) and acute or chronic stress has been shown to facilitate the acquisition of drug self-administration, enhance behavioral sensitization and to cause the reinstatement of drug-seeking (Piazza et al., 1990; Piazza and Le Moal, 1998; Mantsch et al., 2016).”

“…immunoreactivity (Jhou et al., 2009a, 2012; Jalabert et al., 2011), a prominent pattern of psychostimulant-induced Fos-related proteins (Scammell et al., 2000; Perrotti et al., 2005; Geisler et al., 2008; Jhou et al., 2009a; Received July 16, 2012; revised Aug. 13, 2012; accepted Aug. 16, 2012.”

“Moreover, although stimulant or opiate drugs of abuse have been shown to induce ΔFosB in certain other isolated brain regions, which, in addition to nucleus accumbens and dorsal striatum, include prefrontal cortex, amygdala, ventral pallidum, ventral tegmental area, and hippocampus (Liu et al., 2007; McDaid et al., 20…”

“…also influence addictive behavior, as it has been hypothesized that immediate aversive responses to acute drug withdrawal might confer a protective effect against addiction, helping to slow or prevent the transition from casual to compulsive drug use (Rezvani et al., 2010; Barrot et al., 2012).”

“Identification of retrograde labeled neurons within the RMTg in sagittal slices The RMTg was located as previously reported using the increase in cFOS expression following an injection of d-amphetamine (Perrotti et al., 2005; Jhou et al., 2009b; Kaufling et al., 2009).”

“The mesopontine rostromedial tegmental nucleus (RMTg), also named tail of the ventral tegmental area (VTA; Kaufling et al, 2009; Perrotti et al, 2005), is a recently identified nucleus, primarily containing g-aminobutyric acid (GABA) neurons projecting to midbrain dopamine (DA) neurons in the…”

“…same vein, it was a keen sense of neuroanatomical organization revealed with traditional methods that led to the discovery of the RMTg (Jhou, 2005; Perrotti et al., 2005), which has provided a new perspective from which to view the afferent regulation of the midbrain DA complex (Jhou et al.,…”

“In the rat, these inhibitory neurons reside just caudal to the DA neurons of the VTA, in a region termed the rostromedial tegmental nucleus (RMTg), or “GABAergic tail” of the VTA (Perrotti et al., 2005; Jhou et al., 2009a,b).”

“The neurons of Area 2 may have functional relevance to drug abuse, as recent findings indicate that the transcription factor DFosB is upregulated in this region, but not other regions of the VTA, following chronic administration of psychostimulants (Perrotti et al., 2005).”

“Because the last exposure to rewarding stimuli occurred 18 –24 h before analysis, we considered all FosB-like immunoreactivity, detected with a pan-FosB antibody (SC-48; Santa Cruz Biotechnology), to reflect FosB (Perrotti et al., 2004, 2005).”

“…the back of the VTA, bilateral to the IP, initially indicated as the tail of the VTA (Kaufling et al., 2009) and functionally defined as an area that showed a strong c-Fos expression in response to the systemic administration of psychostimulant drugs (Kaufling et al., 2010; Perrotti et al., 2005).”

“1), including morphine, ethanol, diazepam, D9-tetrahydrocannabinol, ketamine, and phencyclidine (Perrotti et al., 2005; Kaufling et al., 2010).”

“c-fos and delta FosB expression in mammalian VTA–SNc; systemic administration of d-amphetamine or cocaine (dopamine reuptake inhibitors) causes induction of c-fos or delta FosB in the GABAergic interneurons of SNc with no induction in the dopaminergic projection neurons (Hebb & Robertson, 2000; Perrotti et al., 2005).”

“…Fos gene expression under the conditions cited above is not limited to the conspicuous cluster at the caudal pole of the VTA first described by Perrotti et al. (2005), but is present in a continuous cell population extending from the caudal pole of the VTA deeply into the mesopontine…”

“The rostromedial tegmental area (RMTg), also known as the posterior tail of the VTA (Perrotti et al., 2005; Kaufling et al., 2009), is composed of inhibitory GABA neurons that project to dopamine neurons in the midbrain (Kaufling et al., 2009).”

“The VTA receives inputs from the tail of the VTA (tVTA)(Perrotti et al., 2005)/rostromedial tegmental nucleus (RMTg) (Jhou et al., 2009a) and the NAc (Figure 3).”

“…mice (Stamatakis and Stuber, 2012) that the inhibitory LHb influence on these cells is mainly mediated by the RMTg, a mostly GABAergic structure (Perrotti et al., 2005; Olson and Nestler, 2007) that stretches from the caudal pole of the VTA deeply into the mesopontine tegmentum (Jhou et al.,…”

“The anti-pan-FosB antibody was raised to the N terminus of FosB and recognizes both FosB and full-length FosB (61).”

“…1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 F. Pistillo et al. / Progress in Neurobiology xxx (2014) xxx–xxx 13 thus confirming their functional heterogeneity (Ikemoto et al., 1998; Ikemoto, 2007; Kaufling et al., 2009; Perrotti et al., 2005).”

“…of two predominant neuronal subtypes as discussed above, there is mounting evidence that this brain structure is not homogeneous but can be divided into discrete subregions including anterior, posterior, and tail (Ikemoto, 2007; Ikemoto et al , 1998; Kaufling et al , 2009; Perrotti et al , 2005).”

“…dissociative drugs ketamine and phencyclidine (PCP), the antidepressants reboxetine, nortriptyline, venlafaxine, and fluoxetine, the 5-HT releaser dexfenfluramine, and the anticonvulsants valproic acid and gabapentin, do not induce Fos in the tVTA (Perrotti et al., 2005; Kaufling et al., 2010b).”

“…express the immediate early gene c-fos and its longlived splice variant, deltaFosB, after stimulant drug administration (Scammell et al., 2000; Perrotti et al., 2005; Geisler et al., 2008), and the RMTg is enriched in prepronociceptin mRNA (Morales et al., 2011), somatostatin, and the…”

“[PubMed: 922511] Perrotti LI, Bolanos CA, Cho KH, Russo SJ, Edwards S, Ulery PG, Wallace DL, Self DW, Nestler EJ, Barrot M. DeltaFosB accumulates in a GABAergic cell population in the posterior tail of the ventral tegmental area after psychostimulant treatment.”

“The high molecular stability of DFosB means it is retained in neurons for several weeks after drug intake has ceased, before returning to baseline levels (35,36).”

“…levels (Balfour et al. 2004); ventral tegmental area (VTA; 1000 × 800 μm) analyzed at three rostral–caudal levels (Balfour et al. 2004) and VTA tail (Perrotti et al. 2005); medial prefrontal cortex [mPFC; anterior cingulate area (ACA); prelimbic cortex (PL); infralimbic cortex (IL); 600 ×…”

“The VTT was introduced by Perrotti et al. (2005) and equals to VTAC according to Ferreira et al. (2008).”

“…and Nauta (1979) is part of a nucleus referred more than 25 years later as the caudal tail of the VTA (Bourdy & Barrot, 2012; Kaufling, Veinante, Pawlowski, Freund-Mercier, & Barrot, 2009; Perrotti et al., 2005) or more commonly RMTg (Jhou, Fields, et al., 2009; Jhou, Geisler, et al., 2009).”

“, 2009a,b) or, alternatively, the tail of the VTA (Barrot et al., 2012; Perrotti et al., 2005) − are continuous with those of the VTA, and they also project to (Jhou et al.”

“During protracted withdrawal, DFosB levels decrease to basal levels, that is, 10–12 days after cessation of chronic cocaine treatment (Hope et al, 1994; Perrotti et al, 2005).”

“Yet another new observation in our study is that in the ventral midbrain, a large, bilateral subset of Syp-mCherry boutons targets a paramedian region known as the “tail of the VTA” or RMTg.”

“…of FosB/DFosB in the tVTA by psychostimulant drugs We previously reported that chronic exposure to cocaine induced the transcription factor DFosB in the tVTA (Perrotti et al., 2005; Kaufling et al., 2010) and we recently observed a similar induction with acute cocaine (Kaufling et al., 2009; 2010).”

“The non-contingent administration of cocaine elevates the levels of Fos, a transcription factor associated with increased neuronal activity, in RMTg neurons (99, 100).”

“Interestingly, several groups have reported that neurons in this region are activated by psychostimulants (Scammell et al., 2000; Perrotti et al., 2005), and our own studies suggest that the psychostimulant-activated neurons are a medial subset of this midbrain GABAergic population.”

“Later, Perrotti et al. (2005) showed a similar cluster that expressed deltaFosB, a long-lived splice variant of FosB, after the chronic administration of amphetamine and called it the ‘‘posterior tail of the VTA’’.”

“…a C-terminally truncated splice variant of FosB, is stable and accumulates with repeated induction over time (e.g. during repeated drug treatment), and can be detected in neurons for several weeks after cessation of drug treatment (Chen et al., 1997, Perrotti et al., 2005, Ulery et al., 2006).”

“The RMTg receives excitatory input from the LHb and has been described as the predominant source of GABAergic input to DA neurons (Jhou, 2005; Perrotti et al., 2005).”

“Inhibitory signals to DA neurons, located in the ventral tegmental area (VTA), substantia nigra pars compacta (SNpc) and retrorubral field (RRF), arrive from neighbouring GABAergic neurons in the VTA, substantia nigra pars reticulata (SNpr) and rostromedial tegmental nucleus (RMTg, also called the tail of VTA) (Perrot…”

“, 2014), contributes to the description of the LHb-RMTg-VTA circuit, also encoding for aversive signals (Perrotti et al., 2005).”

“Overexpression of DFosB enhances sensitivity to the rewarding and locomotor-activating effects of cocaine [20,22,23,24,25,26].”

“(27) for discussion], our immunohistochemical analysis avoided this technical limitation.”

“…LHb neurons projecting to the VTA are excitatory (Geisler et al., 2007), GABAergic interneurons, mainly located in the RMTg, are required to convert the LHb signal to an inhibitory one that can attenuate the firing of DA neurons (Perrotti et al., 2005; Jhou et al., 2009a,b; Li et al., 2019a).”

“Activity in the RMTg-VTA pathway has been observed after psychostimulant administration (Perrotti et al. 2005, Geisler et al. 2008, Jalabert et al. 2011).”

“As mentioned, the RMTg expresses high levels of the GABA synthesizing enzyme GAD67 and the MOR immunoreactivity that distinguish it from surrounding regions (Jhou et al., 2009a; Kaufling et al., 2009, 2010; Olson and Nestler, 2007; Perrotti et al., 2005).”

“As the RMTg gained recognition as a distinct structure (Jhou, 2005; Jhou and Gallagher, 2007; Jhou et al 2009a, b; Perrotti et al, 2005; Kaufling et al, 2009, 2010), its capacity to control the activity of midbrain DA neurons (Hong et al, 2011; Matsui and Williams, 2011; Lecca et al, 2011, 2012;…”

“The mesopontine rostromedial tegmental nucleus (RMTg), also named tail of the VTA (Kaufling et al., 2009, 2010; Perrotti et al., 2005) is a recently identified structure that contains primarily c-aminobutyric acid (GABA) neurons, which are a major source of inhibitory GABAergic input to midbrain…”

“The RMTg lies immediately caudal to the posterior VTA and sends dense GABAergic projections to the VTA (Jhou et al, 2009b; Kaufling et al, 2009, 2010; Perrotti et al, 2005).”

“At the posterior edge of VTA the GABAergic rostromedial tegmental area (RMTg) emerges, however neurons here are genetically distinct from those in VTA and differentially express Foxp1 and Pnoc [4,28,51,64].”

“…of neurons (Bregma: 26.0 to 7.0), which has been variously called the retro-VTA (Scammell et al., 2000), tail of the VTA (Kaufling et al., 2009; Perrotti et al., 2005), VTA area 2 (Olson & Nestler, 2007) ventral tegmental tail of the VTA (Ikemoto, 2007), interstitial nucleus of the decussation…”

“…cocaine administration leads to sustained elevation of ΔFosB levels in brain regions associated with the behavioral effects of cocaine (Hope et al., 1994; Moratalla et al., 1996; Nestler, 2001; Nestler et al., 2001; McClung and Nestler, 2003; Perrotti et al., 2005; Brenhouse and Stellar, 2006).”