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

Abstract

The transcription factor deltaFosB is induced in the nucleus accumbens and dorsal striatum by chronic exposure to several drugs of abuse, and increasing evidence supports the possibility that this induction is involved in the addiction process. However, to date there has been no report of deltaFosB induction by drugs of abuse in the ventral tegmental area (VTA), which is also a critical brain reward region. In the present study, we used immunohistochemistry to demonstrate that chronic forced administration of cocaine induces deltaFosB in the rat VTA. This induction occurs selectively in a gamma-aminobutyric acid (GABA) cell population within the posterior tail of the VTA. A similar effect is seen after chronic cocaine self-administration. Induction of deltaFosB in the VTA occurs after psychostimulant treatment only: it is seen with both chronic cocaine and amphetamine, but not with chronic opiates or stress. The expression of deltaFosB appears to be mediated by dopamine systems, as repeated administration of a dopamine uptake inhibitor induced deltaFosB in the VTA, while administration of serotonin or norepinephrine uptake inhibitors failed to produce this effect. Time course analysis showed that, following 14 days of cocaine administration, deltaFosB persists in the VTA for almost 2 weeks after cocaine withdrawal. This accumulation and persistence may account for some of the long-lasting changes in the brain associated with chronic drug use. These results provide the first evidence of deltaFosB induction in a discrete population of GABA cells in the VTA, which may regulate the functioning of the brain's reward mechanisms.

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

“…Cocaine was shown to evoke DFosB expression on GABA neurons in the VTA tail (Perrotti et al, 2005), and this indicates that psychostimulants might affect DA neurons through the RMTg-VTA projection. Here, we confirmed the finding that methamphetamine induces Fos expression within RMTg.…”

“…GABA neurons in the RMTg have been shown to display strong Fos, FosB, and DFosB activation after both acute and chronic exposure to psychostimulants (ColussiMas et al, 2007;Geisler et al, 2008;Jhou et al, 2009b;Kaufling et al, 2009;Perrotti et al, 2005), thus suggesting a potential role for this area in psychostimulant rewardrelated effects. Therefore, we investigated the possibility that cocaine might influence RMTg neuron discharge activity.…”

“…However, the sparse innervation of DA neurons by excitatory LHb afferents (Brinschwitz et al, 2010;Omelchenko et al, 2009) unlikely explains this inhibition, and the presence of an area intermediate between the LHb and the VTA was originally postulated. Elegant studies by Jhou et al (2009a, b) revealed that g-aminobutyric acid (GABA) neurons in the rostromedial tegmental nucleus (RMTg), a region also denominated as 'tail' of the VTA (Perrotti et al, 2005), integrate input from the LHb and send output projection to midbrain DA neurons. As described, the missing link between LHb and midbrain DA neurons is provided.…”

“…Indeed, one of the hallmarks of drug addiction is the perseverance of drug taking despite of negative and unpleasant consequences of drug use. Recent studies indicate that drugs of abuse affect GABA neurons in the RMTg: these neurons, and notably those projecting to the VTA, express DFosB (Kaufling et al, 2009;Perrotti et al, 2005) and c-Fos following repeated cocaine exposure (Geisler et al, 2008). In addition, RMTg neurons are immunoreactive against m-opioid receptors (Jhou et al, 2009b) and supposedly respond to opioid administration (Jhou et al, 2009c).…”

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

“…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, 2009Kaufling et al, , 2010, its capacity to control the activity of midbrain DA neurons (Hong et al, 2011;Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui et al, 2014) and the implications of this action in aversion (Jhou et al, 2009b), reward (Hong et al, 2011), and neurobiological responses to certain drugs of abuse (Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Jhou et al, 2013;Wasserman et al, 2013;Matsui et al, 2014) continue to concern investigators. Despite this wealth of interest, a fundamental behavior-locomotor activation-has been overlooked, yet we show here that modulation of RMTg activity has profound effects on locomotion.…”