Afferents to the GABAergic tail of the ventral tegmental area in the rat

Abstract

We previously showed that chronic psychostimulant exposure induces the transcription factor DeltaFosB in gamma-aminobutyric acid (GABA)ergic neurons of the caudal tier of the ventral tegmental area (VTA). This subregion was defined as the tail of the VTA (tVTA). In the present study, we showed that tVTA can also be visualized by analyzing FosB/DeltaFosB response following acute cocaine injection. This induction occurs in GABAergic neurons, as identified by glutamic acid decarboxylase (GAD) expression. To characterize tVTA further, we mapped its inputs by using the retrograde tracers Fluoro-Gold or cholera toxin B subunit. Retrogradely labeled neurons were observed in the medial prefrontal cortex, the lateral septum, the ventral pallidum, the bed nucleus of the stria terminalis, the substantia innominata, the medial and lateral preoptic areas, the lateral and dorsal hypothalamic areas, the lateral habenula, the intermediate layers of the superior colliculus, the dorsal raphe, the periaqueductal gray, and the mesencephalic and pontine reticular formation. Projections from the prefrontal cortex, the hypothalamus, and the lateral habenula to the tVTA were also shown by using the anterograde tracer biotinylated dextran amine (BDA). We showed that the central nucleus of the amygdala innervates the anterior extent of the VTA but not the tVTA. Moreover, the tVTA mainly receives non-aminergic inputs from the dorsal raphe and the locus coeruleus. Although the tVTA has a low density of dopaminergic neurons, its afferents are mostly similar to those targeting the rest of the VTA. This suggests that the tVTA can be considered as a VTA subregion despite its caudal location.

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

“…We used a specific antibody for c-Fos raised against a synthetic peptide corresponding to amino acids 4-17 of human c-Fos, which reacts with rat Fos proteins but not with Jun protein. As previously described (Jhou et al, 2009b;Kaufling et al, 2009), 2 h after methamphetamine administration, Fos-IR cells were found in the RMTg, which resides within and ventral to the superior cerebellar decussation (xscp) (Figure 3). As shown in Figure 3c and d, clusters of Fos-IR neurons are observed in the RMTg, symmetrically to the electrophysiological recording site marked with Pontamine sky blue (which appears red at wavelength 594-617 nm).…”

“…Although we selected for our experiments only cells fulfilling precise electrophysiological criteria, the correct localization of recording sites is crucial. Figure 3 shows that these sites were localized within the RMTg region as recently defined (Jhou et al, 2009a, b;Kaufling et al, 2009) (Figure 3a and b). In addition, the RMTg is reliably identified by accumulation of Fosimmunoreactive (Fos-IR) neurons following pharmacological stimuli, such as an acute methamphetamine administration (Jhou et al, 2009b).…”

“…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.…”

“…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).…”

Sensory regulation of dopaminergic cell activity: Phenomenology, circuitry and function

“…Excitotoxic lesions of the PBN block the increased dopamine overflow in the forebrain produced by taste stimuli (Hajnal and Norgren, 2005), suggesting that the PBN may transmit gustatory information to DA neurons. The fact that both the lateral and medial medial subnuclei of the PBN also project to the RMTg (Jhou et al 2009a;Kaufling et al, 2009), suggests that -once again -the direct pathway providing gustatory information to the ventral midbrain may operate in parallel with an indirect pathway acting via a link in the RMTg.…”