Elsevier

Biological Psychiatry

Volume 67, Issue 1, 1 January 2010, Pages 88-92
Biological Psychiatry

Brief Report
γ-Aminobutyric Acid Cells with Cocaine-Induced ΔFosB in the Ventral Tegmental Area Innervate Mesolimbic Neurons

https://doi.org/10.1016/j.biopsych.2009.08.001Get rights and content

Background

The transcription factor ΔFosB is implicated in the plasticity induced by drugs of abuse. We showed that psychostimulants induce ΔFosB in γ-aminobutyric acid (GABA) cells of a caudal subregion of the ventral tegmental area (VTA) that was named tail of the VTA (tVTA). Although tVTA mostly shares VTA inputs, its outputs remain to be characterized.

Methods

The tVTA efferents were studied by iontophoretic injections of the anterograde tracer biotinylated dextran amine (BDA). To further study VTA inputs arising from tVTA, injections of the retrograde tracer Fluoro-Gold were combined with multiple labeling by immunohistochemistry in rats treated with cocaine. Indirect projections from the tVTA to the nucleus accumbens were assessed with a double-tracing approach, cholera toxin B subunit (CTB) being delivered in the nucleus accumbens and BDA in the tVTA.

Results

Tract-tracing studies showed that tVTA heavily projects to the midbrain dopaminergic system and revealed terminal appositions with dopamine cells in the VTA. Double-labeling studies demonstrated that this tVTA output is mostly GABAergic, includes cells in which cocaine exposure induces ΔFosB, and displays appositions to dopamine cells projecting to the nucleus accumbens.

Conclusions

The GABA neurons expressing ΔFosB in the tVTA after cocaine exposure project to the dopamine mesolimbic neurons.

Section snippets

Animals

Experiments were conducted in male Sprague-Dawley rats (280–340 g, Janvier, France) group-housed with food and water ad libitum. Procedures were performed in accordance with European Directives.

Surgery

Rats underwent unilateral stereotaxic surgery under ketamine (87 mg/kg)/xylazine (13 mg/kg) anesthesia. Stereotaxic coordinates relative to bregma (8) were: tVTA, anteroposterior (AP) = −6.3 mm, lateral (L) = +1.6 mm, vertical (V) = −7.6 mm, 6° lateral angle; VTA, AP = −5.2 mm, L = +1.4 mm, V = −7.8 mm,

Results

The tVTA location was defined by cocaine-induced FosB/ΔFosB staining (Figures 1A–1C and Figure S1 in Supplement 1). The tVTA-restricted BDA injections resulted in the presence of a heavy plexus of BDA-positive fibers in the anterior and posterior VTA and in the substantia nigra pars compacta (SNC) (Figures 1D and 1E). Co-staining with TH revealed that a majority of VTA dopamine cells displayed somatic appositions from BDA-positive fibers and boutons (Figures 1F–1J). Because synaptic contacts

Discussion

After cocaine exposure, ΔFosB is expressed in GABA neurons of the tVTA that send dense efferents to the midbrain dopaminergic system. This system influences numerous physiological functions (10) and is implicated in the etiology or treatment of neurological or psychiatric diseases, such as Parkinson's, schizophrenia, mood disorders, and drug abuse (11, 12). The activity of the VTA dopamine neurons is known to be under GABAergic influences from both VTA inputs and intra-VTA GABA interneurons (13

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    The RMTg represents relatively pure GABA cell population (Jhou et al., 2009a; Kaufling et al., 2009; Olson and Nestler, 2007; Perrotti et al., 2005) with high levels of MOR immunoreactivity and mRNA (Galaj et al., 2020; Jalabert et al., 2011; Jhou et al., 2009a, 2012) and high levels of the neuropeptide nociception (Jhou et al., 2012). RMTg GABA neurons send dense projections to the VTA and substantia nigra zona compacta (SNc) (Jhou et al., 2009b; Kaufling et al., 2010), where they form synapses with approximately 80% of DA neurons (Balcita-Pedicino et al., 2011). Matsui and colleagues examined inhibitory GABA postsynaptic currents (IPSCs) evoked by selective optical stimulation of GABA projections from the VTA, NAc, or RMTg and found that inhibition of IPSCs induced by MOR agonists was pathway-dependent (Matsui et al., 2014).

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