Ventral pallidum (VP) is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to ventral tegmental area (VTA) regulates neuronal activity there. However, VP is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. Here we demonstrate that projections to VTA from rostral (RVP), but not caudal VP (CVP) are robustly Fos-activated during cue-induced reinstatement of cocaine seeking—a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA, or functional connectivity between RVP and VTA dopamine neurons blocks the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition instead blocked cocaine-primed, but not cue-induced reinstatement. This novel double dissociation in VP sub-regional roles in drug seeking is likely important for understanding mesocorticolimbic circuits underlying reward seeking and addiction.

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.

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Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract tracing and electron microscopy, we reveal the presence of a tVTA-SNc-dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination, and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable with the performance-enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within the basal ganglia circuitry. They also warrant further research on the tVTA's role in motor and dopamine-related pathological contexts such as Parkinson's disease.

Protracted opiate withdrawal is accompanied by altered responsiveness of midbrain dopaminergic (DA) neurons, including a loss of DA cell response to morphine, and by behavioral alterations, including affective disorders. GABAergic neurons in the tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, are important for behavioral responses to opiates. We investigated the tVTA-VTA circuit in rats after chronic morphine exposure to determine whether tVTA neurons participate in the loss of opiate-induced disinhibition of VTA DA neurons observed during protracted withdrawal. In vivo recording revealed that VTA DA neurons, but not tVTA GABAergic neurons, are tolerant to morphine after 2 weeks of withdrawal. Optogenetic stimulation of tVTA neurons inhibited VTA DA neurons similarly in opiate-naive and long-term withdrawn rats. However, tVTA inactivation increased VTA DA activity in opiate-naive rats, but not in withdrawn rats, resembling the opiate tolerance effect in DA cells. Thus, although inhibitory control of DA neurons by tVTA is maintained during protracted withdrawal, the capacity for disinhibitory control is impaired. In addition, morphine withdrawal reduced both tVTA neural activity and tonic glutamatergic input to VTA DA neurons. We propose that these changes in glutamate and GABA inputs underlie the apparent tolerance of VTA DA neurons to opiates after chronic exposure. These alterations in the tVTA-VTA DA circuit could be an important factor in opiate tolerance and addiction. Moreover, the capacity of the tVTA to inhibit, but not disinhibit, DA cells after chronic opiate exposure may contribute to long-term negative affective states during withdrawal.

BACKGROUND AND PURPOSEThe tail of the ventral tegmental area (tVTA), also called the rostromedial tegmental nucleus, is a newly defined brain structure and a potential control centre for dopaminergic activity. It was identified by the induction of DeltaFosB following chronic cocaine exposure. In this work, we screened 20 drugs for their ability to induce FosB/DeltaFosB in the tVTA. EXPERIMENTAL APPROACHImmunohistochemistry following systemic drug administration was used to study FosB/DeltaFosB induction in the tVTA of adult rats. Double-staining was used to determine whether dopamine or GABA neurones are involved in this induction. KEY RESULTSThe acute injection of the psychostimulant drugs cocaine, D-amphetamine, (+/-)-3,4-methylenedioxymethamphetamine (MDMA), methylphenidate or caffeine, induced the expression of FosB/DeltaFosB in the tVTA GABAergic cells. No induction was observed following exposure to ethanol, diazepam, g-hydroxybutyric acid (GHB), morphine, ketamine, phencyclidine (PCP), D 9 -tetrahydrocannabinol (THC), sodium valproic acid or gabapentin. To evaluate the role of monoamine transporters in the psychostimulant-induced expression of FosB/DeltaFosB, we tested the antidepressant drugs reboxetine, nortriptyline, fluoxetine and venlafaxine (which target the noradrenaline and/or the 5-hydroxytryptamine transporters), the 5-hydroxytryptamine releasing agent dexfenfluramine, and the dopamine transporter inhibitor GBR12909. Only GBR12909 was able to induce FosB/DeltaFosB expression in the tVTA, showing that this induction is mediated by dopamine. CONCLUSIONS AND IMPLICATIONSNewly described brain structures may help to increase our knowledge of brain function, pathology and targets for treatments. FosB/DeltaFosB induction in the tVTA is a common feature of drugs sharing psychostimulant properties but not of drugs sharing risk of abuse. Abbreviations

Potentiation of excitatory inputs onto dopamine neurons of the ventral tegmental area (VTA) induced by cocaine exposure allows remodeling of the mesocorticolimbic circuitry, which ultimately drives drug-adaptive behavior. This potentiation is mediated by changes in NMDAR and AMPAR subunit composition. It remains unknown how this synaptic plasticity affects the activity of dopamine neurons. Here, using rodents, we demonstrate that a single cocaine injection increases the firing rate and bursting activity of VTA dopamine neurons, and that these increases persist for 7 d. This enhanced activity depends on the insertion of low-conductance, Ca 2ϩ -impermeable NMDARs that contain GluN3A. Since such receptors are not capable of activating small-conductance potassium channels, the intrinsic excitability of VTA dopamine neurons increases. Activation of group I mGluRs rescues synaptic plasticity and restores smallconductance calcium-dependent potassium channel function, normalizing the firing activity of dopamine neurons. Our study characterizes a mechanism linking drug-evoked synaptic plasticity to neural activity, revealing novel targets for therapeutic interventions.