This review covers the intrinsic organization and afferent and efferent connections of the midbrain dopaminergic complex, comprising the substantia nigra, ventral tegmental area and retrorubral field, which house, respectively, the A9, A10 and A8 groups of nigrostriatal, mesolimbic and mesocortical dopaminergic neurons. In addition, A10dc (dorsal, caudal) and A10rv (rostroventral) extensions into, respectively, the ventrolateral periaqueductal gray and supramammillary nucleus are discussed. Associated intrinsic and extrinsic connections of the midbrain dopaminergic complex that utilize gamma-aminobutyric acid (GABA), glutamate and neuropeptides and various co-expressed combinations of these compounds are considered in conjunction with the dopamine-containing systems. A framework is provided for understanding the organization of masssive afferent systems descending and ascending to the midbrain dopaminergic complex from the telencephalon and brainstem, respectively. Within the context of this framework, the basal ganglia direct and indirect output pathways are treated in some detail. Findings from rodent brain are briefly compared with those from primates, including human. Recent literature is emphasized, including traditional experimental neuroanatomical and modern gene transfer and optogenetic studies. An attempt was made to provide sufficient background and cite a representative sampling of earlier primary papers and reviews so that people new to the field may find this to be a relatively comprehensive treatment of the subject.

Profound inhibitory control exerted on midbrain dopaminergic neurons by the lateral habenula (LHb), which has mainly excitatory outputs, is mediated by the GABAergic rostromedial tegmental nucleus (RMTg), which strongly innervates dopaminergic neurons in the ventral midbrain. Early reports indicated that the afferent connections of the RMTg, excepting its very strong LHb inputs, do not differ appreciably from those of the ventral tegmental area (VTA). Presumably, however, the RMTg contributes more to behavioral synthesis than to simply invert the valence of the excitatory signal coming from the LHb. So, the present study was done to directly compare the inputs to the RMTg and VTA and, in deference to its substantial involvement with this circuitry, the LHb was also included in the comparison. Data indicated that, while the afferents of the RMTg, VTA and LHb do originate within the same large pool of CNS structures, each also is related to structures that project more strongly to it than to the others. The VTA gets robust input from ventral striatopallidum and extended amygdala, whereas RMTg biased inputs arise in structures with more direct impact on motor function such as deep layers of the contralateral superior colliculus, deep cerebellar and several brainstem nuclei, and, via a relay in the LHb, the entopeduncular nucleus. Input from the ventral pallidal-lateral preoptic-lateral hypothalamus continuum is strong in the RMTg and VTA and dominant in the LHb. Axon collateralization was also investigated, providing additional insights into the organization of the circuitry of this important triad of structures.

Ambulatory locomotion in the rodent is robustly activated by unilateral infusions into the basal forebrain of type A gamma-aminobutyric acid (GABAA) receptor antagonists, such as bicuculline and picrotoxin. The present study was carried out to better localize the neuroanatomical substrate(s) underlying this effect. To accomplish this, differences in total locomotion accumulated during a 20 minute test period following bicuculline versus saline infusions in male Sprague-Dawley rats were calculated, rank ordered and mapped on a diagram of basal forebrain transposed from immunoprocessed sections. The most robust locomotor activation was elicited by bicuculline infusions clustered in rostral parts of the preoptic area. Unilateral infusions of bicuculline into the ventral pallidum produced an unanticipatedly diminutive activation of locomotion, which led us to evaluate bilateral ventral pallidal infusions, and these also produced only a small activation of locomotion, and, interestingly, a non-significant trend toward suppression of rearing. Subjects with bicuculline infused bilaterally into the ventral pallidum also exhibited persistent bouts of abnormal movements. Bicuculline infused unilaterally into other forebrain structures, including the bed nucleus of stria terminalis, caudate-putamen, globus pallidus, sublenticular extended amygdala and sublenticular substantia innominata, did not produce significant locomotor activation. Our data identify the rostral preoptic area as the main substrate for the locomotor activating effects of basal forebrain bicuculline infusions. In contrast, slight activation of locomotion and no effect on rearing accompanied unilateral and bilateral ventral pallidal infusions. Implications of these findings for forebrain processing of reward are discussed.

The mesopontine rostromedial tegmental nucleus (RMTg) is a GABAergic structure in the ventral midbrain and rostral pons that, when activated, inhibits dopaminergic neurons in the ventral tegmental area and substantia nigra compacta. Additional strong outputs from the RMTg to the pedunculopontine tegmental nucleus pars dissipata, dorsal raphe nucleus, and the pontomedullary gigantocellular reticular formation were identified by anterograde tracing. RMTg neurons projecting to the ventral tegmental area express the immediate early gene Fos upon psychostimulant administration. The present study was undertaken to determine if neurons in the RMTg that project to the additional structures listed above also express Fos upon psychostimulant administration and, if so, whether single neurons in the RMTg project to more than one of these structures. We found that about 50% of RMTg neurons exhibiting retrograde labeling after injections of retrograde tracer in the dorsal raphe or pars dissipata of the pedunculopontine tegmental nucleus express Fos after acute methamphetamine exposure. Also, we observed that a significant number of RMTg neurons project both to the ventral tegmental area and one of these structures. In contrast, methamphetamine-elicited Fos expression was not observed in RMTg neurons labeled with retrograde tracer following injections into the pontomedullary reticular formation. The findings suggest that the RMTg is an integrative modulator of multiple rostrally projecting structures.

The mesopontine rostromedial tegmental nucleus (RMTg) is a newly discovered brain structure thought to profoundly influence reward-related pathways. The RMTg is prominently GABAergic, receives dense projections from the lateral habenula and projects strongly to the midbrain ventral tegmental area and substantia nigra compacta. It receives additional afferent connections from widespread brain structures and sends additional strong efferent connections to a number of non-dopaminergic brainstem structures and, to a lesser extent, the forebrain. Projection neurons of the RMTg have been shown to express Fos in response to aversive stimuli and/or reward omission and psychostimulant drug administration. This review will first recount how the RMTg was discovered and then describe in greater detail what is known about its neuroanatomical relationships, including afferent and efferent connections, neurotransmitters, and receptors. Finally, we will focus on what has been reported about its function.