Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex

Abstract

Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.

Figure 1

Self-administration of cocaine into the olfactory tubercle. (A) Injection sites were placed in the medial portion of the olfactory tubercle and are plotted (white dots) on TH stained sections. Abbreviations: ac, anterior commissure; CO, core; OTm, medial olfactory tubercle; OTl, lateral olfactory tubercle; SHm, medial shell; SHl, lateral shell; VP/mfb, ventral pallidum/medial forebrain bundle. (B) Mean self-administration rates (±SEM) are shown over eight sessions, N = 16. * A significant difference compared to respective vehicle sessions, P < 0.05. (C) Event records from a representative rat. Each vertical line on the horizontal line indicates the time of an infusion. The number right of the horizontal line indicates total infusions in that session. These data are modified, with permission from the Society for Neuroscience, from Fig. 1 and 2 of the Ikemoto (2003) paper in which data for other striatal sites, CO, SHm, OTl and dorsal striatum are also available.

Figure 2

Divisions of the ventral midbrain shown on TH-stained horizontal sections. Sections, separated by 160 μm, are arranged from dorsal (A) to ventral (F). For the purpose of projection analyses, each section is divided into anterior-posterior and medial-lateral compartments by red lines. The division between the anterior and posterior compartments, adapted from previous behavioral work (Arnt and Scheel-Kruger, 1979, Ikemoto et al., 1997b, Ikemoto and Wise, 2002), is drawn between the interpeduncular nucleus and the interpeduncular fossa, and is extended dorsally. The mediolateral divide is arbitrarily set at the lateral edge of the fascicular retroflexus. Abbreviations: CL, central (or caudal) linear nucleus raphe; fr, fasciculus retroflexus; IF, interfascicular nucleus; IP, interpeduncular nucleus; IPF, interpeduncular fossa; LHA, lateral hypothalamic area; ml, medial lemniscus; MT, medial terminal nucleus of the accessory optic tract; PBP, parabrachial pigmented area; PFR, parafasciculus retroflexus area; PHA, posterior hypothalamic area; PN, paranigral nucleus; R, red nucleus; RL, rostral linear nucleus raphe; RR, retrorubral nucleus; scp, superior cerebellar peduncle; SNC, substantia nigra compact part; SNR, substantia nigra reticular part; SUM, supramammillary nucleus; sumd, supramammillary decussation; vtd, ventral tegmental decussation; VTT, ventral tegmental tail.

Figure 3

Enlarged panel E of Figure 2, showing cytoarchitectonic features of TH-stained cells at the level of the PN. See the legend of Figure 2 for abbreviations.

Figure 4

Enlarged panel B of Figure 2, showing TH-stained cells at the level of the central linear nucleus.

Figure 5

Coronal sections showing TH-positive cells at the level of the parafasciculus retroflexus area. The areas within the green rectangular frames are enlarged in the bottom panels. The 0.1-mm scale applies to the bottom five images.

Figure 6

Coronal sections showing TH-stained cells at the level of the PN. The areas within the green rectangular frames are enlarged in the bottom panels. The 0.1-mm scale applies to the bottom four images.

Figure 7

Sagital sections showing TH-positive cells at the level of PN. The areas within the green rectangular frames are enlarged in the bottom panels. The 0.1-mm scale applies to the bottom four images.

Figure 8

Coronal sections showing TH- and Nissl-stained cells at the level of the central linear nucleus. The areas within the green rectangular frames of panel A are enlarged in panels B and C. The area in the green frame of Panel D is enlarged in panel E showing Nissl-stained cell-bodies at an adjacent section from that of Panel C. The arrow in panel A points to the same blood vessel as the arrows in panels C, D and E.

Figure 9

Sagital sections showing TH-positive cell-bodies at the midline. The areas within the green rectangular frames are enlarged in the bottom panels. BV, blood vessel (other abbreviations in the legend for Figure 2).

Figure 10

A chart of the distribution of retrogradely-labeled cell-bodies in the ventral midbrain after FG injections into ventral striatal sites and adjacent regions. Photomicrographs (top) show FG deposit sites in representative coronal sections. The numbers in parenthesis are rat identification numbers. Each dot on the drawings represents a labeled cell-body. Retrogradely-labeled cells were most exclusively found in the ipsilateral side and midline area. Very little were found in the contralateral side beyond the midline (not shown). Sections are arranged from dorsal (A) to ventral (F). See the legend of Figure 2 for abbreviations.

Figure 11

The meso-striatal dopamine systems. The data shown in Figure 10 are re-drawn on single sections to contrast ventral midbrain projections of striatal zones. Horizontal sections are arranged from (a) most dorsal to (f) most ventral. Although dopaminergic projections to the striatum are probably continuous from the ventromedial to dorsolateral without abrupt divides, two dopaminergic projection models are suggested to account for the observation that the medial projection system is more important for drug reward.

Figure 12

Midbrain distributions of cells projecting to the ventral striatum. Projection data of sections (a) through (f) of Figure 11 are combined onto a single plane to show how ventral midbrain projections to the striatum are organized with respect to sub-areas of the VTA and midline nuclei. Green- and orange-outlines respectively indicate the midline nuclei and ventral tegmental sub-areas. Dopaminergic neurons projecting to the ventral striatum are lined up with posteromedio-anterolateral topography at an approximate 45° angle (blue line) to the midline.

Figure 13

The meso-ventromedial and ventrolateral striatal dopamine systems and output connections. Abbreviations: Cg, cingulate cortex; CL, central linear nucleus; CO, core; DS, dorsal striatum; GPe, external globus pallidus; GPi, internal globus pallidus; IF, interfascicular nucleus; IL, infralimbic cortex; LHA, lateral hypothalamic area; MDc, central mediodorsal thalamic nucleus; MDm, medial mediodorsal thalamic nucleus; MDl, lateral mediodorsal thalamic nucleus; OTm, medial olfactory tubercle; OTl, lateral olfactory tubercle; PL, prelimbic cortex; SHm, medial shell; SHl, lateral shell; SNC, substantia nigra pars compacta; SNR, substantia nigra pars reticulata; STN, subthalamic nucleus; VM, ventromedial thalamic nucleus; VPm, medial ventral pallidum; VPdl, dorsolateral ventral pallidum; VPvl, ventrolateral ventral pallidum including the polymorph layer of the olfactory tubercle; VTApm, posteromedial ventral tegmental area; VTAl, lateral ventral tegmental area.

Figure 14

The variation-selection hypothesis of striatal functional organization. Striatal regions, shown on top, are divided into four regions: the ventromedial (VM), ventrolateral (VL), dorsomedial (DM), and dorsolateral (DL) striatum. Stimulus-outcome (S→O) association provides the foundation from which selection processes are generated, including stimulus-action (S→A), action-outcome (A→O) and stimulus-response (S→R) associative processes. These associative processes provide mechanisms for selection upon variation.

Figure 15

Effects of response-independent and dependent cocaine administration into the olfactory tubercle on lever-pressing. Panel A shows cumulative lever-press records from a representative rat that received cocaine infusions with response-independent schedules. Although the X and Y-axes were not shown, the horizontal (X)-axis indicates time and every lever-press moved the line up a unit on the vertical (Y)-axis; thus, the slope of the line indicates the rate of lever-presses. The number on the right indicates the total lever-presses for the session. Panel B shows mean lever-press rates per session with SEM, when rats (n = 5) received cocaine or vehicle infusions into the medial tubercle with response-independent schedules. *A significant difference compared to vehicle counts, P < 0.05. Panel C shows mean lever-press rates per session with SEM, when rats (n = 16) earned infusions with a response-dependent schedule into the same brain site. *A significant difference compared to vehicle counts, P < 0.01. The data in panel C were adopted from Ikemoto (2003), with permission from the Society for Neuroscience.

Figure 16

Conscious experience in relation to stimulus-response processes of the central nervous system (CNS). Arrows within rectangular boxes indicate how the perception of stimuli is processed in relation to conscious awareness process before it reaches the motor system for responses. All of the models A–C assume that consciousness is based on the CNS activity. Model A depicts a linear relationship among sensory, conscious and motor processes: sensory processes activate conscious processes, which in turn generate motor processes. This unlikely model assumes that subjective experience has total control over behavioral outputs. Model B depicts conscious experience as an epiphenomenal reflection of higher CNS processes with no causal effects on behavior. From an evolutionary perspective, conscious awareness likely has some survival advantages; therefore, it is reasonable to suppose that subjective experience should interact with on-going subconscious processes to modify behavioral outputs (Model C). The figure is adapted from Fig. 6 of Ikemoto and Panksepp (1999), with permission from Elsevier.

Figure 17

Interaction of dopamine systems with cortical and action-arousal systems (A). Conditioned responses that indicate drug reinforcement depend on dopamine-cortical interactions (B), whereas unconditioned responses do not as much (C).

Figure 18

Extent of iontophoretic FG deposits for individual cases shown by lines. Each case is assigned with a unique number and color to help distinguish from others within the zone. The drawings are coronal sections adapted from Swanson (1998).

Figure 19

Co-localization of FG- and TH-labeling. (A) FG-labeling is shown. (B) TH-labeling is shown. (C) The red and green channels of panel A were removed and then the image was superimposed over panel B. Arrows indicate FG-labeled cells that are not labeled with TH.

Figure 20

Retrogradely labeled cell counts by compartments, divided by the anterior-posterior (ANT-PST), medial-lateral (M-L) and ventral-dorsal (V-D) dimensions. Error bars indicate SEM. See Figure 2 for divisions of ANT-PST, M-L, and D-V (divided between sections C and D) dimensions.