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

In the paper

“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.”

What the sources say

• Not checked yetcites Ikemoto et al., 2006 source
• Partly supported

  The Discussion reports that endomorphin-1 established conditioned place preference only after injection into the posterior VTA, supporting a posterior-versus-anterior difference for this opioid. The paper does not report the same injection-site comparison for nicotine or identify the central linear nucleus as a rewarding injection site. (LLM, conf=0.88)

  cites Zangen et al., 2002 sourceExperimental — accuracy not yet measured

In the paper

“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)”

In the paper

“and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle)”

In the paper

“whereas the anteromedial VTA has few if any projections to the ventral striatum”

In the paper

“The cell-bodies of dopaminergic neurons projecting to the nucleus accumbens and olfactory tubercle distribute from the posteromedial to anterolateral dimensions at an approximate 45° angle to the anteroposterior axis.”

In the paper

“The TH-positive cell-bodies in the parafasciculus retroflexus area are continuous with those in the posterior hypothalamic area including the supramammillary nucleus”

In the paper

“Thus, the PBP appears to send its efferents to the ventral striatum with mediolateral topography.”

In the paper

“Dopamine neurons in the PN appear to selectively project to the ventromedial striatum.”

In the paper

“The medial part of the PBP provides a selective projection to the ventromedial striatum.”

In the paper

“This dopamine rich sub-area is divided into two zones consistent with previous studies”

What the sources say

• Not checked yetcites Phillipson, 1979b
• Not checked yetcites Halliday and Tork, 1986

In the paper

“The VTT contains a low density of TH-positive cell-bodies, localized in the zone just posterior to the PN and just lateral to the posterior interpeduncular nucleus.”

In the paper

“The middle two-thirds of the VTA consist of dense TH-positive cell-bodies.”

In the paper

“Overall, the ventromedial striatum, consisting of the medial olfactory tubercle and medial accumbens shell, receives dopaminergic innervations from the posteromedial VTA, interfascicular nucleus and central linear nucleus.”

In the paper

“The lateral part of the PBP provides heavy projections to the ventrolateral striatum.”

In the paper

“However, the ventrolateral striatum, consisting of the lateral tubercle, lateral shell and accumbens core, receives dopaminergic innervations from the lateral half of the VTA”

In the paper

“Similarly, dopamine neurons in the central linear nucleus selectively project to the ventromedial striatum, connectivity that is consistent with recent data obtained with the anterograde tracer PHA-L”

What the sources say

• Not checked yetcites Del-Fava et al., 2007 source

In the paper

“As shown in Figure 12, the cells of dopaminergic neurons projecting to the ventral striatum distribute with posteromedio-anterolateral topography at an approximate 45° angle to the midline.”

In the paper

“In summary, these data indicate that not all VTA and midline zones project to the ventral striatum.”

In the paper

“In particular, the data suggest that rats learn to lever-press even if cocaine is delivered in a response-independent manner (see section 6.4 for methods).”

In the paper

“The response-independent cocaine administration into the medial olfactory tubercle significantly increased lever-pressing (Fig. 15A and B).”

In the paper

“Comparison of the present data with those from the self-administration study (Fig. 15B vs. C), which involved virtually identical procedures with the same equipment, suggests that the levels of lever-pressing obtained with the response-independent schedule are strikingly similar to those obtained with the response-dependent schedule.”

In the paper

“High doses of quinpirole injections into the anterolateral VTA or substantia nigra did not induce these effects.”

In the paper

“In addition, the present analyses revealed the roles of the anteroposterior and dorsoventral dimensions in projection patterns.”

In the paper

“FG deposits confined in the medial olfactory tubercle labeled many cells in the posteromedial portion of the PBP, PN and central linear nucleus, but few in other ventral midbrain zones such as anterolateral VTA or SNC (Fig. 10).”

In the paper

“FG deposited into the slightly more ventral area of the medial shell (case 219) labeled cells that were mostly confined to the medial portion of the PBP and central linear nucleus.”

In the paper

“Over 96% of retrogradely labeled cell-bodies that were identified in the ventral midbrain after FG was deposited into the olfactory tubercle, nucleus accumbens or dorsal striatum were also labeled with TH”

In the paper

“This procedure resulted in reduction in the detection of retrogradely labeled cells by approximately 50% from those detected by the immunohistochemical detection procedure.”

In the paper

“Although previous studies reported that injections of horseradish peroxidase or unconjugated WGA into the medial nucleus accumbens labeled the supramammillary nucleus (Carter and Fibiger, 1977; Phillipson and Griffiths, 1985), the deposits of FG confined to the medial shell in the present experiment did not result in labeling in the supramammillary nucleus.”

In the paper

“FG deposited into the lateral shell, like FG deposited into the lateral tubercle, largely labeled cells in the lateral portion of the PBP (Fig. 10).”

In the paper

“The ventromedial striatum sends both direct and indirect projections to the lateral VTA, influencing the meso-ventrolateral striatal dopamine system.”

In the paper

“The ventrolateral striatum sends both direct and indirect projections to the substantia nigra, influencing the meso-dorsal striatal dopamine system.”

In the paper

“Unlike deposits into the striatal regions, FG deposited into the nucleus of the diagonal band retrogradely labeled many cells in the parafasciculus retroflexus area and the posterior hypothalamic area including the supramammillary nucleus, and a few in the rostral linear nucleus and medial PBP (Fig. 10).”

In the paper

“only 10% of cell-bodies labeled after FG application into the nucleus of the diagonal band were co-localized with TH”

In the paper

“Very little FG labeling was found in the anteromedial zone corresponding the parafasciculus retroflexus area after FG injections into the ventral striatum”

In the paper

“Indeed, FG deposited into the lateral tubercle mostly labeled cells in the lateral portion of the PBP.”

In the paper

“FG deposited into the dorsomedial portion of the accumbens shell (cases 234, 279, and 280) retrogradely labeled cells mostly in the PN, central linear nucleus and interfascicular nucleus (Fig. 10).”

In the paper

“The ventral anterolateral compartments, containing dense dopaminergic cells, had extensive labeling after FG injections into the ventrolateral striatum including the lateral tubercle, lateral accumbens shell and accumbens core.”

In the paper

“The dorsal posteromedial compartments had extensive FG labeling after FG injections into both the medial tubercle and the medial accumbens shell”

In the paper

“The ventral posteromedial compartments, on the other hand, had heavy labeling after FG injections into the medial accumbens, but not the medial tubercle.”

In the paper

“as well as by the blockade of nicotinic receptors administered into the VTA”

What the sources say

• Not checked yetcites Corrigall et al., 1994 source

In the paper

“The shell portion of the accumbens appears to be more important than the core for drug reward.”

What the sources say

• Not checked yetcites Carlezon et al., 1995 source
• Not checked yetcites Ikemoto et al., 1997a
• Not checked yetcites Rodd-Henricks et al., 2002 source

In the paper

“(3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function.”

In the paper

“Depletion of dopamine in the nucleus accumbens induced by local 6-hydroxydopamine (6-OHDA) injections severely attenuates the rewarding effects of cocaine or amphetamine, as assessed by instrumental responses”

What the sources say

• Not checked yetcites Lyness et al., 1979 source
• Not checked yetcites Roberts et al., 1980 source
• Not checked yetcites Caine and Koob, 1994

In the paper

“These results confirm functional differences between the two accumbens compartments inferred from anatomical observations that the afferents to and efferents from the accumbens differ significantly between the shell and core”

What the sources say

• Not checked yetcites Zahm and Brog, 1992 source

In the paper

“Conditioned place preference induced by intravenous administration of cocaine or amphetamine is attenuated by lesions on dopamine terminals in the shell rather than the core”

What the sources say

• Not checked yetcites Sellings and Clarke, 2003
• Not checked yetcites Sellings et al., 2006a
• Not checked yetcites Sellings et al., 2006b

In the paper

“Intravenous self-administration of nicotine in rats is attenuated by selective lesions to VTA dopamine neurons projecting to the ventral striatum”

What the sources say

• Not checked yetcites Corrigall et al., 1992 source

In the paper

“Rats learn to self-administer psychomotor stimulants such as amphetamine or cocaine or dopamine receptor agonists into the accumbens shell, but not the core”

What the sources say

• Not checked yetcites Carlezon et al., 1995 source
• Not checked yetcites Ikemoto et al., 1997a
• Not checked yetcites Ikemoto et al., 2005

In the paper

“(2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell;”

In the paper

“A review of the literature suggests that: (1) the midbrain has corresponding zones for the accumbens core and medial shell;”

In the paper

“The medial projection system is important in the regulation of arousal characterized by affect and drive”

In the paper

“The VTA at least partly mediates the rewarding effects of nicotine, opiates, cannabinoids and ethanol.”

What the sources say

• Not checked yetcites Corrigall et al., 1992 source
• Not checked yetcites Bozarth and Wise, 1981
• Not checked yetcites Zangen et al., 2006 source

In the paper

“In addition, microinjections of dopaminergic antagonists into the shell, but not the core, disrupt conditioned place preference induced by systemic nicotine or morphine”

What the sources say

• Not checked yetcites Fenu et al., 2006 source
• Not checked yetcites Spina et al., 2006 source

In the paper

“Rats learn to lever-press for administration of drugs such as nicotine (Ikemoto et al., 2006), carbachol (Ikemoto and Wise, 2002), opiates (Zangen et al., 2002), cannabinoids (Zangen et al., 2006), cocaine (Rodd et al., 2005), ethanol (Rodd-Henricks et al., 2000) and its metabolite acetaldehyde (Rodd et al., 2004) into the posterior VTA more readily than into the anterior VTA.”

What the sources say

• Not checked yetcites Ikemoto et al., 2006 source
• Not checked yetcites Zangen et al., 2002 source
• Not checked yetcites Rodd et al., 2005 source

In the paper

“Consistently, lesions on dopaminergic terminals in the medial olfactory tubercle disrupt conditioned place preference induced by intravenous psychomotor stimulants”

What the sources say

• Not checked yetcites Sellings et al., 2006a
• Not checked yetcites Sellings et al., 2006b

In the paper

“These behavioral effects are mediated by dopaminergic systems as shown by pharmacological manipulations (no data is available on cannabinoids in this context).”

In the paper

“This arrangement of dopaminergic neurons can provide an explanation for the behavioral data, suggesting that the anterior and posterior VTA are functionally heterogeneous.”

In the paper

“Previous data clearly suggest that the neurons in the VTA project into the nucleus accumbens with mediolateral topography”

What the sources say

• Not checked yetcites Fallon and Moore, 1978
• Not checked yetcites Nauta et al., 1978
• Not checked yetcites Brog et al., 1993

In the paper

“The pattern of drug-reward trigger zones described above appears to be partly explained by cellular connectivity between the ventral midbrain and the ventral striatum.”

In the paper

“Similar mediolateral topography appears to exist for the projection from the ventral midbrain to the olfactory tubercle”

What the sources say

• Not checked yetcites Newman and Winans, 1980

In the paper

“These data suggest that the parafasciculus retroflexus area is more closely related to the posterior hypothalamus than the PN or PBP of the VTA.”

In the paper

“In light of the pattern of midbrain projections to the ventral striatum (Fig. 12), the heterogeneity of the VTA may be better described by differences between the posteromedial VTA, centering around the PN, versus the rest of the VTA.”

In the paper

“However, these receptors appear to be desensitized within a few seconds after exposure to high, reward-mediating concentrations of nicotine (Pidoplichko et al., 1997; 2004; Wooltorton et al., 2003).”

What the sources say

• Not checked yetcites Pidoplichko et al., 1997 source
• Not checked yetcites Pidoplichko et al., 2004 source
• Not checked yetcites Wooltorton et al., 2003 source

In the paper

“Consistent with previous data (Fallon and Moore, 1978), the parafasciculus retroflexus area projects heavily into the nucleus of the diagonal band”

What the sources say

• Not checked yetcites Fallon and Moore, 1978

In the paper

“Therefore, the rewarding effects of picrotoxin into the anterior VTA are readily explained by the notion that picrotoxin administered into the anterior VTA diffuses to the supramammillary nucleus for its rewarding effects.”

In the paper

“Other drugs of abuse such as nicotine and opiates appear to act in the posteromedial VTA and central linear nucleus.”

What the sources say

• Not checked yetcites Ikemoto et al., 2006 source
• Not checked yetcites Zangen et al., 2002 source

In the paper

“It was found that rats learn to self-administer the excitatory amino acid AMPA or nicotine into the supramammillary nucleus (Ikemoto et al., 2004; 2006), localized just anteromedial to the anterior VTA and dorsal to the mammillary body”

What the sources say

• Not checked yetcites Ikemoto et al., 2004
• Not checked yetcites Ikemoto et al., 2006 source

In the paper

“This organization of dopaminergic projections appears to provide an explanation for the pattern of self-administration data described in section 1.2 and discussed below.”

In the paper

“Psychomotor stimulants such as cocaine and amphetamine act at protein targets on the axon terminals of the medial accumbens shell and medial olfactory tubercle”

What the sources say

• Not checked yetcites Carlezon et al., 1995 source
• Not checked yetcites Ikemoto et al., 1997a
• Not checked yetcites Ikemoto et al., 2005

In the paper

“Nicotine can directly excite dopaminergic neurons via the nicotinic receptors on the somatodendritic region of dopaminergic neurons (Calabresi et al., 1989; Pidoplichko et al., 1997).”

What the sources say

• Not checked yetcites Calabresi et al., 1989 source
• Not checked yetcites Pidoplichko et al., 1997 source

In the paper

“The observations described above and the behavioral data described in section 1.2 led to the proposal of a heuristic model of two dopaminergic projection systems from the ventral midbrain to the ventral striatum, to address reward function (Fig. 11).”

In the paper

“The meso-ventromedial striatal dopamine system appears to be a common circuitry for triggering drug reward.”

In the paper

“It should be emphasized that their targets are not necessarily on dopaminergic neurons.”

In the paper

“The notion that drugs trigger rewarding effects from the anterior VTA, however, is no longer viable.”

In the paper

“It is most likely that protein targets localized in the posteromedial VTA mediate these drugs’ actions.”

In the paper

“The study that initially suggested possible VTA heterogeneity in drug reward reported that rats self-administered the GABAA antagonist picrotoxin into the anterior VTA, but not the posterior VTA”

What the sources say

• Not checked yetcites Ikemoto et al., 1997b

In the paper

“Moreover, picrotoxin administration into the supramammillary nucleus appears to be more rewarding than administration into the anterior VTA”

What the sources say

• Not checked yetcites Ikemoto, 2005

In the paper

“Nicotinic receptors are also found on presynaptic glutamatergic terminals in the VTA.”

What the sources say

• Not checked yetcites McGehee et al., 1995 source

In the paper

“The central linear nucleus, into which rats quickly learn to self-administer nicotine or the GABAA receptor agonist muscimol (Ikemoto et al., 1998; Ikemoto et al., 2006), provides heavy dopaminergic inputs to the ventromedial striatum.”

What the sources say

• Not checked yetcites Ikemoto et al., 1998
• Not checked yetcites Ikemoto et al., 2006 source

In the paper

“Therefore, this mechanism may play a major role in nicotine’s persistent reward-related effects.”

In the paper

“Both the medial olfactory tubercle and the medial accumbens shell receive afferents from common zones, including the infralimbic cortex (Berendse et al., 1992), the posterior basolateral amygdaloid nucleus (Krettek and Price, 1978; Russchen and Price, 1984), the ventral subiculum of the hippocampal formation (Kelley and Domesick, 1982; Groenewegen et al., 1987), and the paraventricular thalamic n”

What the sources say

• Not checked yetcites Berendse et al., 1992
• Not checked yetcites Krettek and Price, 1978 source
• Not checked yetcites Russchen and Price, 1984

In the paper

“In addition to the posteromedial VTA, the central linear nucleus and interfascicular nucleus should be included in the dopamine reward circuitry in the meso-ventromedial striatal dopamine system (Fig. 11).”

In the paper

“The central linear nucleus, into which rats quickly learn to self-administer nicotine or the GABAA receptor agonist muscimol (Ikemoto et al., 1998; Ikemoto et al., 2006), provides heavy dopaminergic inputs to the ventromedial striatum.”

In the paper

“The brief excitatory capacity that nicotine has on dopaminergic neurons does not readily explain the finding that rats self-administer nicotine continuously over minutes or hours and that a single systemic injection of nicotine increases and maintains extracellular dopamine levels in the nucleus accumbens for over an hour (Imperato et al., 1986; Pidoplichko et al., 2004).”

In the paper

“Administration of opiates, systemically or locally, appears to disinhibit dopaminergic neurons in the VTA (Gysling and Wang, 1983; Matthews and German, 1984; Johnson and North, 1992).”

What the sources say

• Not checked yetcites Gysling and Wang, 1983
• Not checked yetcites Matthews and German, 1984
• Not checked yetcites Johnson and North, 1992 source

In the paper

“Dopaminergic afferent connections and functions of the ventromedial striatum are considerably different from those of the ventrolateral striatum.”

In the paper

“Glutamatergic transmission can be facilitated by the presynaptic action of nicotine (McGehee et al., 1995), which then may activate dopaminergic neurons.”

What the sources say

• Not checked yetcites McGehee et al., 1995 source

In the paper

“The net effect of nicotine administration into the VTA appears to increase the frequency of dopaminergic neuron firing.”

In the paper

“Other mechanisms are needed to explain the maintenance of nicotine self-administration and prolonged dopamine release.”

In the paper

“Thus, the axon-terminals of the neurons originating from the interfascicular nucleus are most likely targets of psychomotor stimulants, which then increase extracellular dopamine in the medial shell.”

In the paper

“Glutamatergic transmission can be facilitated by the presynaptic action of nicotine (McGehee et al., 1995), which then may activate dopaminergic neurons.”

In the paper

“Although the olfactory tubercle receives olfactory inputs, the striatal district of the tubercle shares strikingly similar inputs with the nucleus accumbens, especially the accumbens shell.”

In the paper

“Afferents including dopaminergic afferents from the midbrain to the ventral striatum most likely change gradually rather than divide abruptly.”

In the paper

“The ventral striatum sends its major projection to the ventral pallidum (Heimer et al., 1987; 1991; Zahm and Heimer, 1987; 1990; Zahm et al., 1987; O’Donnell et al., 1997; Usuda et al., 1998; Zhou et al., 2003).”

What the sources say

• Not checked yetcites Heimer et al., 1987 source
• Not checked yetcites Zahm and Heimer, 1987
• Not checked yetcites O’Donnell et al., 1997

In the paper

“The medial ventral pallidum, which receives inputs from the medial shell and medial tubercle, sends its efferent to the medial segment of the mediodorsal thalamic nucleus (Zahm et al., 1987; Groenewegen, 1988; Ray and Price, 1992; Zahm et al., 1996; O’Donnell et al., 1997).”

What the sources say

• Not checked yetcites Zahm et al., 1987
• Not checked yetcites Groenewegen, 1988 source
• Not checked yetcites Ray and Price, 1992 source

In the paper

“Similarly, the lateral shell and lateral olfactory tubercle appear to project to the ventrolateral portion of the ventral pallidum, including the lateral polymorph layer of the olfactory tubercle containing pallidal neurons (Heimer et al., 1987; 1991; Zahm and Heimer, 1987; 1990; O’Donnell et al., 1997; Usuda et al., 1998; Zhou et al., 2003).”

What the sources say

• Not checked yetcites Heimer et al., 1987 source
• Not checked yetcites Zahm and Heimer, 1987
• Not checked yetcites O’Donnell et al., 1997

In the paper

“Based on afferents and efferents, which will be discussed next, the core appears to be more similar to the lateral shell/lateral tubercle than to the medial shell/medial tubercle.”

In the paper

“It should be noted that these olfactory inputs appear to go to the striatal zone, which consists of medium spiny neurons that are morphologically similar to the medium spiny neurons in the accumbens and dorsal striatum (Millhouse and Heimer, 1984).”

What the sources say

• Not checked yetcites Millhouse and Heimer, 1984

In the paper

“Ventral striatopallidal projections link to the thalamocortical projection systems that, in turn, link back to the ventral striatum (Fig. 13).”

In the paper

“Thus, signals elaborated in the ventromedial and ventrolateral striatum also reach the meso-dorsal striatal dopamine system, via the pallido-mesencephalic systems.”

In the paper

“In general, the features of spiny neurons in the lateral shell are intermediate between those of the medial shell and the core.”

In the paper

“Ventral striatal projections to the ventral pallidum display a mediolateral topographical organization and have been particularly well established for the medial shell and the core.”

What the sources say

• Not checked yetcites Zahm and Heimer, 1990
• Not checked yetcites Heimer et al., 1991 source
• Not checked yetcites Usuda et al., 1998 source

In the paper

“The ventral pallidum participates in lateral information flow via pallido-mesencephalic projections.”

In the paper

“In summary, medium spiny neurons in the ventral striatum receive varying afferents between the structure’s medial and lateral areas.”

In the paper

“In other words, differences between the medial shell and the medial tubercle appear to be smaller than differences between the medial shell and the lateral shell or the medial tubercle and the lateral tubercle.”

In the paper

“It may be stated that the ventral striatum is functionally more different on the mediolateral dimension than the dorsoventral dimension.”

In the paper

“Previous data suggest that the olfactory tubercle provides little (Swanson, 1976; Newman and Winans, 1980; Berendse et al., 1992b; Geisler and Zahm, 2005) or no projection (Heimer et al., 1987; Zhou et al., 2003) to the ventral midbrain.”

What the sources say

• Not checked yetcites Swanson, 1976 source
• Not checked yetcites Newman and Winans, 1980
• Not checked yetcites Berendse et al., 1992b

In the paper

“These similarities between the shell and tubercle suggest that the striatal district of the tubercle is a ventral extension of the shell.”

In the paper

“Therefore, functional differences between them may be thought of as a continuum.”

In the paper

“However, the ventrolateral ventral pallidum, which receives its afferents from the lateral shell and lateral tubercle, sends its efferent to the central and lateral segments of the dorsomedial thalamic nucleus (Groenewegen, 1988; Ray and Price, 1992; Zahm et al., 1996; O’Donnell et al., 1997).”

What the sources say

• Not checked yetcites Groenewegen, 1988 source
• Not checked yetcites Ray and Price, 1992 source
• Not checked yetcites Zahm et al., 1996 source

In the paper

“In particular, the meso-ventromedial striatal dopamine system appears to participate in the variation process, generating unconditioned responding.”

In the paper

“Indeed, tonic signals in the ventral striatum as measured by microdialysis procedures appear to correlate with hyper-activity effects as indicated by locomotion (Sharp et al., 1987; Steinpreis and Salamone, 1993).”

What the sources say

• Not checked yetcites Sharp et al., 1987 source
• Not checked yetcites Steinpreis and Salamone, 1993

In the paper

“The olfactory tubercle sends its efferent to the nucleus Gemini, localized in the posterolateral hypothalamus (Scott and Leonard, 1971; Scott and Chafin, 1975; Price et al., 1991).”

What the sources say

• Not checked yetcites Scott and Leonard, 1971
• Not checked yetcites Scott and Chafin, 1975
• Not checked yetcites Price et al., 1991 source

In the paper

“Careful investigation has led to the conclusion that this projection originates from pallidal parts of the olfactory tubercle (Heimer et al., 1990).”

What the sources say

• Not checked yetcites Heimer et al., 1990 source

In the paper

“The meso-ventrolateral striatal dopamine system, in addition to the meso-dorsal striatal dopamine system, appears to participate in behavioral selection by modulating associative learning.”

In the paper

“In addition, ventral pallidal neurons, which receive inputs from the medial shell and medial tubercle, project substantially to the lateral hypothalamic area (Groenewegen et al., 1993).”

What the sources say

• Not checked yetcites Groenewegen et al., 1993 source

In the paper

“In particular, medial shell neurons project to the lateral hypothalamic area (Heimer et al., 1991; Berendse et al., 1992b; Usuda et al., 1998).”

What the sources say

• Not checked yetcites Heimer et al., 1991 source
• Not checked yetcites Berendse et al., 1992b
• Not checked yetcites Usuda et al., 1998 source