The distribution of dopamine (DA) D2-like receptors in the human thalamus was studied using in vitro autoradiographic techniques and in vivo positron emission tomography in normal control subjects. [125I]Epidepride, which binds with high affinity to DA D2 and D3 receptors, was used in autoradiographic studies to determine the distribution and density of D2-like receptors, and the epidepride analogue [18F]fallypride positron was used for positron emission tomography studies to delineate D2-like receptors in vivo. Both approaches revealed a heterogeneous distribution of thalamic D2/3 receptors, with relatively high densities in the intralaminar and midline thalamic nuclei, including the paraventricular, parataenial, paracentral, centrolateral, and centromedian/parafascicular nuclei. Moderate densities of D2/3 sites were seen in the mediodorsal and anterior nuclei, while other thalamic nuclei expressed lower levels of D2-like receptors. Most thalamic nuclei that express high densities of D2-like receptors project to forebrain DA terminal fields, suggesting that both the thalamic neurons expressing D2-like receptors and the projection targets of these neurons are regulated by DA. Because the midline/intralaminar nuclei receive prominent projections from both the ascending reticular activating core and the hypothalamus, these thalamic nuclei may integrate activity conveying both interoceptive and exteroceptive information to telencephalic DA systems involved in reward and cognition.
The midline and intralaminar nuclei of the thalamus have historically been considered to be part of the nonspecific thalamus, a diencephalic way-station of the ‘ascending reticular activating system’ (Jasper, 1949). However, contemporary studies have revealed that the projections of neurons within the midline/intralaminar complex are specific for distinct forebrain targets (Berendse and Groenewegen, 1990, 1991; Moga et al, 1995; Turner and Herkenham, 1991), and have challenged the concept of ‘nonspecificity’ of these nuclei (Groenewegen and Berendse, 1994). The midline/intralaminar nuclei have figured prominently both in recent post-mortem and imaging studies and in theoretical considerations of the pathophysiology of schizophrenia (Andreasen, 1997; Buchsbaum et al, 1996; Byne et al, 2002; Cohen and Yurgelun-Todd, 2001; Deutch et al, 1995; Popken et al, 2000) addictive disorders (Staley and Mash, 1996; Volkow et al, 1996, 1997; Wang et al, 1997; Yousef et al, 1995), and Parkinson's disease (PD) (Feigin et al, 2002; Filion, 2000; Freeman et al, 2001; Henderson et al, 2000; Hershey et al, 1998; Kaasinen et al, 2000).
There have been few studies of thalamic dopamine (DA) function in humans, and relatively little is known of the organization and distribution of dopaminergic axons and receptors in the human thalamus. We and others, using both binding studies in post-mortem tissue and in vivo radiolabeling approaches, have previously reported that D2-like DA receptors are present in the human thalamus in moderately high density (Delforge et al, 2001; Farde et al, 1997; Gurevich and Joyce, 1999; Hagelberg et al, 2002; Hall et al, 1996a; Halldin et al, 1995; Kessler et al, 1993b, 1997; Mukherjee et al, 2001; Wang et al, 1997). However, extant studies have typically examined DA receptors of the thalamus as part of more global analyses of extrastriatal DA systems, and there are almost no focused studies on the intra-thalamic distributions of D2-like receptors using both autoradiographic and in vivo imaging approaches. We therefore assessed the regional distribution of DA D2-like receptors in the human thalamus both in vitro and in vivo, as revealed with epidepride analogues that bind with high affinities to D2/3 receptors.
Brains were obtained from three male subjects (ages 43, 55, and 60 years) who were free of neurological and psychiatric disease and were not maintained on any psychotropic medications. The subjects all died in the hospital, two of acute cardiac events and the other from a pulmonary embolism; in all cases the post-mortem intervals were less than 6 h. In no subject was there a previous history of neurological or psychiatric illnesses. The brains were examined for gross structural abnormalities and then divided along the mid-sagittal plane, with one hemisphere being stored in 10% formalin and the other frozen and stored at −80°C. Coronal sections from the fixed hemisphere were prepared and stained conventionally to determine if any neuropathological changes were present; none were noted. The frozen hemisphere was slowly thawed to −20°C and then cut coronally into tissue blocks 1–2 cm thick, from which 30 μm frozen sections were cut. The slide-mounted sections were stored at −20°C.
Autoradiographic methods using [125I]epidepride were used to determine the densities of D2-like-binding sites. The sections were preincubated at room temperature for 30 min in 50 mM Tris-HCl (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgSO4, 1 mM EDTA, and 100 μM ascorbate. The tissue was then incubated in Tris buffer containing 50 pM [125I]epidepride for 3 h at room temperature. Sections were exposed to HyperB film (Amersham) for 2–6 days, and from these camera lucida drawings were made through the thalamus; nuclear boundaries were defined as shown in the atlas of Mai et al (1997).
In order to assess basal ganglia D2-like binding the sections were apposed to film for 2 days. Due to the markedly different densities of DA receptors in the basal ganglia and thalamus, sections through the thalamus were subsequently exposed to film for 7 days. Linearity was assessed by comparing optical densities with brain paste standards containing known levels of radioactivity; these standards were coexposed with the brain sections. All thalamic nuclei were within the linear range of optical densities at the 7-day exposure time.
The densities of D2/3-binding sites were determined by computer-assisted densitometry using NIH Image 1.6 (developed at the US National Institutes of Health and available on the internet at http://rsb.info.nih.gov/nih-image). Standards containing varying concentrations of 125I in homogenized brain tissue were used to generate Bmax values, based on a KD of 24 pM for epidepride. Regions of interest were defined and outlined with reference to the nuclei defined in the atlas of Mai et al (1997).
In Vivo PET Imaging
Positron emission tomographic imaging was performed in five normal subjects (three males and two females, ages 21–45 years) who were free of documented neuropsychiatric illnesses and use of psychoactive medications. All subjects had a complete physical examination, including a neurological examination. In addition, neuropsychological tests to assess cognitive function and urinary drug screens were performed. The studies were conducted in accord with the guidelines of the Declaration of Helsinki and were approved and overseen by the Vanderbilt University Institutional Review Board.
PET scans were performed using a General Electric Advance PET scanner in the 3-D mode; this unit has an in-plane and axial resolution of 4.5–5.5 mm. Subjects were positioned on the scanner bed and 4.5–5.0 mCi of the epidepride analogue [18F]fallypride (specific activity >2000 Ci/mmol) was administered intravenously; serial emission scans were then obtained for up to 240 min. A measured attenuation correction was performed, and regional binding potentials determined using the reference region method (Lammertsma et al, 1996). MRI scans of the brain were performed using thin section inversion prepared T1-weighted gradient echo sequences (IR SPGR, TE=3.6, TR=19, TI=400, 24 cu field of view) in the sagittal (slice thickness 1.2–1.3 mm) and coronal (slice thickness 1.4–1.5 mm) planes. In addition, fast spin echo axial spin density weighted (TE=19, TR=5000, 3 mm thick) and T2-weighted (TE=106, TR=5000, 3 mm thick) slices were obtained to exclude any structural abnormalities. The PET scans were coregistered with each other and the thin section IR SPGR MRI scans using a mutual information rigid body registration (Maes et al, 1997). Regions of interest were outlined on the MRI scans and automatically transferred to the serial PET scans.
In Vitro Autoradiography
[125I]Epidepride binding revealed a heterogeneous distribution of D2/3 receptors in the human thalamus (see Figures 1 and 2; Table 1). The distribution of thalamic [125I]epidepride binding largely conformed to recognized nuclear boundaries, with the most dense labeling seen in the anterior midline group, including the paraventricular (PVT) and parataenial (PT) nuclei (Figure 1 and Table 1). The density of D2/3-binding sites in this region was roughly comparable to that seen in the substantia nigra (see Table 1).
Relatively dense [125I]epidepride binding was present throughout the midline/intralaminar nuclei (Figures 1 and 2). The highest density of D2/3-binding sites in the PVT was in the anterior half of the structure. More ventral midline nuclei also exhibited a moderately high density of [125I]epidepride-binding sites (Table 1). Radioligand binding was also relatively high in a continuous lateral sweep from the ventral aspects of the midline thalamus to the parafascicular and central median nucleus (Figure 1 and Table 1). This band of D2/3-binding sites extended dorsolaterally at lower density in the paracentral and central lateral nuclei, thus encircling the mediodorsal thalamic nucleus (MD).
D2-like binding was lower in the MD than in the medially contiguous midline nuclei, with a clear mediolateral gradient in [125I]epidepride binding (Figure 1 and Table 1). In addition, small ‘islands’ of dense [125I]binding were seen in both the lateral and medial MD (Figure 3). The degree to which these ‘islands’ of high receptor binding correspond to regions that are identified by cytoarchitectonic or histochemical criteria (Ilinksy et al, 1985) is not clear.
The remaining thalamic nuclei exhibited low-to-moderate [125I]epidepride binding (see Table 1 and Figures 1 and 2). The lateral tier complex, including the lateral posterior nuclei and pulvinar, showed moderate D2-type receptor binding. A moderate density of binding sites was observed in the magnocellular medial geniculate nucleus (Figure 3), in contrast to the lateral geniculate nucleus where lower densities of DA receptors were noted. A faint band of [125I]epidepride binding was seen in the reticular nucleus; these binding sites were most apparent in the ventral aspects of the reticular nucleus. Moderate binding was also present in the parageniculate nucleus.
In Vivo Studies
[18F]Fallypride studies revealed a heterogenous pattern of radioligand accumulation in the thalamus (see Figure 4). Radioligand binding was highest in the midline thalamus, with greater densities seen in the anterior midline regions (Figure 4), in a region centered just above the anterior commissure–posterior commissure (AC–PC) line and 8 mm posterior to the anterior commissure. MRI coregistration revealed that this region corresponds to the medial wall of the thalamus, including the PVT and PT nuclei. Significantly less radioligand accumulation was present in the MD. More caudally uptake was most prominent in the area including the centromedian/parafascicular (CM/PF) nuclei, that is, approximately 25 mm posterior to the anterior commissure, 5 mm lateral to the midline, and just above the AC–PC line. Comparison of medial thalamic binding potentials to those in putamen and temporal cortex (Table 2) revealed that the in vivo binding potentials have a similar proportional relationship to the density of sites measured in post-mortem brain (Figure 4).
DA D2/3 receptors are expressed in the human thalamus in a regionally specific manner. There was a good correlation between the densities of D2-like receptors as revealed by in vitro (autoradiographic) and in vivo (PET) measures. D2-like-binding sites were present in relatively high densities in so-called ‘nonspecific’ thalamic nuclei, but were present in relatively low density in motor nuclei. The highest densities of D2-like receptors were present in thalamic nuclei that project to the striatal complex and mesocorticolimbic DA terminal fields, suggesting that thalamic D2-like receptors are in a position to modulate limbic and basal ganglia function. This observation is consistent with a variety of data pointing to the involvement of thalamic DA systems in neuropsychiatric disorders.
Epidepride ligands have been used extensive for both in vitro and in vivo studies assessing the distribution and levels of D2-like DA receptors. [125I]Epidepride has a high affinity for D2 and D3 receptors but not D1, D2, or D4, α1 noradrenergic, 5-HT2a/c serotonergic, or GABAA sites (Kessler et al, 1993a, 1993b); approximately 10% of [125I]epidepride binding in certain cortical regions appears to reflect interaction with α2 noradrenergic receptors (Joyce et al, 1991). We did not distinguish between D2 and D3 receptors in our autoradiographic studies because we wanted these data to reflect as closely as possible thalamic D2/3-binding sites as seen in the PET studies.
The subjects used in our study were free of neurological or psychiatric disorders. They were also relatively young, thus minimizing any age-related declines in thalamic DA receptor densities (Inoue et al, 2001).
Comparison with Previous Studies
Our autoradiographic studies confirm and extend previous descriptions of the presence and distribution of D2-like receptor binding in the human thalamus. (Hall et al 1996a, 1997) used autoradiographic methods to describe the distribution of brain [125I]epidepride-binding sites. They noted that the greatest density of extrastriatal D2-like receptors was found in the thalamus, particularly in what they termed the PT. Our data agree well with this conclusion and indicate that the PVT and PT have the highest density of D2-like receptors in the thalamus. Our data extend the observations of Hall and colleagues by detailing the distribution of D2-like sites throughout the thalamus, both across and within individual thalamic nuclei. For example, we described the hitherto unappreciated pattern of binding in the mediodorsal nucleus, where we observed a moderate level of D2-like-binding sites in a distinct mediolateral gradient, upon which were superimposed ‘islands’ of high-density D2/3 binding.
Our [18F]fallypride PET data confirm the presence of D2-like-binding sites in the human brain. Previous SPECT (Kornbuher et al, 1995; Kuikka et al, 1997) and PET (Christian et al, 2000; Farde et al, 1997; Halldin et al, 1995; Mukherjee et al, 2001; Yousef et al, 1995) studies using various ligands have reported low-to-moderate densities of D2-like-binding sites in the thalamus. Consistent with the dopaminergic nature of these binding sites, Yousef et al (1995) reported that the D2-like antagonist haloperidol blocked thalamic radioligand accumulation.
Our PET imaging studies extend previous in vivo imaging studies of the thalamus by revealing a heterogeneous distribution of D2/3 receptors in the human thalamus with relatively high resolution. We found an anteroposterior gradient in [18F]fallypride accumulation, with the highest accumulation being seen in the rostral half of the dorsal midline thalamic nuclei, a region corresponding to the PVT and PT; in our autoradiographic data we found a significantly greater density of binding sites in the anterior half of the PVT. More caudally in the thalamus we observed relatively high accumulation of the radioligand in a lateral extension from the midline (in the vicinity of the reuniens nucleus) to the CM/PF complex.
Dopaminergic Receptors and the Dopaminergic Innervation of the Human Thalamus
Neither [125I]epidepride nor [18F]fallypride distinguish between D2 and D3 receptors. Both receptors appear to be present in the human thalamus, although the relative proportions of the two is unclear. Hall et al (1996b) failed to find any specific D3 receptor binding in the human thalamus, while Herroelen et al (1994) reported the presence of specific D3 but not D2-binding sites in the human thalamus. Gurevich and Joyce (1999) reported that both D3 receptors predominate in several thalamic areas, but in some areas (central lateral and central medial nuclei) only D2 sites are present; they did not examine the PVT and PT because blocking of the brain cut through the midline thalamus. D2-like mRNAs have been reported in the human thalamus, with some neurons of the midline, anteroventral, and mediodorsal nuclei expressing both D3 and D2 mRNAs (Gurevich and Joyce, 1999). It seems likely that the relatively minor discrepancies concerning D2/3 receptor distributions in the human thalamus reflect the use of different ligands (Flietstra and Levant, 1998; Hall et al, 1996b, 1997). Although additional studies are needed to clarify the relative contribution of D2 and D3 receptors to the total pool of thalamic D2-like-binding sites, most studies suggest that D3 receptors are relatively enriched in the midline and anteroventral nuclei, whereas D2 receptors may be more abundant in other thalamic nuclei.
We have focused our studies on D2-like receptors in the thalamus, and did not examine D1-like receptors, including D1 and D5 receptors. Previous studies have indicated that there is diffuse low abundance thalamic expression of D1 receptor mRNA in primate species, including humans (Choi et al, 1995; Meador-Woodruff et al, 1999). However, some thalamic nuclei in humans, including several in which we observed relatively high D2-like receptor gene expression (dorsomedial, anterior, central medial), express D1 mRNA at somewhat higher levels than others (reticular and ventral nuclei) (J Meador-Woodruff, personal communication). Expression of the D5 transcript is very low in the thalamus.
The presence of DA-like receptors in the human thalamus implies the presence of a thalamic DA innervation. In the rat there is a discrete DA innervation of the midline thalamic nuclei, particularly the PVT; the density of DA-immunoreactive fibers decreases sharply in more ventral midline nuclei and at the PVT–MD border (Groenewegen, 1988). DA axons in the rat PVT arise predominantly from hypothalamic sources, although a few ventral tegmental area DA neurons also project to the PVT (Otake and Nakamura, 1998; Takada et al, 1990). In the human thalamus early data on thalamic DA was ambiguous. Oke et al (1992) reported very low tissue concentrations of DA in the human thalamus, comparable to that present as a precursor pool in the noradrenergic and adrenergic thalamic innervations (Bosler et al, 1987; Rico and Cavada, 1998). However, post-mortem studies sharply underestimate DA concentrations relative to concentrations of the amine in biopsy samples obtained during surgical interventions (Goldstein et al, 1988). An in vivo microdialysis study of the human thalamus in PD patients reported that extracellular DA levels could be reliably detected in the thalamus (Meyerson et al, 1990). Recent anatomical studies found a significant density of dopamine transporter (DAT)-like immunoreactive axons in the thalamus, particularly the midline/intralaminar nuclei and the MD (Freeman et al, 2001; Melchitzky and Lewis, 2001). These observations are consistent with PET data suggesting the presence of DAT-binding sites in the human thalamus (Gunther et al, 1997), and the finding that methylphenidate administration reduces [11C]raclopride binding in the thalamus (Volkow et al, 1997), consistent with displacement of the radioligand by released DA.
There are some mismatches between the distribution of D2/3 receptors as revealed by our autoradiographic studies and the distribution of the human thalamic DA innervation as revealed by DAT immunohistochemistry. We found that the density of D2/3 receptors in the MD followed a mediolateral gradient, but DAT-immunoreactive axons are localized most densely to the lateral and ventral MD (Freeman et al, 2001; Melchitzky and Lewis, 2001), and are in low density in the medial MD and virtually absent from the midline nuclei. Similarly, we found that the D2/3 receptors in the reticular nucleus were present in very low density but most apparent in the ventral reticular nucleus, whereas DAT-immunoreactive axons are distributed more heavily to the middle third of the nucleus. It appears most likely that these discrepancies are due to the use of DAT as a marker of DA neurons. DAT mRNA levels are low or below detection thresholds in cells of the medial VTA (Little et al, 1998), and similarly some midbrain DA neurons (especially in the medial VTA) are not DAT immunoreactive (Ciliax et al, 1999).
The adjective ‘nonspecific’ is a misnomer when applied to the midline/intralaminar nuclei (Groenewegen and Berendse, 1994). The efferent projections of different midline and intralaminar thalamic nuclei are to regionally distinct regions in the forebrain (Berendse and Groenewegen, 1990, 1991; Krout et al, 2002; Moga et al, 1995; Su and Bentivoglio, 1990), and relatively few of the neurons in these nuclei collateralizing to innervate multiple targets (Bubser and Deutch, 1998; Calderazzo et al, 1996). Among the projection targets of the midline/intralaminar nuclei are distinct territories in the striatal complex, prefrontal cortex, amygdala, and hippocampus (Berendse and Groenewegen, 1990; Bubser and Deutch, 1998; Calderazzo et al, 1996; Jayaraman, 1985). These areas also all receive DA inputs from the midbrain (Deutch et al, 1988, Moore and Bloom, 1978; Swanson, 1982). The thalamic neurons that project to forebrain DA terminal field regions are glutamatergic (Christie et al, 1987; Fuller et al, 1987) and can readily influence dopaminergic function (Calabresi et al, 1997; Whitton, 1997).
The origins of DA inputs to thalamic nuclei in the human are not known. The widespread distribution of thalamic D2-like receptors suggests that there may be a comparably broad distribution of DA afferents to the human thalamus. The PVT and other midline/intralaminar nuclei have long been known to receive information from brainstem reticular formation neurons (Jasper, 1949; Krout et al, 2002; Niimi et al, 1990). Single cholinergic reticular formation neurons collateralize to innervate both the PVT and ventral tegmental area (Bolton et al, 1993), thus providing a means by which reticular core information can directly (through the ventral tegmental area) and indirectly (via PVT projections to forebrain DA terminal fields) regulate forebrain dopaminergic function. These anatomical data suggest that signaling through DA receptors on midline thalamic neurons may convey information to mesocorticolimbic DA terminal fields, particularly the frontal cortices, and thus potentially be involved in the attention deficits seen in schizophrenia (Kornetsky and Orzack, 1978; Matthysse, 1978). Consistent with this speculation is the fact that neurons of the PVT and other midline/intralaminar nuclei are targets of atypical antipsychotic drugs (Cohen et al, 1998; Deutch et al, 1995). In addition, several recent studies have reported decreased numbers of neurons in the mediodorsal nucleus (Pakkenberg, 1990; Popken et al, 2000, Young et al, 2000).
A number of findings suggest that DA D3 receptors in midline thalamic nuclei may play an important role in the actions of psychostimulants (see Deutch et al, 1998). Among the afferents to the midline nuclei are those arising from the hypothalamus and nucleus tractus solitarius (Krout et al, 2002; Ruggiero et al, 1998), which relay interoceptive information to the PVT and thus allow the PVT to integrate exteroceptive (via the reticular formation) and interoceptive cues. The ability to coordinate afferent activity conveying both exteroceptive and interoceptive information may be of critical importance in drug abuse, and lesions of the PVT block the conditioned locomotor response associated with cocaine administration (Young and Deutch, 1998). Although neurons in many brain areas are activated in response to acute cocaine challenge, the PVT is among the few sites that is activated in animals exposed to a neutral stimulus that was previously paired with cocaine (Brown et al, 1992). These data and corresponding in vivo imaging data (Volkow et al 1997; Wang et al, 1997) argue for medial thalamic involvement in the drug craving cued by environmental stimuli.
There has been considerable interest in thalamic involvement in PD because the basal ganglia gain access to the cortex via the thalamus. Recent data indicate that thalamic involvement may be more widespread in PD than previously suspected. Thus, in addition to imaging data indicating changes in ventrolateral thalamic regional cerebral blood in response to L-DOPA that are associated with movement (Feigin et al, 2002; Hershey et al, 1998; Pakkenberg, 1990; Popken et al, 2000; Young et al, 2000), changes in midline/intralaminar nuclei have also been found. Henderson et al (2000) reported a striking decrease in the numbers of neurons in the CM/PF complex in PD patients. Moreover, recent data suggest the involvement of specific thalamic dopaminergic systems. The density of DAT-immunoreactive axons is decreased in the thalamic reticular nucleus of PD patients (Freeman et al, 2001), and in vivo imaging data indicate a decrease in D2-like receptor density in the medial thalamus of patients with advanced but not early PD (Kaasinen et al, 2000).
One final function in which thalamic DA receptors may play a role is pain perception. The thalamus is a key nociceptive relay, and electrophysiological studies have revealed that neurons in the CM/PF complex respond to nociceptive stimuli (Dong et al, 1978; Willis, 1985). The presence of D2-like receptors in the CM/PF complex offers a mechanism for the reported involvement of dopaminergic systems in the subjective components of pain (Chudler and Dong, 1995; Kamei and Saitoh, 1996). However, a recent imaging study of striatal and extrastriatal DA receptors reported that the D2 binding potential in the putamen but not thalamus is associated with pain responses (Hagelberg et al, 2002). It is possible that intralaminar thalamic neurons respond to DA and convey this information to the striatum (Matsumoto et al, 2001).
DA D2-like receptors were present in moderately high density in several nuclei of the human thalamus. The pattern of expression of D2-like receptors was heterogeneous, being most enriched in the midline and intralaminar nuclei that give rise to limbic forebrain regions. The presence of these D2-like receptors suggests that dopaminergic mechanisms may play an important role in neuropsychiatric disorders that involve a dysfunction of thalamocortical and thalamostriatal systems.
Andreasen NC (1997). The role of the thalamus in schizophrenia. Can J Psychiatry 42: 27–33.
Berendse HW, Groenewegen HJ (1990). Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum. J Comp Neurol 299: 187–228.
Berendse HW, Groenewegen HJ (1991). Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42: 73–102.
Bolton RF, Cornwall J, Phillipson OT (1993). Collateral axons of cholinergic pontine neurones projecting to midline, mediodorsal and parafascicular thalamic nuclei in the rat. J Chem Neuroanat 6: 101–114.
Bosler O, Beaudet A, Denoroy L (1987). Electron-microscopic characterization of adrenergic axon terminals in the diencephalon of the rat. Cell Tissue Res 248: 393–398.
Brown EE, Robertson GS, Fibiger HC (1992). Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures. J Neurosci 12: 4112–4121.
Bubser M, Deutch AY (1998). Thalamic paraventricular nucleus neurons collateralize to innervate the prefrontal cortex and nucleus accumbens. Brain Res 787: 304–310.
Buchsbaum MS, Someya T, Teng CY, Abel L, Chin S, Najafi A et al (1996). PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 153: 191–199.
Byne W, Buchsbaum MS, Mattiace LA, Hazlett EA, Kemether E, Elhakem SL et al (2002). Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia. Am J Psychiatry 159: 59–65.
Calabresi P, Pisani A, Centonze D, Bernardi G (1997). Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum. Neurosci Biobehav Rev 21: 519–523.
Calderazzo L, Cavalheiro EA, Macchi G, Molinari M, Bentivoglio M (1996). Branched connections to the septum and to the entorhinal cortex from the hippocampus, amygdala, and diencephalon in the rat. Brain Res Bull 40: 245–251.
Choi WS, Machida CA, Ronnekleiv OK (1995). Distribution of dopamine D1, D2, and D2 receptor mRNAs in the monkey brain: ribonuclease protection assay analysis. Mol Brain Res 31: 86–94.
Christian BT, Narayanan TK, Shi B, Mukherjee J (2000). Quantitation of striatal and extrastriatal D-2 dopamine receptors using PET imaging of [(18)F]fallypride in nonhuman primates. Synapse 38: 71–79.
Christie MJ, Summers RJ, Stephenson JA, Cook CJ, Beart PM (1987). Excitatory amino acid projections to the nucleus accumbens septi in the rat: a retrograde transport study utilizing D[3H]aspartate and [3H]GABA. Neuroscience 22: 425–439.
Chudler EH, Dong WK (1995). The role of the basal ganglia in nociception and pain. Pain 60: 3–38.
Ciliax BJ, Drash GW, Staley JK, Haber S, Mobley CJ, Miller GW et al (1999). Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol 409: 38–56.
Cohen BM, Wan W, Froimowitz MP, Ennulat DJ, Cherkerzian S, Konieczna H (1998). Activation of midline thalamic nuclei by antipsychotic drugs. Psychopharmacology (Berl) 135: 37–43.
Cohen BM, Yurgelun-Todd D (2001). Alterations of thalamic activity in schizophrenia and in response to antipsychotic drugs: studies in the legacy of Seymour S. Kety. Neuropsychopharmacology 25: 305–312.
Delforge J, Bottlaender M, Loc'h C, Dolle F, Syrota A (2001). Parametric images of the extrastriatal D2 receptor density obtained using a high-affinity ligand (FLB 457) and a double-saturation method. J Cereb Blood Flow Metab 21: 1493–1503.
Deutch AY, Bubser M, Young CD (1998). Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus. J Neurosci 18: 10680–10687.
Deutch AY, Goldstein M, Baldino Jr F, Roth RH (1988). The telencephalic projections of the A8 dopamine cell group. Ann NY Acad Sci 537: 27–50.
Deutch AY, Ongur D, Duman RS (1995). Antipsychotic drugs induce Fox protein in the thalamic paraventricular nucleus: a novel locus of antipsychotic drug action. Neuroscience 66: 337–346.
Dong WK, Ryu H, Wagman IH (1978). Nociceptive responses of neurons in medial thalamus and their relationship to spinothalamic pathways. J Neurophysiol 41: 1592–1613.
Farde L, Suhara T, Nyberg S, Karlsson P, Nakashima Y, Hietala J et al (1997). A PET-study of [11C]FLB 457 binding to extrastriatal D2-dopamine receptors in healthy subjects and antipsychotic drug-treated patients. Psychopharmacology (Berl) 133: 396–404.
Feigin A, Ghilardi MF, Fukuda M, Mentis MJ, Dhawan V, Barnes A et al (2002). Effects of levodopa infusion on motor activation responses in Parkinson's disease. Neurology 59: 220–226.
Filion M (2000). Physiologic basis of dyskinesia. Ann Neurol 47: S35–S40; discussion S-1.
Flietstra RJ, Levant B (1998). Comparison of D2 and D3 dopamine receptor affinity of dopaminergic compounds in rat brain. Life Sci 62: 1825–1831.
Freeman A, Ciliax B, Bakay R, Daley J, Miller RD, Keating G et al (2001). Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models. Ann Neurol 50: 321–329.
Fuller TA, Russchen FT, Price JL (1987). Sources of presumptive glutamergic/aspartergic afferents to the rat ventral striatopallidal region. J Comp Neurol 258: 317–338.
Goldstein M, Lieberman AN, Helmer E, Koslow M, Ransohoff J, Elsworth JD et al (1988). Biochemical analysis of caudate nucleus biopsy samples from parkinsonian patients. Am Neurol 24: 685–688.
Groenewegen HJ (1988). Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography. Neuroscience 24: 379–431.
Groenewegen HJ, Berendse HW (1994). The specificity of the ‘nonspecific’ midline and intralaminar thalamic nuclei. Trends Neurosci 17: 52–57.
Gunther I, Hall H, Halldin C, Swahn CG, Farde L, Sedvall G (1997). [125I] beta-CIT-FE and [125I] beta-CIT-FP are superior to [125I] beta-CIT for dopamine transporter visualization: autoradiographic evaluation in the human brain. Nucl Med Biol 24: 629–634.
Gurevich EV, Joyce JN (1999). Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 20: 60–80.
Hagelberg N, Martikainen I, Mansikka H, Hinkka S, Nagren K, Hietala J et al (2002). Dopamine D2 receptor binding in the human brain is associated with the response to painful stimulation and pain modulatory capacity. Pain 99: 273.
Hall H, Farde L, Halldin C, Hurd YL, Pauli S, Sedvall G (1996a). Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride. Synapse 23: 115–123.
Hall H, Halldin C, Dijkstra D, Wikstrom H, Wise LD, Pugsley TA et al (1996b). Autoradiographic localisation of D3-dopamine receptors in the human brain using the selective D3-dopamine receptor agonist (+)-[3H]PD 128907. Psychopharmacology (Berl) 128: 240–247.
Hall H, Halldin C, Jerning E, Osterlund M, Farde L, Sedvall G (1997). Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors. Nucl Med Biol 24: 389–393.
Halldin C, Farde L, Hogberg T, Mohell N, Hall H, Suhara T et al (1995). Carbon-11-FLB 457: a radioligand for extrastriatal D2 dopamine receptors. J Nucl Med 36: 1275–1281.
Henderson JM, Carpenter K, Cartwright H, Halliday GM (2000). Degeneration of the centre median-parafascicular complex in Parkinson's disease. Ann Neurol 47: 345–352.
Herroelen L, De Backer JP, Wilczak N, Flamez A, Vauguelin G, De Keyser J (1994). Autoradiographic distribution of D3-type dopamine receptors in human brain using [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin. Brain Res 648: 222–228.
Hershey T, Black KJ, Stambuk MK, Carl JL, McGee-Minnich LA, Perlmutter JS (1998). Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias. Proc Natl Acad Sci USA 95: 12016–12021.
Ilinksy IA, Jouandet ML, Goldman-Rakic PS (1985). Organization of the nigrothalamocortical system in the rhesus monkey. J Comp Neurol 236: 315–330.
Inoue M, Suhara T, Sudo Y, Okubo Y, Yasuno F, Kishimoto T et al (2001). Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life Sci 69: 1079–1084.
Jasper H (1949). Diffuse projection systems: the integrative action of the thalamic reticular system. EEG Clin Neurophysiol 1: 405–419.
Jayaraman A (1985). Organization of thalamic projections in the nucleus accumbens and the caudate nucleus in cats and its relation with hippocampal and other subcortical afferents. J Comp Neurol 231: 396–420.
Joyce JN, Janowsky A, Neve KA (1991). Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain. J Pharmacol Exp Ther 257: 1253–1263.
Kaasinen V, Nagren K, Hietala J, Oikonen V, Vilkman H, Farde L et al (2000). Extrastriatal dopamine D2 and D3 receptors in early and advanced Parkinson's disease. Neurology 54: 1482–1487.
Kamei J, Saitoh A (1996). Involvement of dopamine D2 receptor-mediated functions in the modulation of morphine-induced antinociception in diabetic mouse. Neuropharmacology 35: 273–278.
Kessler RM, Mason NS, Jones C, Price RC, Manning RG et al (1997). In vivo quantitation of striatal and extrastriatal dopamine D2 receptors in human brain using PET and [18F]N-allyl-5-fluoropropylepidepride. J Nucl Med 38: 1214.
Kessler RM, Votaw JR, Schmidt DE, Ansari MS, Holdeman KP, de Paulis T et al (1993a). High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain. Life Sci 53: 241–250.
Kessler RM, Whetsell WO, Ansari MS, Votaw JR, de Paulis T, Clanton JA et al (1993b). Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride. Brain Res 609: 237–243.
Kornbuher J, Brucke T, Angelberger P, Asenbaum S, Podreka I (1995). SPECT imaging of dopamine receptors with [123I]epidepride: characterization of uptake in the human brain. J Neural Transm Gen Sect 101: 95–103.
Kornetsky C, Orzack MH (1978). Physiological and behavioral correlates of attention dysfunction in schizophrenic subjects. In: Wynne LC, Cromwell RL, Matthysse S (eds). The Nature of Schizophrenia. John Wiley and Sons: New York. pp 196–204.
Krout KE, Belzer RE, Loewy AD (2002). Brainstem projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol 448: 53–101.
Kuikka JT, Akerman KK, Hiltunen J, Bergstrom KA, Rasanen P, Vanninen E et al (1997). Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography. Eur J Nucl Med 24: 483–487.
Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ et al (1996). Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 16: 42–52.
Little KY, McLaughlin DP, Zhang L, McFinton PR, Dalack GW, Cook Jr EH et al (1998). Brain dopamine transporter messenger RNA and binding sites in cocaine users: a postmortem study. Arch Gen Psychiatry 55: 793–799.
Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997). Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16: 187–198.
Mai JK, Assheuer J, Paxinos G (1997). Atlas of the Human Brain. Academic Press: San Diego.
Matsumoto N, Minamimoto T, Graybiel AM, Kimura M (2001). Neurons in the thalamic CM-Pf complex supply striatal neurons with information about behaviorally significant sensory events. J Neurophysiol 85: 960–976.
Matthysse S (1978). A theory of the relationship between dopamine and attention. In: Wynne LC, Cromwell RL, Matthysse S (eds). The Nature of Schizophrenia. John Wiley and Sons: New York. pp 307–310.
Meador-Woodruff JH, Ibrahim HM, Richardson-Burns SM, Haroutunian V, Davis KL, Watson SJ (1999). Dopamine receptor transcript expression in schizophrenic thalamus. Biol Psychiatry 45: 28S–29S.
Melchitzky DS, Lewis DA (2001). Dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of the macaque monkey. Neuroscience 103: 1033–1042.
Meyerson BA, Linderoth B, Karlsson H, Ungerstedt U (1990). Microdialysis in the human brain: extracellular measurements in the thalamus of parkinsonian patients. Life Sci 46: 301–308.
Moga MM, Weis RP, Moore RY (1995). Efferent projections of the paraventricular thalamic nucleus in the rat. J Comp Neurol 359: 221–238.
Moore RY, Bloom FE (1978). Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. Annu Rev Neurosci 1: 129–169.
Mukherjee J, Christian BT, Narayanan TK, Shi B, Mantil J (2001). Evaluation of dopamine D-2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride. Neuropsychopharmacology 25: 476–488.
Niimi K, Kusunose M, Ono K, Yanagihara M (1990). Brainstem afferents to the intralaminar nuclei of the cat thalamus studied by the horseradish peroxidase method. J Hirnforsch 31: 107–122.
Oke AF, Putz C, Adams RN, Bird ED (1992). Neuroleptic treatment is an unlikely cause of elevated dopamine in thalamus of schizophrenic subjects. Psychiatry Res 45: 203–208.
Otake K, Nakamura Y (1998). Single midline thalamic neurons projecting to both the ventral striatum and the prefrontal cortex in the rat. Neuroscience 86: 635–649.
Pakkenberg B (1990). Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 47: 1023–1028.
Popken GJ, Bunney Jr WE, Potkin SG, Jones EG (2000). Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci USA 97: 9276–9280.
Rico B, Cavada C (1998). Adrenergic innervation of the monkey thalamus: an immunohistochemical study. Neuroscience 84: 839–847.
Ruggiero DA, Anwar S, Kim J, Glickstein SB (1998). Visceral afferent pathways to the thalamus and olfactory tubercle: behavioral implications. Brain Res 799: 159–171.
Staley JK, Mash DC (1996). Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci 16: 6100–6106.
Su HS, Bentivoglio M (1990). Thalamic midline cell populations projecting to the nucleus accumbens, amygdala, and hippocampus in the rat. J Comp Neurol 297: 582–593.
Swanson LW (1982). The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9: 321–353.
Takada M, Campbell KJ, Moriizumi T, Hattori T (1990). On the origin of the dopaminergic innervation of the paraventricular thalamic nucleus. Neurosci Lett 115: 33–36.
Turner BH, Herkenham M (1991). Thalamoamygdaloid projections in the rat: a test of the amygdala's role in sensory processing. J Comp Neurol 313: 295–325.
Volkow ND, Ding YS, Fowler JS, Wang GJ (1996). Cocaine addiction: hypothesis derived from imaging studies with PET. J Addict Dis 15: 55–71.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R et al (1997). Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386: 830–833.
Wang GJ, Volkow ND, Fowler JS, Logan J, Abumrad NN, Hitzemann RJ et al (1997). Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology 16: 174–182.
Whitton PS (1997). Glutamatergic control over brain dopamine release in vivo and in vitro. Neurosci Biobehav Rev 21: 481–488.
Willis WD (1985). Nociceptive pathways: anatomy and physiology and nociceptive ascending pathways. Philos Trans R Soc Lond B Biol Sci 308: 253–270.
Young CD, Deutch AY (1998). The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization. Pharmacol Biochem Behav 60: 753–758.
Young KA, Manaye KF, Liang C, Hicks PB, German DC (2000). Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 47: 944–953.
Yousef KA, Volkow ND, Schlyer DJ, Fowler JS, Wolf AP, Wang GJ et al (1995). Haloperidol blocks the uptake of [18F]N-methylspiroperidol by extrastriatal dopamine receptors in schizophrenic patients. Synapse 19: 14–17.
This work was supported in part by Grants MH 46943 and MH 60890 (RMK), MH 45124, MH 57995, and NS 44282 (AYD), and by the National Parkinson Foundation Center of Excellence at Vanderbilt University.
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Rieck, R., Ansari, M., Whetsell, W. et al. Distribution of Dopamine D2-Like Receptors in the Human Thalamus: Autoradiographic and PET Studies. Neuropsychopharmacol 29, 362–372 (2004). https://doi.org/10.1038/sj.npp.1300336
- prefrontal cortex
- midline thalamic nuclei
- paraventricular thalamic nucleus
- parkinson's disease
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