Distribution of Dopamine D2-Like Receptors in the Human Thalamus: Autoradiographic and PET Studies

Rieck, Richard W.; Ansari, M. Sib; Whetsell, William O.; Deutch, Ariel Y.; Kessler, Robert

doi:10.1038/sj.npp.1300336

Cited by 86 publications

(62 citation statements)

References 84 publications

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“…18 F]fallypride binding potentials in extrastriatal regions of human brain, including the substantia nigra, with quantitative autoradiographic measurements of DA D 2 r levels in post-mortem human brain (Rieck et al, 2004). The sensitivity of DA D 2 r occupancy measurements for the substantia nigra is demonstrated by the differences in occupancies seen for clozapine and quetiapine in the current study as well as the significant differences in nigral occupancy.…”

Section: Discussionmentioning

confidence: 50%

Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine

Kessler

Ansari

Riccardi

et al. 2006

Neuropsychopharmacol

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117

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Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D 2 receptors (DA D 2 r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D 2 r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D 2 r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D 2 r using PET with [18 F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D 2 r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D 2 r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D 2 r, 59.8% (p ¼ 0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p ¼ 0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D 2 r, 46.9% (p ¼ 0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D 2 r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D 2 r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D 2 r, sparing occupancy of substantia nigra receptors, and non-DA D 2 r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.

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Section: Discussionmentioning

confidence: 50%

Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine

Kessler

Ansari

Riccardi

et al. 2006

Neuropsychopharmacol

Self Cite

117

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“…There was no change in V ND (cerebellum V T ) on aripiprazole compared to baseline in the six subjects with arterial access during both scans ( ( Lahti et al, 1995;Rieck et al, 2004). At baseline, extrastriatal uptake was about 5% of striatal uptake (see Figure 2 and left 'baseline' panel of Figure 3, where the average baseline [ 18 F]fallypride BP ND computed on a voxelwise basis using the SRTM across the nine patients in group A is displayed in a common anatomic space).…”

Section: Resultsmentioning

confidence: 99%

Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D2 Receptors by Aripiprazole in Schizophrenia with PET and [18F]Fallypride

Kegeles

Slifstein

Frankle

et al. 2008

Neuropsychopharmacol

125

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Positron emission tomography (PET) and the high affinity D 2/3 radiotracer [18 F]fallypride allow the assessment of D 2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D 2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR + camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6 ± 5.5% at 2 mg/day to 96.8 ± 5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D 2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

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“…2). Moreover, D 2 -like dopamine receptor binding sites have been shown in the human thalamus using in vivo radioligands, with a distribution that resembles that of the dopamine innervation described here (Rieck et al, 2004). Finally, dopamine and D 1 -like and D 2 -like dopamine receptor agonists modulate visual responses of the cat dorsal lateral geniculate thalamic nucleus (Zhao et al, 2001(Zhao et al, , 2002).…”

Section: Discussionmentioning

confidence: 99%

The Primate Thalamus Is a Key Target for Brain Dopamine

Sánchez-González

García‐Cabezas²,

Rico³

et al. 2005

J. Neurosci.

258

187

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The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.

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Distribution of Dopamine D2-Like Receptors in the Human Thalamus: Autoradiographic and PET Studies

Cited by 86 publications

References 84 publications

Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine

Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine

Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D2 Receptors by Aripiprazole in Schizophrenia with PET and [18F]Fallypride

The Primate Thalamus Is a Key Target for Brain Dopamine

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