Dopamine Receptor Imaging in Mood Disorders

The dopaminergic projections from the substantia nigra and the ventral tegmental area into the ventral striatum and medial prefrontal cortex (mPFC) play major roles in the neural processing underlying motivated behavior. Hypofunction of this system is hypothesized to underlie the anhedonia, psychomotor slowing and amotivation that characterize major depressive disorder (MDD; (Fibiger, 1991; Swerdlow and Koob, 1987). A variety of indirect evidence supports this hypothesis (Wilner, 1995) as: 1) Cerebrospinal fluid (CSF) concentrations of the DA metabolite, homovanillic acid, are reduced in nondelusional, depressives. 2) Dextroamphetamine (AMPH) improves mood in depressed patients, and direct DA receptor agonists (e.g. pramapaxil) and DA reuptake inhibitors (e.g. nomiphensine) exert antidepressant effects. 3) Many somatic antidepressant therapies enhance D(2/3) receptor sensitivity in limbic structures and/or increase interstitial DA concentrations in the mPFC and accumbens in rats. 4) Conditions in which DA is depleted increase the risk for developing major depression, and DA receptor antagonist administration produces dysphoria, avolition and fatigue in healthy humans.

In more direct assessments of DA receptor pharmacology, Suhara et al. (1992) reported an abnormal decrease in D1 receptor binding using [(11)C]SCH 23390 in the frontal cortex of bipolar subjects. However, [(11)C]SCH 23390 has some affinity for 5-HT(2) receptors in the frontal cortex (De Keyser et al.,1988) so the specificity of this result remains unclear. In contrast, [(11)C]NNC 112 is selective for D1 receptors and shows sufficient receptor selectivity to access D(1) receptor binding in the frontal cortex in mood disorders.

Previous studies of D(2) receptors using [(11)C]raclopride, [11C]NMSP and [(123)I]IBZM have been limited by the lack of sensitivity of those radioligands to receptors outside the striatum. Striatal D(2) receptor binding has been reported to be abnormally increased in psychotic bipolar subjects relative to both controls and non-psychotic bipolar subjects using [(11)C]NMSP (Pearlson et al., 1995) and unaltered in subjects with Major Depressive Disorder (MDD) compared to controls in two studies using [(123)I]IBZM (Klimke et al., 1999; Parsey et al., 2001). An increased basal ganglia-to-cerebellum ratio of D(2) receptor binding using [(123)I]IBZM has been reported in depressed MDD subjects compared to controls (D'Hanenen and Bossuyt, 1994; Ebert et al., 1996). SPECT imaging studies show that [(123)I]IBZM binding to striatal D(2/3) receptors is abnormally elevated in MDD. Although these studies were confounded by medication effects and small subject samples, because [(123)I]IBZM binding is sensitive to competition from endogenous DA, this abnormality could reflect reduced intrasynaptic DA levels in the striatum of MDD subjects.

The current study will address the limitations of the previous studies by characterizing D1 and D2 receptor binding in depression in extrastriatal, as well as striatal regions. PET measures of [11C]NNC 112 and [(18)F]fallypride binding to assess D(1) and D(2/3) receptor binding potential (BP), respectively, in unmedicated depressed subjects (part A). The 11C-Raclopride Bolus plus constant infusion (B/I) PET scan will assess D(2) receptor binding in vivo in the striatum while the subjects perform a monetary reward task, specifically designed to induce changes in the striatal dopaminergic transmission (part B).

The application of high resolution 3D PET and MRI-based region-of-interest analysis will permit specific assessment of abnormalities of the D(2/3) receptor system in currently depressed individuals with MDD and BD and of correlations with clinical ratings in ventral and dorsal striatum as well as in extrastriatal areas such as the amygdala, anterior cingulate cortex, medial prefrontal cortex and orbital cortex. Possible relationships of polymorphisms in the genes coding for elements of the dopaminergic system as well as the dopamine receptors being studied in MDD or BD with the level of binding detected will be investigated collecting preliminary data.