α2-adrenergic drugs modulate the binding of [18F]fallypride to dopamine D2/3 receptors in striatum of living mouse.

AIM: To test for alpha(2) adrenergic modulation of dopamine D(2/3) receptor availability in striatum of living mice using the high-affinity ligand [(18)F]fallypride and microPET. METHODS: Groups of anesthetized mice were pretreated with saline, the alpha(2)-agonist clonidine (1 mg/kg), and the alpha(2)-antagonists RX821002 (1 mg/kg) and yohimbine (1 mg/kg). Dynamic microPET recordings lasting 120 min were then initiated upon i.v. tracer injection of [(18)F]fallypride. Parametric maps of [(18)F]fallypride binding potential (BP(ND)) were calculated using the Logan method, with cerebellum serving as the reference region. RESULTS: Mean striatal [(18)F]fallypride BP(ND) was 10.6 +/- 1.7 in the saline control animals, 8.9 +/- 1.7 (-16%; P < 0.05) in the RX821002 group, 8.3 +/- 2.6 (-22%; P < 0.05) in the yohimbine group and 10.3 +/- 2.2 (n.s.) in the clonidine group. CONCLUSIONS: These findings are consistent with a tonic inhibition of dopamine release by alpha(2) adrenergic receptors, such that alpha(2) blockade increased the competition from endogenous dopamine at D(2/3) receptors, thus reducing the [(18)F]fallypride BP(ND) by about 20%. Absent effects of clonidine suggest a ceiling effect in the tonic inhibition of dopamine release. This in vivo PET evidence for alpha(2)/dopaminergic interaction may be relevant to putative actions of atypical antipsychotic medications via adrenergic receptors.

Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder.

BACKGROUND: In a previous study, binding of Tc-TRODAT-1 to the dopamine transporter (DAT) was found to be higher in patients with attention deficit hyperactivity disorder (ADHD) as compared to healthy controls. AIM: To determine whether the degree of Tc-TRODAT-1 binding to the striatal DAT may have a predictive role on the response to methylphenidate (MPH) in patients with ADHD. METHODS: Twenty-two adult patients suffering from ADHD underwent a brain SPECT scan with Tc-TRODAT-1. After the scan patients received MPH, individually medicated up to 60 mg.day. Severity of illness was estimated using the Clinical Global Impression (CGI-S) Scale before treatment. Ten weeks after the beginning of MPH treatment the improvement in global symptoms was rated by the Clinical Global Improvement Scale (CGI-I). RESULTS: Before treatment 17/22 patients with ADHD presented with higher striatal DAT binding as compared to age-matched healthy controls (+23.8%; P<0.01). After treatment with MPH a significant improvement of ADHD symptoms was demonstrated by the CGI-I in 16 of these 17 patients (CGI-S before: 4.8; CGI-I after MPH: 1.9; P<0.01). Five patients showed reduced DAT binding prior to therapy (-14.4%; P=0.04); these patients did not respond to MPH therapy (CGI-S before: 4.5; CGI-I after MPH: 4.2; P=0.40). CONCLUSION: Our findings suggest that ADHD patients with primarily elevated binding of Tc-TRODAT-1 to the striatal DAT responded better to therapy with MPH as compared to those with normal or low DAT binding. Consequently, our results - even if obtained on a small collective indicate that measurement of DAT may be an important prognostic predictor for therapy response to MPH.