PET and microdialysis measurement of dopamine release in striatum and extrastriatal brain regions following amphetamine

Introduction:. The amphetamine challenge (AMPH) is a frequently used paradigm for estimating dopamine (DA) release non invasively in the brain by measuring changes in the specific binding of radioligands for the D2/D3 receptors. Previous studies have correlated the change in radioligand binding with DA efflux increases following AMPH as measured by microdialysis using radioligands that can only image the striatum such as C-11 raclopride or I-123 IBZM . Fallypride (C-11 or F-18) provides quantifiable images in striatum and extrastrial regions. In this study, we measured the correlation between changes in [11C] fallypride binding and DA efflux increases following AMPH in baboons. Methods:. Three female baboons (A, B and C) were studied under isoflurane anesthesia. Data were acquired for 2hr on the HR+ following a bolus injection of C-11 fallypride. A baseline scan was acquired, then after 1 additional hr, amphetamine was injected as a bolus in doses of 1 mg/kg (A, B) or 1.5 mg/kg (C). The post-challenge scan was started 1/2 hr after amphetamine. The parameter V3" was estimated under both conditions using SRTM with cerebellum as reference region. The change following amphetamine was quantified as ?V3? = V3?_post / V3?_ pre ? 1. Microdialysis was later performed on 2 of the animals (A and C) using the same anesthesia protocol. Probes were placed in striatum, anterior cingulate and thalamus and perfused with aCSF. After probe equilibration, dialysates were collected every 15 min. After 1 hr, animals received the same AMPH dose as during the PET study, and 3 more dialysates were collected. DA concentration was quantified by HPLC-ED. Post-AMPH values were expressed as % increase relative to mean pre-AMPH samples (ΔDA). Average regional ΔDA was correlated with ΔV3′ within and across subjects. Results: Regional ΔV3? was highly correlated with ΔDA, both within and across animals: ΔDA = -46.4* ΔV3? ? 7.7 for animal A (R_squared = 0.97), -12.6*ΔV3? +2.0 for animal C (R_squared = 0.80) and -21.7*ΔV3? -0.4 across all 3 animals (R_squared = 0.91). Mean ΔV3? was -19 +/- 10%, -9 +/- 7% and -3 +/- 17% and mean ΔDA was 406 +/- 72% 95 +/- 76% 73 +/-31% in striatum, thalamus and cingulate. Conclusions: : The high correlation between ΔV3? and ΔDA supports the validity of PET measurements of DA release following AMPH in extrastriatal regions as well as striatum using fallypride.