[¹⁸F]fallypride PET measurement of striatal and extrastriatal dopamine D_2/3 receptor availability in recently abstinent alcoholics

Abstract

Positron emission tomography (PET) shows reduced binding of the dopamine D(2/3) antagonist [(11) C]raclopride in striatum of withdrawn psychostimulant abusers, but not consistently in patients with alcohol dependence (AD). We make first use of the high affinity ligand [(18) F]fallypride to obtain serial measures of D(2/3) receptor availability in striatal and extrastriatal regions of AD patients undergoing detoxification. Seventeen patients (mean age 44 ± 5y) with AD and 14 age-matched healthy volunteers participated. Each patient underwent [(18) F]fallypride PET upon hospital admission, and again 1-2 weeks later; two patients achieving abstinence, and two with substantial harm reduction had additional PET follow-up at 1 year. Dynamic 180-minute PET recordings were used for volume of interest (VOI)-based and voxel-wise analysis of [(18) F]fallypride binding potential (BP(ND) ). Mean baseline BP(ND) in striatum of the AD patients (15.7 ± 3.6) was unaltered during short-term follow-up, and did not differ from that in healthy controls (16.8 ± 3.0); however, BP(ND) was 10-20% lower in thalamus, hippocampus, and insular and temporal cortex of the AD patients (P < 0.05). Age-dependent declines in BP(ND) were very small in controls, but more pronounced and widespread in the AD group. Striatal and thalamic BP(ND) increased by 30% in four patients with long-term abstinence or reduced alcohol consumption. VOI-based [(18) F]fallypride PET analyses revealed group differences in D(2/3) receptor availability primarily in extra-striatal regions. Age-related loss of dopamine D(2/3) receptors was more pronounced in AD patients. Receptor availability was unaltered by acute withdrawal, but increased in the subgroup of patients with long-term follow-up, suggesting reversibility of receptor changes.

Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence

“…Experimental support for this view comes from animal work (35) and human PET studies that found reduced availability of striatal D2-like receptors compared with controls (10)(11)(12)(13)(14)(15)(16). Because these PET studies do not provide a coherent picture (20)(21)(22), we used saturated receptor autoradiography techniques to measure the number of DA receptor and DAT-binding sites in postmortem brain tissues of alcoholics and controls. Surprisingly, we found a highly significant reduction in both D1-and DAT-binding sites in striatal tissue but no change in D2-like binding; these results imply a hyperrather than a hypodopaminergic state, especially in protracted abstinence.…”

“…Control animals show an increase in extracellular DA levels after ethanol (2 g/kg, i.p. ), whereas alcohol-dependent rats show a blunted response to the treatment (n = with healthy controls (22). In vivo data for D1 are not available for alcoholics.…”

“…However, this interpretation of in vivo receptor availability seen in PET studies is inherently ambiguous, because decreased signal can be caused either by a reduced number of receptors or by increased ligand concentration. Furthermore, unchanged or even increased striatal D2-like binding in alcohol-abstinent patients has been found also (20)(21)(22). Naltrexone, one of the few medications approved by US Food and Drug Administration for treatment of relapse, reduces alcohol-induced accumbal DA release (23), and this effect seems argue against the importance of a hypodopaminergic state for increased propensity for relapse.…”

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

“…Studies assessing the effect of prolonged alcohol abstinence on the regulation of DRD2/3 binding (Heinz et al, 2004;Hietala et al, 1994;Volkow et al, 1996;Volkow et al, 2002) have generally not detected any signs of recovery. On the other hand, recently (Rominger et al, 2012) striatal DRD2/3 binding has been reported to increase significantly by 29% between the first day and 1 year of abstinence. Furthermore, it is interesting to note that in a recent [ 11 C]raclopride study by Martinez et al (2011), in cocaine addiction the patients who responded to contingency management treatment and thus remained abstinent did not differ from healthy controls in DRD2/3 levels measured pre-treatment.…”

Effects of acute detoxification of the herbal blend ‘Spice Gold’ on dopamine D2/3 receptor availability: A [18F]fallypride PET study

“…The [ 18 F]fallypride tracer synthesis as well as PET recording and image reconstruction methods are reported in detail elsewhere (Rominger et al, 2012). The entire attenuation, decay and motioncorrected emission sequence was spatially normalized to standard MNI coordinates.…”