Euphorigenic doses of cocaine reduce [123I]β-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

Abstract

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.

Positron emission tomography and its use to image the occupancy of drug binding sites

“…123 I]RTI-55 as the DAT radioligand suggested that a pharmacologically active dose of cocaine, injected after the radiotracer has reached a constant level in striatum and occipital cortex, occupied only 6% of the transporters [Malison et al, 1995]. Similar experiments in mice also indicated low occupancy of the DAT by cocaine when [ 123 I]RTI-55 was used to probe unoccupied DAT .…”

PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects

“…The neuroanatomical correlates of these stimulant euphorigenic mechanisms in the dopaminergic reward regions of the human brain is very important because it might provide new avenues for potential treatments (23). Despite this, we are aware of only one study that tried to correlate cocaineinduced euphoria with changes in dopamine concentration in human subjects (24).…”

[ 123 I]β-CIT SPECT imaging of dopamine transporter availability after mazindol administration in human cocaine addicts

“…Neuroreceptor imaging methods, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), permit the pharmacokinetics and receptor occupancy of drugs to be studied in clinical populations (Farde et al 1992;Volkow et al 1992;Malison et al 1995a). The application of such techniques to the measurement of mazindol's in vivo potency for DAT binding would help to inform medication development strategies aimed at treating cocaine abuse by DAT antagonism (Rothman 1990).…”