Summary

 

The systems-oriented approach of this program will suggest new potential anti-relapse drugs

(SP3, 5-8, 11). To help deciding which of those should to be tested in clinical trials, we here

suggest using a Human Test Platform for Anti-relapse Drugs (HTP-AD), whose components

were previously developed by us. The HTP-AD translates several animal behavioral paradigms

of alcohol self-administration (ASA) into corresponding human experiments.

 

In year 1-3, we will calibrate this platform against two drugs whose anti-relapse effect is well documented:

study A will test the opiate antagonist naltrexone 50 mg/d as a reference drug for validation. Study B will

test topiramate 300 mg/d, whose suggested mode of action is to dampen hyper-glutamatergic

activity through the blockade of AMPA receptors and L-type calcium channel currents. We will

use the obligatory 8-week dose escalation period to explore whether repeated HTP-AD testing

at different dosages can generate a first signal regarding the optimal dose.

 

Drug treatment will follow a randomized, double-blind, placebo-controlled parallel-group design.

Alcohol administration will be single-blind with respect to dose.

 

We previously demonstrated that for such experiments, model-based intravenous alcohol infusion

exhibits many advantages over oral ASA and therefore use it for the HTP-AD, which currently consists

of the following procedures: (i) free access ASA using computer-assisted self-infusion of ethanol (CASE) to test

alcohol “liking”, (ii) an ASA paradigm requiring work according to a progressive schedule to

make the next dose of ASA available, thereby testing “wanting” (iii) experimenter-controlled

alcohol infusion in a 3T-MR scanner using resting state fMRI and arterial spin labeling to assess

drug effect on alcohol-induced neural activity in the ventral striatum.

 

In year 4-5 we will apply the HTP-AD to test one new drug, which by then will be

suggested by data of the other SPs.