Understanding the neurobiology of relapse to cocaine addiction and in related psychopathologies

• Applicant: Privatdozent Dr. Davide Amato, Ph.D.
• Subject Area: Biological Psychiatry
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320878203

As described in the research plan there are two main studies still ongoing in addition to new experiments we just started and that are briefly summarized in the supplementary section of the renewal. We have individuated the main results and now we are working on to achieve acceptable group size and parallelly to generate adequate control groups. In some cases, as in the calcium imaging studies, we are also working on refining the data analysis, which are quite complicated. In summary, in Study N. 1 we are working on defining the response patterns of the dopamine D1- and D2- expressing MSNs in the nucleus accumbens (NAcc) core in a substantial number of Cre-mice (see General Methods) on treatment with clinical equivalent doses of HAL alone an in combination with cocaine (see Research Plan and General Methods). In Study N.2 we hypothesize that HAL increases excitability of both D1- and D2-MSNs by facilitating glutamate transmission. (a) We found that an occlusion effect of HAL increases spike probability in both D1- and D2-MSNs of brain tissue collected from mice treated with chronic HAL (Figure 1A). We are currently completing this work. Based on these results we expect that the size and/or duration of excitatory facilitation will increase with duration of HAL treatment and also in combination with cocaine (HAL 14 days + 7 days abstinence + acute cocaine > HAL 14 days > HAL acute). Furthermore, we expect that blocking D2 receptors with HAL will increase sEPSC, whereas the D2 agonist quinpirole (2uM) will decrease EPSC in both D1- and D2-MSNs under a naïve condition, and this will be occluded after chronic HAL. If our prediction is correct, the data from this experiment will suggest that chronic HAL treatment increases glutamate transmission by disinhibiting presynaptic glutamate input onto NAcc D1- and D2-MSNs. (b) We found that HAL increases firing during both synaptic stimulation and post-synaptic current injections of D2 MSNs in naïve mice, and this can be occluded after chronic HAL treatment. This would suggest that HAL can increase D2 MSN excitability by either facilitating presynaptic glutamate transmission (Figure 1A) or by directly altering D2-MSN intrinsic excitability (Figure 1B). Based on the ongoing work we expect that bath application of HAL will increase the firing of D1 MSNs only during synaptic stimulation in naïve mice and this will be occluded after chronic HAL treatment. We are not sure how chronic HAL regimens alone or in combination with cocaine will affect the passive properties of D1 & D2-MSNs, but based on previous studies we expect that these adaptations will be consistent over the course of drug treatments. However, a different outcome cannot be ruled out since those studies were carried out using a different treatment procedure and dose for the delivering HAL.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Peter Kalivas, Ph.D.