The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) subunit GluN2B are two central mediators of long-term potentiation (LTP), a form of synaptic plasticity thought to underlie both physiological and maladaptive addiction-related learning and memory.. The proposal will test the hypotheses that transient disruption of the CaMKII/GluN2B complex (a) persistently reverses amphetamine- and cocaine-induced addiction- related behavior and (b) acutely interferes with memory consolidation but does not reverse established memory. These hypotheses are based on recent preliminary data on addiction behavior and on recent results with "normal" LTP. Notably, the results of this study will be equally significant even if they lead to rejection of our hypotheses (for instance in case we instead find that inhibition of CaMKII activity is sufficient for reversal of addiction behavior, without requirement for disruption of th CaMKII/GluN2B complex).
(Aim 1) We will here first establish a pharmacological treatment that disrupts the CaMKII/GluN2B complex in vivo.
(Aim 2) Then, we will determine the effect of such treatment on reversal of addiction behavior. This will directly determine feasibility of a novel therapeutic approach to addiction.
(Aim 3) Finally, we will determine the effect on "normal" memory, which is also clinically important. Acute but reversible interference with memory acquisition and even erasure of recent not yet consolidated memory would be clinically acceptable side-effects. However, while an unexpected erasure also of already consolidated memory would be of high scientific impact, it would need to be overcome in therapy development (for instance by targeting a specific brain region, i.e. the NAc, which could be done but would require more intensive care). We will here utilize a highly rigorous pharmaco-genetic approach. While the pharmacological treatment enables determining the therapeutic relevance (by enabling the temporal distinction between prevention and reversal of addiction behavior), two specific mouse mutant will determine target-specificity: a CaMKII knock-out mouse will test for CaMKII-specificity, while a mouse with mutant GluN2B incapable of CaMKII binding will test for the CaMKII/GluN2B complex as the specific target. Importantly, this approach also overcomes potential compensatory effects that are frequently seen in mutant mice: If the mutant mice still develop addiction behavior (either to normal or to somewhat reduced levels) due to such compensatory effects, the pharmacological treatment should be no longer effective in these mice, if their mutation is indeed the relevant target of the treatment.
This project will test a novel pharmacological approach to persistently reverse addiction-related behavior (specifically for amphetamine and cocaine addiction). Importantly, this pharmacological approach does not involve a chronic treatment (which comes with inherent compliance problems), but instead an acute short-term treatment (eliminating such compliance problems). A treatment that successfully reverses mal-adaptive addiction-related learning and memory raises the question how it would affect normal learning and memory. This will be formally tested here, with the expectation that the treatment acutely interferes with learning abilities, but only during the actual treatment regimen and no longer on the following days. Such temporary and reversible learning deficit would be a highly acceptable side-effect. Regarding memory, the expectation is that the treatment may erase short-term memory of events 24-48 h before the treatment, but will not affect already consolidated long-term memory. Again, such short- but not long-range retrograde amnesia would be highly acceptable for a successful addiction therapy. By contrast, an unexpected erasure of long-range memory would be of high scientific interest but would pose a contra-indication that would need to be overcome in therapy development, for instance by brain-region specific application (which would be entirely feasible, but require more intensive care).
|Barcomb, Kelsey; Hell, Johannes W; Benke, Tim A et al. (2016) The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength. J Biol Chem 291:16082-9|
|Goodell, Dayton J; Eliseeva, Tatiana A; Coultrap, Steven J et al. (2014) CaMKII binding to GluN2B is differentially affected by macromolecular crowding reagents. PLoS One 9:e96522|
|Liu, Xiaojie; Liu, Yong; Zhong, Peng et al. (2014) CaMKII activity in the ventral tegmental area gates cocaine-induced synaptic plasticity in the nucleus accumbens. Neuropsychopharmacology 39:989-99|
|Barcomb, Kelsey; Coultrap, Steven J; Bayer, K Ulrich (2013) Enzymatic activity of CaMKII is not required for its interaction with the glutamate receptor subunit GluN2B. Mol Pharmacol 84:834-43|