Funded Projects

Methamphetamine (METH) abuse and dependence is a significant medical, psychiatric, and public health concern. Identifying effective pharmacotherapies for the management of METH abuse is a priority. The MT1 and MT2 melatonin receptor types are novel therapeutic targets for substance use disorders. Genetic deletion and antagonist induced blockade of these receptors prevent METH-induced locomotor sensitization. Realistically, genetic deletion of these receptors is not an ideal intervention, therefore using melatonin receptor antagonists (small molecules) could be an equivalent therapy. A current limitation of melatonin receptor antagonists is their short half-lives. Chemical structure modification is one possibility to make these antagonists longer acting compounds. However, the design, synthesis, pharmacological characterization and determination of pharmacokinetic parameters is costly, lengthy and impractical. An alternative approach is the development of a sustained release nanosuspension containing melatonin receptor antagonists, which provides a straightforward affordable approach to support our proof of concept studies. Slow release of antagonists from nanosuspensions/drug depots will allow for exposure of the drug over a long period of time mimicking the actions of putative long acting antagonists. The overall project goal is to synthesize a sustained release nanosuspension containing the small molecule luzindole (MT1/MT2 competitive melatonin receptor antagonist). Multiple long acting nanosuspensions/drug depots will be synthesized using 1) Hydrogels, 2) polyethylene glycol coated-liposomes, or 3) poly(lactic-co-glycolic acid) nanosuspensions. Encapsulation efficiency and release of luzindole from each nanosuspension will be determined. The optimized nanosuspension/drug depot will then be tested in mice to determine drug concentrations in plasma and brain tissues, followed by assessment of efficacy to block METH-induced sensitization over time.