Phosphodiesterase 7 inhibitors as novel therapeutic approach for substance use disorders

Substance use disorders are public health issue resulting millions of death worldwide (UNODC, 2023; World Health Organization, 2024). A major risk factor for developing maladaptive behaviors following the substance abuse is the social isolation stress in early adolescence (Le et al., 2021; Xiong et al., 2023). To the resolution of the public health burden due to the abuse of the substances such as alcohol and cocaine, the potential of phosphodiesterase 7 inhibitors in the management and possible treatment of substance use disorders has become a novel field of understanding in the neuroscience of addiction (Ciccocioppo et al., 2021; Gil et al., 2008). In the context, from the ethical perspective and considerations for an optimal treatment assessment, the animal models used to mimick the SUD-driven behaviors are implemented in the present study (Lynch et al., 2010; Spanagel, 2017), considering Wistar strain and Marchigian-Sardinian Alcohol preferring (msP) rats strains, as well as male and female C57BL/6J strain mice as the animal strains of choice in the studies. Thereafter, the treatment potential evaluation of the phosphodiesterase 7 inhibitors OMSPDE79 and OMSPDE71 are made considering a distinct range of dosage (from 0.1mcg/0.6mcl to 9mg/ml) and administration methods (intracranial and intraperitoneal). As a result to implementing adolescence social isolation protocol in male and female rats, the social isolation was effective to induce anxiety-like behaviors and further long-lasting alcohol seeking behaviors. What concerns to the effect of phosphodiesterase 7 inhibitors in the alcohol use disorder and cocaine use disorder behavior models, the OMSPDE71 was able to attenuate alcohol seeking behavior in the alcohol self-administration paradigm in msP rats, and it did not affect the behavior of the same strain animals in alcohol drinking two-bottle choice paradigm. Yet, the OMSPDE71 and OMSPDE79 were effective in attenuating alcohol deprivation phenomenon observed in the Wistar strain male and female rats. The molecules, conversely, did not affect the synaptic loss recovery and the further neuronal viability when tested for their effects in the mouse organotypic hippocampal slice cultures. When the effects of OMSPDE79 were evaluated in the cocaine seeking behaviors, the intraperitoneal injection of the molecule was effective in attenuating cue- and stress-induced relapse behaviors to cocaine seeking. In the context, the intracranial injections targeting the nucleus accumbens shell and the dorsolateral striatum, were ineffective, taken into account also for the molecule’s effects observed in the habitual cocaine seeking behavior management. In conclusion, the social isolation protocol implemented to test the long-term effects of adolescence social isolation stress in early adulthood alcohol drinking compulsivity has been successful. On the other hand, the OMSPDE71 in the highest 9mg/ml dose hasbeen effective in attenuating alcohol seeking behavior and alcohol deprivation phenomenon. In case of the OMSPDE79, in the highest 9mg/kg dose it has successfully attenuated not only the alcohol deprivation effect, but also the cocaine seeking active lever pressing in the cue- and stress-induced relapse. As a matter of fact, the findings are of crucial addition to the resolution of SUD management and treatment approaches.