We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEGhaloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [ 35 S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEGhaloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the biding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small

The choice of drug delivery carrier is of paramount importance for the fate of a drug in a human body. In this study, we have prepared the hybrid nanoparticles composed of FDA-approved Eudragit L100-55 copolymer and polymeric surfactant Brij98 to load haloperidol—an antipsychotic hydrophobic drug used to treat schizophrenia and many other disorders. This platform shows good drug-loading efficiency and stability in comparison to the widely applied platforms of mesoporous silica (MSN) and a metal–organic framework (MOF). ZIF8, a biocompatible MOF, failed to encapsulate haloperidol, whereas MSN only showed limited encapsulation ability. Isothermal titration calorimetry showed that haloperidol has low binding with the surface of ZIF8 and MSN in comparison to Eudragit L100-55/Brij98, thus elucidating the striking difference in haloperidol loading. With further optimization, the haloperidol loading efficiency could reach up to 40% in the hybrid Eudragit L100-55/Brij98 nanoparticles with high stability over several months. Differential scanning calorimetry studies indicate that the encapsulated haloperidol stays in an amorphous state inside the Eudragit L100-55/Brij98 nanoparticles. Using a catalepsy and open field animal tests, we proved the prolongation of haloperidol release in vivo, resulting in later onset of action compared to the free drug.

Introduction. Behavioral methods on laboratory animals are recognized as the main approach in studying the activity of potential psychotropic drugs and allow us to evaluate the main effects of new compounds, increase the possibility of predicting a successful outcome of future clinical trials.Text. This review article analyzes the main modern behavioral models in rodents that are widely used for screening and studying the pharmacological activity of potential psychotropic drugs. The advantages and disadvantages of each test are highlighted and complexes of behavioral methods are demonstrated that most conclusively confirm the reproducibility of the results obtained in clinical trials. The description and evaluation of behavioral methods that characterize the state of anxiety, which are used to screen for new compounds with anxiolytic activity (tests «Open field», «Dark-light chamber», «Elevated plus maze», «Sequence of rays»). The range of tests used to study cognitive functions and memory processes is widely presented (various mazes – T-shaped, U-shaped, radial maze, Barnes maze, E-maze; water mazes – Morris, T-maze) with a description of a comparative analysis and necessary conditions that ensure the reliability of information. An important direction in the field of behavioral pharmacology is the modeling of violations of social behavior and the study of approaches for its correction – the main methods necessary for the study of social behavior are presented in the review by the tests «Three-chamber social test», «Open field» extended test, etc.Conclusion. Behavioral pharmacology dictates the need for close interaction between preclinical and clinical stages of research in the framework of the development of translational medicine and the development of approaches that provide evidence for the reproducibility of the results obtained in clinical trials. It is also necessary to improve existing and develop new behavioral models of mental disorders and to search for new ways to study the mechanisms of formation of behavioral disorders.

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