Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats' hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine.

Tyrosine hydroxylase (TH) catalyzes the hydroxylation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the rate-limiting step in dopamine (DA) synthesis in the brain. Certain mutations in the human TH gene are associated with severe neurological and psychiatric disorders. The c.886C>T mutation in the mouse Th gene, which results in the R278H substitution, decreases TH activity in the mouse midbrain. Here, we compared the molecular characteristics of the wild-type (TH-278R) and mutant (TH-278H) recombinant forms of TH. Both recombinant proteins were expressed in Escherichia coli BL21 cells and purified by immobilized metal affinity chromatography using Ni-NTA agarose resin. TH activity was assayed by HPLC, and the thermal stability of the recombinant proteins was assessed by differential scanning fluorimetry. The R278H substitution markedly decreased V_max and increased the K_M for the cofactor 6,7-dimethyltetrahydropterin (DMPH₄), but had no effect on the K_M for the substrate L-tyrosine. The substitution did not affect the T₅₀ of thermal inactivation but markedly increased the T_m of thermal unfolding of the TH-278H protein. The substitution decreased the IC₅₀ values for dopamine and 1,2-dihydroxybenzene several-fold, both of which contain a catechol moiety that is also present in L-DOPA. These results indicate that the R278H substitution alters the sensitivity of TH to catechol-containing compounds. Although direct evidence is lacking, endogenous L-DOPA produced during the reaction may interact differently with the catalytic center of the TH-278H mutant than with that of the wild-type TH-278R.

Pharmacological chaperones (PCs)—small molecules that normalize the 3D structure of mutant protein molecules—are promising substances for pharmacological treatment of grave hereditary pathologies. In this study, possible chaperone-like effects of the Fe(II) with tris(1-pyrasolyl)methane complex, [Fe(TPM)₂]Cl₂, on the mutant 447R form of mouse tryptophan hydroxylase 2 (TPH2) in vitro and in vivo were investigated. The experiments were carried out on Balb/c mice homozygous for the mutant TPH2. This complex in concentrations of 0.01, 0.05 and 0.1 mM markedly increased the temperature (T₅₀) and free energy (ΔG) of the mutant TPH2 thermal denaturation in vitro. Seven intramuscular administrations of 30 and 60 mg/kg of [Fe(TPM)₂]Cl₂ markedly increased the TPH2 activity in the midbrain of Balb/c mice. This increase in the TPH2 activity was not accompanied with an increase in the Tph2 gene mRNA and TPH2 protein levels. It is the first demonstration of chaperone-like activity of [Fe(TPM)₂]Cl₂. This complex is a promising chemical for correction of genetic alterations in TPH2 and the associated hereditary psychic disorders.