**7. Other pharmacological effects**

#### **7.1 The effect of TRK-820 on a rat model of schizophrenia**

The effects of TRK-820 on hyperlocomotion and stereotyped behaviors (head-weaving, sniffing, and turning) induced by PCP were evaluated. These behaviors are thought to resemble the schizophrenia-like effects in humans. TRK-820 (10–100 g/kg, s.c.) dosedependently inhibited PCP (10 mg/kg, i.p.)-induced hyperlocomotion, and this effect was antagonized with nor-BNI (20 mg/kg, s.c.). PCP-induced stereotyped behaviors were also inhibited by treatment with TRK-820 in a dose-dependent manner. These findings that TRK-820 potentially ameliorates abnormal behaviors induced by PCP suggest its therapeutic potential against the symptoms of schizophrenia (Yoshikawa et al., 2009).

#### **7.2 The effect of TRK-820 on dyskinesia symptoms in a parkinsonian rat model**

The effects of TRK-820 on rotational behavior were investigated in unilateral 6 hydroxydopamine (6-OHDA)-treated rats (hemi-parkinsonian rats), and on dyskinesia produced by administering L-DOPA to hemi-parkinsonian rats for 3 weeks (dyskinesia rats). TRK-820 significantly ameliorated abnormal behavior in hemi-parkinsonian rats at 30 g/kg (s.c.), and L-DOPA induced dyskinesia at 10 and 30 g/kg (s.c.). This effect was antagonized by pretreatment with nor-BNI (20 mg/kg, s.c.). Additionally, co-administration of TRK-820 (3 and 10 μg/kg, s.c.) with L-DOPA for 3 weeks suppressed the development of L-DOPA-induced dyskinesia. TRK-820 may be a suitable drug for the treatment of parkinsonian patients with dyskinesia symptoms (Ikeda et al., 2009).

#### **7.3 The diuretic effect of TRK-820 in rats**

Diuresis is a well-recognized effect of conventional agonists in animals and humans. A diuretic effect of TRK-820 in rats has also been reported. TRK-820 (0.005-0.02 mg/kg, s.c.) dose-dependently induced a diuretic effect without developing tolerance, and this effect was inhibited by selective antagonist 5'-GNTI (Inan et al., 2009b).

#### **7.4 The effects of TRK-820 on endothelial cell differentiation and development of vasculature**

The roles of the opioid system in vascular development were investigated (Yamamizu et al., 2011). U-50,488H and TRK-820 significantly inhibited endothelial cell differentiation and vascular formation through the inhibition of cAMP/PKA signaling.
