Supersensitivity to Amphetamine in Protein Kinase-C Interacting Protein/HINT1 Knockout Mice

Abstract

Protein kinase C interacting protein/histidine triad nucleotide binding protein 1 (PKCI/HINT1) is a member of the histidine triad protein family. Although this protein is widely expressed in the mammalian brain including mesocorticolimbic and mesostriatal regions, its physiological function in CNS remains unknown. Recent microarray studies reported decreased mRNA expression of PKCI/HINT1 in the frontal cortex of individuals with schizophrenia, suggesting the possible involvement of this protein in the pathophysiology of the disease. In view of the documented link between dopamine (DA) transmission and schizophrenia, the present study used behavioral and neurochemical approaches to examine the influence of constitutive PKCI/HINT1 deletion upon: (i) basal and amphetamine (AMPH)-evoked locomotor activity; (ii) DA dynamics in the dorsal striatum, and (iii) postsynaptic DA receptor function. PKCI/HINT1À/À (KO) mice displayed lower spontaneous locomotion relative to wild-type (WT) controls. Acute AMPH administration significantly increased locomotor activity in WT mice; nonetheless, the effect was enhanced in KO mice. Quantitative microdialysis studies revealed no alteration in basal DA dynamics in the striatum or nucleus accumbens of KO mice. The ability of acute AMPH to increase DA levels was unaltered indicating that function in presynaptic DA neurotransmission in these regions do not underlie the behavioral phenotype of KO mice. In contrast to WT mice, systemic administration of the direct-acting DA receptor agonist apomorphine (10 mg/kg) significantly increased locomotor activity in KO mice suggesting that postsynaptic DA function is altered in these animals. These results demonstrate an important role of PKCI/HINT1 in modulating the behavioral response to AMPH. Furthermore, they indicate that the absence of this protein may be associated with dysregulation of postsynaptic DA transmission.

Effects of Hint1 deficiency on emotional‐like behaviors in mice under chronic immobilization stress

“…Some results did not reach statistical differences but had a trend of statistical differences, small samples may be one of the possible reason. Furthermore, in the OFT, there were no significant differences in the general locomotor activity of Hint1 ‐KO, ‐HT, and WT littermates, which were in line with the previous findings of Varadarajulua and colleagues, and Barbier and colleagues (Barbier et al., 2007; Varadarajulu et al., 2011). Interestingly, the mood behavior results found by Varadarajulua et al.…”

“…CIS resulted in changes in emotional‐like behavior in Hint1 ‐KO (from the trend for anxiolytic‐like behavior to the elevated anxiety‐related behavior) and HT mice (from the trend of anxiolytic‐like and antidepression‐like behaviors, to the elevated anxiety‐related behavior and increased depression‐like behavior), may through other underlying molecular mechanisms. Barbier reported that absence of HINT1 may involve dysregulation of postsynaptic dopamine transmission (Barbier et al., 2007). It is possible that such variation in dopamine transmission may exert important role in HINT1‐related emotional‐like behaviors alterations after CIS; therefore, the molecular mechanism still needs further clarification.…”

Autosomal Recessive Peripheral Neuropathy With Neuromyotonia (Aran-Nm): Description of a Clinical Case Confirmed by a Mutation in the Hint1 Gene

“…Данный белок присутствует во всех тканях человеческого организма, но его наибольшая экспрессия характерна для головного и спинного мозга [9,25,26]. В результа-те экспериментальных исследований установлено, что большинство известных мутаций в гене HINT1 относятся к мутациям, приводящим к преждевременной терми-нации трансляции и, как следствие, к частичной потере функции белка [9].…”

Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca2+ signaling in mouse fibroblasts and neuronal cells via store-operated Ca2+ entry pathway

“…Moreover, the levels of HINT1 are increased in brains from patients with major depressive disorder (28). A potential role of HINT1 in depression and anxiety disorders was also described in studies of HINT1 KO mice (2,3,42). Recently, using a combination of linkage analysis and next generation sequencing, Zimon et al (52) demonstrated that loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia.…”