While daridorexant, a dual orexin receptor antagonist (DORA), demonstrated dose-dependent improvements in sleep parameters in a Japanese Phase II trial, its effects on sleep architecture remain incompletely characterized. This secondary analysis examined daridorexant’s effects on sleep fragmentation and architecture in Japanese patients with insomnia disorder. Forty-seven Japanese patients with insomnia (mean age 50.4 ± 8.0 years) underwent 10 nights of polysomnographic (PSG) recordings in a randomized protocol (baseline, placebo, daridorexant 10 mg, 25 mg, 50 mg; 2 nights each). Key parameters included latency to persistent sleep (LPS), total sleep time (TST), wake after sleep onset (WASO), sleep stage durations, and the number of persistent awakenings (NAW). The 8-hour recording was divided into quarters for temporal analysis. Dose-response trends were assessed using Jonckheere-Terpstra tests. Significant dose-response relationships were observed for LPS (P = 0.004), TST (P < 0.001), WASO (P < 0.001), and NAW (P = 0.004). Changes from baseline showed dose-dependent reductions in N1 time (P = 0.006) and increases in N2 (P = 0.049), N3 (P = 0.050), and REM sleep times (P < 0.001). Quartile analysis revealed a significant reduction in NAW in the first quarter with 50 mg (P = 0.012) and a significant increase in REM sleep in the first and fourth quarters with 25 mg and 50 mg (P < 0.05). Daridorexant dose-dependently improves sleep architecture by reducing fragmentation and enhancing deeper NREM and REM sleep. Temporal analysis demonstrated sustained effects throughout the night with REM sleep enhancement persisting through the final quarter. These findings suggest restoration of natural sleep architecture supporting daridorexant’s potential as a comprehensive sleep-promoting agent.

Rett syndrome is an X-linked neurodevelopmental disorder characterised by cognitive, attentional, and communicative impairments along with sensory and motor deficits. Optimal activation of dopamine D1 receptor signalling in the prefrontal cortex (PFC) is essential for cognition and object-based attention. Ghrelin has been observed to modulate dopaminergic neurotransmission and improve cognitive function and attention impairments in various animal models. Herein, we investigated the effects of ghrelin on D1 receptor-mediated dopaminergic neurotransmission in the PFC of male Mecp2 knockout (KO) mice, a mouse model of Rett syndrome, using in vivo microdialysis. External stimuli, such as saline injection and novelty induced increases in the dopamine levels in the PFC of wild-type mice, and the dopamine release was bidirectionally regulated by D1 receptors. In the PFC of Mecp2 KO mice, the dopaminergic responses to external stimuli were attenuated, and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signalling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection (8.6 μg/mouse, s.c.) restored dopaminergic responses to external stimuli by adjusting the altered function of D1 receptor signalling. While ghrelin injection failed to improve the impaired object recognition ability in Mecp2 KO mice, it enhanced attention and exploratory activity toward objects. These findings in Mecp2 KO mice suggest that ghrelin may enhance D1 receptor-mediated dopaminergic neurotransmission and exert beneficial effects on dopamine-related behaviour, such as attention and investigatory motivation towards objects, in Rett syndrome.

Abstract Social defeat stress is a recognized method to induce depressive-like behaviors in mice. Our study found that when mice subjected to social defeat stress were later administered with cocaine, their depressive state significantly worsened. Notably, the typical anti-depressive effects gained from overexpressing DFosB in the nucleus accumbens (NAc), a region known for mediating anti-depressive states, failed to counteract the exacerbating effects of cocaine. Interestingly, a pre-treatment involving electrical shocks to the brain triggered the induction of endogenous DFosB, generating an anti-depressive effect. Nevertheless, even in this mitigated state, subsequent cocaine administration reinstated the depressive behaviors. To robustly verify the intensification of the depressive state, behavioral paradigms like the elevated plus maze and forced swim test were conducted both before and after cocaine treatment. A notable deterioration in performance was observed specifically in the forced swim test post-cocaine administration. Given our understanding that male attractiveness in mice is influenced by physical appearance and perceived confidence, we postulated how this intensified depressive state might affect a male's attractiveness. Observations revealed that during the depressive state induced by social defeat, dopaminergic neurons in the ventral tegmental area (VTA) exhibit hyperactivity. Building on this, we employed a retrograde AAV DIO Gi and Gq injection into the NAc of TH-cre mice. The objective is to delineate the impact of dopaminergic neuron activity on both male attractiveness and the depressive state under the combined influence of social defeat and cocaine. In conclusion, this study illuminates the intricate relationship between cocaine, social defeat-induced depression, and male attractiveness, providing crucial insights into the underlying neurobiological mechanisms and potential therapeutic interventions.

L-DOPA-induced dyskinesia (LID) is a debilitating motor complication that develops following prolonged L-DOPA therapy in patients with Parkinson's disease (PD). Aberrant activation of dopamine D1 receptor (DRD1) signaling in D1-type/direct pathway medium spiny neurons (MSNs) of the striatum plays a critical role in the pathophysiology of LID. We previously characterized DRD1 signaling in seven striatal subregions and found that upregulation of DRD1 signaling in the intermediate/caudal part (IC) is associated with LID in a mouse model of PD. Here, we investigated whether DRD1 expression in the IC plays a causal role in LID development. Using an adeno-associated virus (AAV) expressing a short hairpin RNA against Drd1 (AAV-shDrd1), we selectively knocked down DRD1 expression in the IC of male mice. In unilateral 6-hydroxydopamine-lesioned mice, DRD1 knockdown in the IC significantly attenuated LID after acute and chronic L-DOPA treatment. In contrast, knockdown in either the rostral or intermediate/rostral part, previously identified as the LID-unrelated subregion, did not affect LID. These findings highlight the essential role of DRD1 and its signaling in the IC in LID development, providing valuable insights for developing novel therapeutic approaches.

Rett syndrome (RTT) is a severe neurodevelopmental disorder mainly caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies reported sleep problems characterized by changes in architecture and sleep-wake patterns in both RTT patients and animal models of RTT. However, little is known about the neural mechanisms underlying the sleep-wake problems in humans or animals. In this study, Mecp2-null mice showed decreased locomotor activity during the dark period of light-dark conditions, but behaviorally showed no significant deficits in the photic regulation of circadian rhythms. Piezoelectric monitoring demonstrated that Mecp2-null mice slept mainly in short bouts and spent less time in long sleep bouts than their wild-type littermates. Electroencephalographic analysis revealed that Mecp2-null mice had very short, frequent periods of sleep during the dark period, indicating frequent state transitions between wakefulness and non-REM sleep during the dark period. Greater numbers of short sleep bouts during the dark period than during the light period could indicate that Mecp2-null mice spent more time napping during their typically active period. MeCP2 deficiency affected the expression of several neuromodulator genes in hypothalamic regions. Specifically, the expression of hypocretin/orexin receptor (Hcrtr) 1 and 2 genes were significantly lower in several brain regions of Mecp2-null mice, and these mice exhibited attenuated hypocretin/orexin receptor signaling in in vivo microdialysis studies of hypocretin/orexin receptor agonist YNT-185. These results indicate disturbance of the hypocretin/orexin system in Mecp2-null mice, which might cause sleep-wake problems such as increased somnolence in the active phase.

Neuronal adhesion is regulated by interactions between neurons and the extracellular matrix and plays a critical role in neural development. Chondroitin sulfate proteoglycans (CSPGs), key structural components of the extracellular matrix in the nervous system, are involved in various processes including neuronal migration, neurite outgrowth, and axonal regeneration. The diverse functions of CSPGs are controlled by the sulfated structures of chondroitin sulfate (CS) polysaccharides. In this study, we found that CS-E, a highly sulfated CS polysaccharide, but not CS-A, CS-B, CS-C, or CS -D, induced the formation of neuronal aggregates in primary cortical cells with features of immature neurons. This effect is likely due to the unique properties of CS-E, which altered cell adhesion to the coated surface of culture coverslips, leading to cell detachment and subsequent aggregate formation. Pharmacological and phosphorylation analyses aimed at elucidating signaling cascades revealed that the VEGF receptor is a cell surface target of CS-E, and subsequent activation of the Akt/GSK3β pathway plays a crucial role in aggregate formation. The c-Raf/GSK3β pathway is also involved in CS-E-induced aggregate formation. Furthermore, actin polymerization and the organization of the F-actin cytoskeleton, which are mediated through activation of the Akt/GSK3β pathway, were required for CS-E-induced aggregate formation. In summary, CS-E regulates neuronal adhesion by activating the VEGF receptor/Akt/GSK3β pathway. The identification of signaling cascades involving CS-E may provide insights into the mechanisms underlying neuronal development.

Pharmacology role-play works well for students playing the role of the medical doctor or patient, but students without any roles behave just like observers, resulting in a relatively low learning effectiveness. To improve this issue, a personal drug (P-drug) report was introduced to the role-play program. To examine to what extent the P-drug report affected the learning effectiveness of role-play, we performed questionnaire surveys for players and audiences and subsequent nominal logistic regression analysis. The questionnaire topics were (1) understanding of medical treatment, (2) understanding patient's feelings, (3) improvement of awareness and motivation as a medical doctor, and (4) positive influence upon study attitude. In the topics (1) and (2), the statistical analyses in audiences showed significant relationship between the introduction of the report and observer's recognition of the learning effectiveness, indicating the improvement of learning effectiveness after the introduction of the P-drug report. In players, the percentage of high marks was higher than that in audiences, and no significant differences were found between before and after the introduction of the report. In addition, in the free description, many students realized the importance of selection of therapeutic drugs based on P-drug methods. These results suggest that the introduction of the P-drug report seems useful to make all students participate in the activity of role-play with understanding the selection process of therapeutic drugs, and improves the learning effectiveness of role-play especially in observers. It may be useful to combine P-drug with pharmacology role-play in practical pharmacotherapy education.

Depression can be associated with chronic systemic inflammation, and production of peripheral proinflammatory cytokines and upregulation of the kynurenine pathway have been implicated in pathogenesis of depression. However, the mechanistic bases for these comorbidities are not yet well understood. As tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO), which convert tryptophan to kynurenine, are rate-limiting enzymes of the kynurenine pathway, we screened TDO or IDO inhibitors for effects on the production of proinflammatory cytokines in a mouse macrophage cell line. The TDO inhibitor 680C91 attenuated LPS-induced pro-inflammatory cytokines including IL-1β and IL-6. Surprisingly, this effect was TDO-independent, as it occurred even in peritoneal macrophages from TDO knockout mice. Instead, the anti-inflammatory effects of 680C91 were mediated through the suppression of signal transducer and activator of transcription (STAT) signaling. Furthermore, 680C91 suppressed production of proinflammatory cytokines and STAT signaling in an animal model of inflammatory bowel disease. Specifically, 680C91 effectively attenuated acute phase colon cytokine responses in male mice subjected to dextran sulfate sodium (DSS)-induced colitis. Interestingly, this treatment also prevented the development of anxiodepressive-like neurobehaviors in DSS-treated mice during the recovery phase. The ability of 680C91 to prevent anxiodepressive-like behavior in response to chemically-induced colitis appeared to be due to rescue of attenuated dopamine responses in the nucleus accumbens. Thus, inhibition of STAT-mediated, but TDO-independent proinflammatory cytokines in macrophages can prevent inflammation-associated anxiety and depression. Identification of molecular mechanisms involved may facilitate the development of new treatments for gastrointestinal-neuropsychiatric comorbidity.

Dopamine regulates psychomotor function by D1 receptor/PKA-dependent phosphorylation of DARPP-32. DARPP-32, phosphorylated at Thr34 by PKA, inhibits protein phosphatase 1 (PP1), and amplifies the phosphorylation of other PKA/PP1 substrates following D1 receptor activation. In addition to the D1 receptor/PKA/DARPP-32 signaling pathway, D1 receptor stimulation is known to activate Rap1/ERK signaling. Rap1 activation is mediated through the phosphorylation of Rasgrp2 (guanine nucleotide exchange factor; activation) and Rap1gap (GTPase-activating protein; inhibition) by PKA. In this study, we investigated the role of PP1 inhibition by phospho-Thr34 DARPP-32 in the D1 receptor-induced phosphorylation of Rasgrp2 and Rap1gap at PKA sites. The analyses in striatal and NAc slices from wild-type and DARPP-32 knockout mice revealed that the phosphorylation of Rasgrp2 at Ser116/Ser117 and Ser586, but not of Rasgrp2 at Ser554 or Rap1gap at Ser441 or Ser499 induced by a D1 receptor agonist, is under the control of the DARPP-32/PP1. The results were supported by pharmacological analyses using a selective PP1 inhibitor, tautomycetin. In addition, analyses using a PP1 and PP2A inhibitor, okadaic acid, revealed that all sites of Rasgrp2 and Rap1gap were regulated by PP2A. Thus, the interactive machinery of DARPP-32/PP1 may contribute to efficient D1 receptor signaling via Rasgrp2/Rap1 in the striatum.

The role of the prefrontal cortex (PFC), particularly the prelimbic region (PL), in determining male dominance has been previously reported (Zhou, et.al, Science, 2017). Apart from this established dominance hierarchy, our team has developed a Female-Male Preference Test (FMPT) by comparing four male mice. This test effectively differentiates between males perceived as attractive and unattractive from a female mouse's perspective. The correlation between a male's dominance and its attractiveness to females remains elusive.

The program of pharmacology role-play was started as a part of pharmacological Practice for 3rd-grade medical students at Kurume University in 2013. Pharmacology role-play is active learning program, in which medical students learn how medical doctors chose medicines to treat the presented cases and explain the medical treatment to patients. Students have the basis of pharmacotherapy after almost 1 year of pharmacology course, and this program becomes the first step of the education of clinical pharmacology. Pharmacology role-play was highly evaluated by students, as presented by other symposiasts. However, we realized that this program works well for students playing the role of doctor or patient, but that students without any roles behave like observers. To improve this issue, personal drug training was added to the program of pharmacology role-play in 2016. All the students, not only those playing the role of doctor, need to select therapeutic drugs for the presented cases based on the elements of personal drug (i.e. efficacy, safety, compatibility and cost). This process is required to make a report of personal drug, and facilitate the discussion at pharmacology role-play. Thus, the program of pharmacology role-play integrated with personal drug training seems useful to make all students participate in the activity and to improve motivation for learning clinical pharmacology. In this session, we will discuss the effectiveness of this integrated program.

We've found the presence of attractive or unattractive male mice among four littermate male mice by behavior-based measurement with video camera tracking system. This trend of preference disappeared by hiding male mice with four-layered air-permeable filter. Furthermore, genetically blind female mice showed completely different trend of preference against the same male mice set, indicating that appearance may be one of major factors of male attractiveness.

Rett syndrome is an X-linked neurodevelopmental disorder characterized by cognitive impairments along with sensory and motor deficits. Ghrelin is known to improve cognitive function in various animal models with cognitive deficits. Optimum activation of dopamine D1 receptor signaling in the prefrontal cortex (PFC) plays a critical role in cognitive performance. In this study, we investigated the effects of ghrelin on cognitive function and D1 receptor-mediated dopamine neurotransmission in the PFC of Mecp2 knockout (KO) mice, a mouse model for Rett syndrome. In the modified novel object recognition test, cognitive function was impaired in Mecp2 KO mice, and ghrelin injection (8.6 µg/mouse, s.c.) improved the cognition of objects and investigatory behaviors. In in vivo microdialysis studies, external stimuli such as saline injection and novelty induced increases in dopamine levels in the PFC of wild-type mice, and the dopamine release was bidirectionally regulated by D1 receptors. In the PFC of Mecp2 KO mice, the dopamine responses to external stimuli were attenuated and the dopamine reuptake system was upregulated. Pharmacological analyses revealed that the ability of D1 receptor signaling to inhibit dopamine release would be upregulated and/or its ability to stimulate dopamine release would be downregulated in Mecp2 KO mice. Ghrelin injection restored dopamine responses to external stimuli by adjusting the altered function of D1 receptor signaling. These results suggest that the ability of ghrelin to restore dopamine neurotransmission via D1 receptor-mediated mechanisms likely contributes to its therapeutic effects on cognitive deficits in Mecp2 KO mice.

Occasional incidents of drug addiction among celebrities have been reported, and sometimes the presence of the opposite sex flickers. Even trafficking of women sometimes involves the use of illegal drugs. Whether drugs induce not only drug dependence but also an associated preference for the opposite sex is an important question in understanding and solving such cases.

Calcineurin (Cn), a phosphatase important for synaptic plasticity and neuronal development, has been implicated in the etiology and pathophysiology of neuropsychiatric disorders, including schizophrenia, intellectual disability, autism spectrum disorders, epilepsy, and Alzheimer's disease. Forebrain-specific conditional Cn knockout mice have been known to exhibit multiple behavioral phenotypes related to these disorders. In this study, we investigated whether Cn mutant mice show pseudo-immaturity of the dentate gyrus (iDG) in the hippocampus, which we have proposed as an endophenotype shared by these disorders. Expression of calbindin and GluA1, typical markers for mature DG granule cells (GCs), was decreased and that of doublecortin, calretinin, phospho-CREB, and dopamine D1 receptor (Drd1), markers for immature GC, was increased in Cn mutants. Phosphorylation of cAMP-dependent protein kinase (PKA) substrates (GluA1, ERK2, DARPP-32, PDE4) was increased and showed higher sensitivity to SKF81297, a Drd1-like agonist, in Cn mutants than in controls. While cAMP/PKA signaling is increased in the iDG of Cn mutants, chronic treatment with rolipram, a selective PDE4 inhibitor that increases intracellular cAMP, ameliorated the iDG phenotype significantly and nesting behavior deficits with nominal significance. Chronic rolipram administration also decreased the phosphorylation of CREB, but not the other four PKA substrates examined, in Cn mutants. These results suggest that Cn deficiency induces pseudo-immaturity of GCs and that cAMP signaling increases to compensate for this maturation abnormality. This study further supports the idea that iDG is an endophenotype shared by certain neuropsychiatric disorders.

SLITRK1 is an obsessive-compulsive disorder spectrum-disorders-associated gene that encodes a neuronal transmembrane protein. Here we show that SLITRK1 suppresses noradrenergic projections in the neonatal prefrontal cortex, and SLITRK1 functions are impaired by SLITRK1 mutations in patients with schizophrenia (S330A, a revertant of Homo sapiens-specific residue) and bipolar disorder (A444S). Slitrk1-KO newborns exhibit abnormal vocalizations, and their prefrontal cortices show excessive noradrenergic neurites and reduced Semaphorin3A expression, which suppresses noradrenergic neurite outgrowth in vitro. Slitrk1 can bind Dynamin1 and L1 family proteins (Neurofascin and L1CAM), as well as suppress Semaphorin3A-induced endocytosis. Neurofascin-binding kinetics is altered in S330A and A444S mutations. Consistent with the increased obsessive-compulsive disorder prevalence in males in childhood, the prefrontal cortex of male Slitrk1-KO newborns show increased noradrenaline levels, and serotonergic varicosity size. This study further elucidates the role of noradrenaline in controlling the development of the obsessive-compulsive disorder-related neural circuit.

Cast immobilization causes sensory hypersensitivity, which is also a symptom of neuropathic pain and chronic pain. However, the mechanisms underlying immobilization-induced hypersensitivity remain unclear. The present study investigated the role of dopamine neurotransmission in the nucleus accumbens shell (NAcSh) of rats with cast immobilization-induced mechanical hypersensitivity using in vivo microdialysis. Cast immobilization of the hind limb decreased the paw withdrawal threshold (PWT). Mechanical stimulation of the cast-immobilized hind limb induced a decrease in dopamine in the NAcSh, and this decrease was associated with the upregulation of presynaptic D2-like receptors. A D2-like receptor antagonist infused into the NAcSh reversed the decrease in PWT in rats with cast immobilization, whereas a D2-like receptor agonist infused into the NAcSh induced a decrease in PWT in control rats. In addition, the expression of the D2 receptor (Drd2) mRNA in the NAcSh was increased by cast immobilization. Importantly, systemic administration of the D2-like receptor antagonist reversed the decrease in PWT in rats with cast immobilization. As dopamine levels regulated by presynaptic D2-like receptors did not correlate with the PWT, it is presumed that the D2-like receptor antagonist or agonist acts on postsynaptic D2-like receptors. These results suggest that immobilization-induced mechanical hypersensitivity is attributable to the upregulation of postsynaptic D2-like receptors in the NAc. Blockade of D2-like receptors in the NAcSh is a potential therapeutic strategy for immobilization-induced hypersensitivity.

Dopamine D1 receptors (D1Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D1Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D1Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D1Rs and β adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D1Rs with minor effects on β-receptor-dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D1R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline-D1R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D1R antagonist. These results suggest a critical role of noradrenaline-induced activation of D1Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline-D1R signaling may determine responsiveness to antidepressant drugs in depressive disorders.

Cholinergic interneurons (ChIs) of the nucleus accumbens (NAc) are important for mediating the behavioral response to rewarding stimuli. A major role for these cells is to regulate dopamine (DA) transmission by activating cholinergic receptors at local DAergic nerve terminals. Here we report that the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) in NAc ChIs mediates an enhancement in DA signaling in response to rewarding stimuli. The HCN current in NAc ChIs and its modulation by DA, as well as the increase in cholinergic efflux by local cocaine infusion were impaired in mice with deletion of HCN2 in cholinergic cells. Enhancement in the DA efflux and signaling in the NAc in response to rewarding stimuli, as well as cocaine conditioning were also dependent on HCN2 in ChIs. These results provide a mechanistic link between the activity of NAc ChIs and reward encoding.

The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons (MSNs) is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase (PDE)10A and muscarinic M4 receptors. In an animal model of 6-hydroxydopamine (6-OHDA)-induced hemi-parkinsonism, D1 receptor signaling was upregulated in almost all subregions including the DL-IR, but not in the IC. When L-DOPA-induced dyskinesia (LID) was developed, D1 receptor signaling in the IC was upregulated and correlated with the severity of LID. Our results suggest that the function of the striatum is maintained through the subregion-specific regulation of dopamine D1 receptor signaling and that the aberrant activation of D1 receptor signaling in the IC is involved in LID. Future studies focusing on D1 receptor signaling in the IC of the striatum will facilitate the development of novel therapeutics for LID. SIGNIFICANCE STATEMENT Recent progress in striatal mapping based on corticostriatal connectivity and striosome-matrix compartmentalization allowed us to subdivide the striatum into seven subregions. Analyses of D1 receptor signaling in the seven subregions identified two unique subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Aberrant activation of D1 receptor signaling in the IC is involved in L-DOPA-induced dyskinesia (LID). Previous studies of LID have mainly focused on the DL-IR, but not on the IC of the striatum. Future studies to clarify aberrant D1 receptor signaling in the IC are required to develop novel therapeutics for LID.