Hidenori Sagara

Effect of GBR12909 on affective behavior: Distinguishing motivational behavior from antidepressant-like and addiction-like behavior using the runway model of intracranial self-stimulation

RATIONALE It was recently demonstrated that the priming stimulation effect (PSE) in the runway model of intracranial self-stimulation (ICSS) can be used as a model system to study the motivational effects of drugs. However, the characteristics of this novel experimental model have not been fully clarified. OBJECTIVE To elucidate the involvement of dopamine uptake inhibition in motivated behavior and the difference in experimental characteristics between closely related experimental models, we investigated the effects of the dopamine uptake inhibitor GBR12909 in the runway ICSS model, in the forced swimming test (FST), and on conditioned place preference (CPP). In addition, the role of dopamine receptor signaling in the runway model was evaluated using dopamine receptor agonists and antagonists. RESULTS GBR12909 dose-dependently increased running speed on the runway and decreased immobility time in the FST without affecting the time spent in the drug-associated compartment in CPP tests. The effect of GBR12909 in the runway model was inhibited by pre-treatment with the dopamine receptor antagonists haloperidol and raclopride. The dopamine receptor agonists SKF38393 and quinpirole dose-dependently decreased running speed. CONCLUSIONS These results demonstrate that GBR12909 displays motivation-enhancing and antidepressant-like effects without place conditioning effects. In addition, the mechanisms of PSE enhancement in the runway ICSS model are different from those underlying closely associated experimental models and are mediated by increases in dopamine signaling.

Differential effects of nomifensine and imipramine on motivated behavior in the runway model of intracranial self-stimulation

A motivational deficit (the loss of pleasure or interest in previously rewarding stimuli) is one of the core symptoms of major depression, and valid models evaluating the motivational effects of drugs are needed. It was recently demonstrated that the priming stimulation effect in the runway model of intracranial self-stimulation (ICSS) can be used as a model system to study the motivational effects of drugs. However, the characteristics of this novel experimental model have not been fully clarified. In this study, we investigated the effects of nomifensine and imipramine in the runway ICSS model, forced swim tests, and locomotor activity tests to differentiate motivation from affective-like states. Nomifensine dose-dependently increased running speed on the runway and decreased immobility time in the forced swim test. In contrast, imipramine decreased running speed on the runway although it also decreased immobility time in the forced swim test. In addition, the motivation-enhancing effect of nomifensine in the runway model was completely inhibited by pretreatment with the dopamine receptor antagonist haloperidol, although nomifensine-induced increases in locomotion were not affected by haloperidol. These results demonstrate that nomifensine displays motivation-enhancing and antidepressant-like effects. In addition, the motivational effects of nomifensine in the runway ICSS model are primarily mediated by dopamine receptors and enhancements of motivated behavior do not simply reflect hyperlocomotion.

Administration of kampo medicine through a tube at an advanced critical care center

n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.

Intracranial self-stimulation and immobilization had different effects on neurite extension and the p38 MAPK pathway in PC12m3 cells

Aim: In mammals, rewarding and aversive states are motivational drivers of behavioral expression. However, it is unclear whether such states affect neuronal functions at the level of individual neurons. In the present study, the neuronal effects of rewarding and aversive states were investigated in using PC12 mutant cells (PC12m3 cells) with low sensitivity to nerve growth factor. Main methods: The intracranial self‐stimulation (ICSS) and immobilization (IMM) methods were used to create rewarding and aversive states, respectively, in rats. Furthermore, experiments involving voluntary running on a wheel and forced running on a rotating rod were used to evaluate the effects of behavioral excitement on neurons. Then, the effects of plasma samples collected from the animals on neurite extension were examined microscopically, and p38 mitogen‐activated protein kinase (MAPK) activity was assessed using Western blotting. Key findings: Plasma samples from the ICSS and IMM rats facilitated neurite outgrowth to different degrees. However, their effects were not influenced by behavioral excitement. Furthermore, the plasma from the ICSS rats also induced upregulated p38 MAPK activity, whereas that from the IMM rats produced the same or slightly lower levels of MAPK activity to the control plasma. Significance: These findings indicate that rewarding and aversive states might cause morphological changes, such as neurite extension. As for the effects of these states on p38 MAPK activity, the former state might directly increase p38 MAPK activity, but the latter state might have no effect or cause a slight reduction in p38 MAPK activity. Graphical abstract Figure. No caption available.

PS119. Effect of pramipexole for learned helplessness behavior and cranial nerve activities

Objective: One third of major depressive disorder (MDD) patients are unresponsive to antidepressant drugs, a sub-type known as treatment resistant depression (TRD). Acute intravenous administration of ketamine at sub-anaesthetic dosage is the only efficacious pharmacological treatment in TRD. Development of TRD preclinical assays to screen for more efficacious antidepressant drugs and identification of diagnostic biomarkers is therefore of immediate importance. The neuronal microtubule modulator Pregnenolone-Methyl-Ether (PME; also known as 3β-MethoxyPregnenolone) has been shown to have antidepressant efficacy. Methods: The Wistar Kyoto (WKY) rat was used as a model of TRD to investigate the effectiveness of fluoxetine (10mg/kg, i.p.), ketamine (5mg/kg, i.p.) and PME (10mg/kg, s.c.) in the forced swimming test (FST). Hippocampal acetylated α-tubulin (Acet-Tub) was previously shown increased in preclinical models of depression and was here investigated as a potential plasma biomarker. Results: WKY rats demonstrated depressive-like behaviour indicated by increased immobility in the FST associated with overexpression of plasma Acet-Tub compared to Sprague Dawley rats. Acute treatment with the selective serotonin inhibitor (SSRI) fluoxetine had no effect on FST immobility but increased plasma Acet-Tub in WKY rats. Acute administration of ketamine or PME demonstrated rapid antidepressant efficacy in the FST with the effects of ketamine persisting for 7 days. Ketamine and PME demonstrated long-lasting antidepressant efficacy in the FST 24h post-administration. Furthermore, both drugs decreased plasma Acet-Tub overexpression only when their antidepressant efficacy was evident. Conclusion: WKY rats are a suitable model for screening of novel pharmacological treatments for TRD due to their sensitivity to ketamine and lack thereof to SSRIs. PME demonstrates antidepressant efficacy in this model of TRD while plasma AcetTub represents a potential biomarker of disease progression and pharmacological efficacy. Therefore, microtubules represent a potential target for future drug development in TRD. PS119 Effect of pramipexole for learned helplessness behavior and cranial nerve activities Hidenori Sagara1, Hiroaki Araki2, Nami Isooka1, Rina Jougataki1, Takahiro Okabe1, Shimon Takahashi1, Akihiro Tanaka2 1Matsuyama University, Japan, 2Ehime University Hospital, Japan Abstract Purpose: In recent years, research has been reported that dopamine agonists used in the treatment of Parkinson’s disease have also shown effectiveness in treating patients for depression. We treated animals with the pramipexole (PRM) and observed behavioral changes and changes in the function of the cranial nerves in animal models of learned helplessness. The purpose of the experiment is to investigate the dopamine agonist’s effect as an antidepressant for depressive states as well as its role regarding the cranial nerves. Method: The experiment included a learned helplessness behavior test, and an assessment of the cranial nerve function using c-Fos immunohistochemistry staining. The learned helplessness model involved a 5-day protocol. The drug was given for four consecutive days, and on the fifth day we measured the number of failed escape attempts using the same method as the second day. The increase or decrease in number of escape attempts was used as an indicator of the drug’s effectiveness. In order to examine the effect of PRM on cranial nerve activities in learned helplessness, after completion of the test on the fifth day, the brains were collected and any changes to nerve function in the nucleus accumbens, amygdala and hippocampus were assessed using c-Fos immunohistochemistry staining. Results and Observations: In learned helplessness models given a single dose of PRM (1.0mg/kg, i.p.), a significant decrease was observed in the number of failed escape attempts related to learned helplessness behavior. This therefore suggests that PRM, in addition to improving Parkinson’s symptoms, is a drug that also has antidepressant effects. Furthermore, regarding the parts of the brain affected by PRM’s antidepressant function, the nerves of the nucleus accumbens shell, central nucleus and basolateral of the amygdala, and dentate gyrus and CA3 regions of the hippocampus were shown to be affected by the antidepressant function.Purpose: In recent years, research has been reported that dopamine agonists used in the treatment of Parkinson’s disease have also shown effectiveness in treating patients for depression. We treated animals with the pramipexole (PRM) and observed behavioral changes and changes in the function of the cranial nerves in animal models of learned helplessness. The purpose of the experiment is to investigate the dopamine agonist’s effect as an antidepressant for depressive states as well as its role regarding the cranial nerves. Method: The experiment included a learned helplessness behavior test, and an assessment of the cranial nerve function using c-Fos immunohistochemistry staining. The learned helplessness model involved a 5-day protocol. The drug was given for four consecutive days, and on the fifth day we measured the number of failed escape attempts using the same method as the second day. The increase or decrease in number of escape attempts was used as an indicator of the drug’s effectiveness. In order to examine the effect of PRM on cranial nerve activities in learned helplessness, after completion of the test on the fifth day, the brains were collected and any changes to nerve function in the nucleus accumbens, amygdala and hippocampus were assessed using c-Fos immunohistochemistry staining. Results and Observations: In learned helplessness models given a single dose of PRM (1.0mg/kg, i.p.), a significant decrease was observed in the number of failed escape attempts related to learned helplessness behavior. This therefore suggests that PRM, in addition to improving Parkinson’s symptoms, is a drug that also has antidepressant effects. Furthermore, regarding the parts of the brain affected by PRM’s antidepressant function, the nerves of the nucleus accumbens shell, central nucleus and basolateral of the amygdala, and dentate gyrus and CA3 regions of the hippocampus were shown to be affected by the antidepressant function. PS120 Effects of linalool on chronic stress-induced depressive-like behaviour and BDNF protein in the hippocampus of rats Somrudee Saiyudthong, Chantana Mekseepralard, Dawrung