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Various actions trigger pleasure (reward) or aversion (punishment) as emotional responses. Emotional factors that negatively affect brain neural control processes for long periods of time might cause various mental diseases by inducing neuronal changes. In the present study, newly developed PC12m12 cells which are　highly sensitivity to neurotransmitters such as acetylcholine (ACh), were used. Exposing the cells to plasma from rats that had been subjected to intracranial self-stimulation (ICSS) markedly upregulated neurite outgrowth. In addition, voluntary running in a wheel or forced on a rotating rod was used to induce behavioral excitation in rats, and examinations of their plasma confirmed that the ICSS-induced neurite outgrowth was not associated with the ICSS behavior itself. Furthermore, immunoblotting and treatment with U0126, an ERK (extracellular signal-regulated kinase) antagonist, showed that the ICSS-induced neurite outgrowth was related to neuronal ERK activity. Exposing the same cells to plasma from rats that had been subjected to immobilization (IMM) also increased neurite outgrowth. Although the degree of enhancement was not as great as that seen after the ICSS rat plasma treatment, it was less than that observed after treatment with ACh as a positive control. These results indicate that ICSS or IMM lead to varying degrees of morphological changes, such as enhanced neurite outgrowth, in PC12m12 cells, but the neuronal signal transduction pathways underlying these effects differ; i.e.,the former morphological change might involve the activation of the ERK pathway, whereas the latter changes might not. Using PC12m12 cells which exhibit sensitivity to neurotransmitters, it might be possible to clarify the pathogeneses of mental diseases at the neuronal level and search for therapeutic drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We investigated the differentiation and activation of p38 MAPK induced by contrast bath in drug-hypersensitive PC12m3 mutant cells. The rate of neurite outgrowth in PC12m3 cells induced by contrast bath was much higher than that induced by warming or cooling alone or that induced by two warmings with an interval of room temperature, indicating that contrast bath has a synergistic effect. The results of an experiment using a p38 MAPK inhibitor, SB203580, showed that neurite outgrowth of PC12m3 cells induced by contrast bath is p38 MAPK-dependent. Moreover, p38 MAPK activity induced by contrast bath was greater than that induced by warming or cooling alone, indicating that the synergistic effect of a contrast bath on neurite outgrowth depends on the activity of p38 MAPK. Since calcium ions are involved in the activations of P38 MAPK, we investigated the effect of the TRP ion channel inhibitor (Capsazepine) that inhibits calcium influx in the cells. Neurite outgrowth induced by contrast bath treatment was greatly suppressed by the addition of Capsazepine. These findings suggest that calcium dependent activation of the p38 MAPK pathway induced by contrast bath is responsible for the neurite outgrowth of PC12m3 cells., (© 2019 The Authors. Published by Elsevier Ltd.)

Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85β regulatory subunit of PI3K results in a prolonged lifespan. In p85β mutant cells, nerve growth factor (NGF) activates the longevity protein FOXO, and the mutant p85β gene produces strong resistance to oxidative stress, which contributes to aging. The p85β gene mutation causes increased serum insulin and low blood glucose in p85β mutant transgenic mice. Our results indicate that the p85β mutant allele alters the activity of downstream targets of PI3K by NGF and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85β transforms p85β into a novel anti-aging gene by abnormally regulating PI3K.

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., (Copyright © 2017. Published by Elsevier Inc.)

Factors that trigger emotional expression may be divided into two patterns according to the type of motivation, acquiring reward (pleasure) and avoiding aversion (punishment). Repeated exposure to certain external stimuli accompanied by aberrant motivation may produce psychiatric diseases such as bipolar disorder and addiction via dysregulation of the central nervous system. However, neurobiological underpinnings of such diseases have not been clarified, especially at the neuronal level. In the present study, plasma from rats undergoing intracranial self-stimulation (ICSS) produced neurite outgrowth in PC12-variant cells (PC12m3). Stimulated PC12m3 cells also exhibited heightened activity of the p38 MAPK pathway. These findings indicate that reward states lead to not only morphological changes but also increases in p38 MAPK activity at the neuronal level in the central nervous system., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Motivation incorporates several psychological aspects that produce reward-related and learning behaviors. Although reward-related behavior is reported to be mediated by the dopaminergic reward pathway, the involvement of dopaminergic systems in motivated behavior has not been fully clarified. Several experimental methodologies for motivational behavior have been reported, but pharmacological characteristics seem to vary among these methodologies. In this review, we attempt to summarize three main concepts:(1) the relationship of dopamine neuron physiology with motivated behavior, (2) the pharmacological characteristics of the runway intracranial self-stimulation model, and (3) the behavioral distinction of disparate motivated behaviors.

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 ICCS 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 nomifesine 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.

Previous studies have shown that the antidepressive-like effect of tricyclic antidepressants is blocked by repeated treatments with adrenocorticotropic hormone (ACTH). However, little is known about the neuroanatomy underlying the mechanism of the imipramine treatment-resistant depression model. In the present study, first experimental evidence showed no significant difference of the serum imipramine concentrations between the saline and ACTH-treated rats. In further study, imipramine produced significant increases in the c-Fos expression in the medial prefrontal cortex (mPFC), the dentate gyrus of the hippocampus (DGH), and the central nucleus of the amygdala (CeA), in rats repeatedly treated with saline. The imipramine-increased c-Fos immunoreactivity was suppressed in the mPFC of rats repeatedly treated with ACTH. However, there was no significant difference in c-Fos expression in the DGH and CeA between ACTH- and saline-treated rats. These results suggest that the mPFC is maybe involved in effects of the imipramine in the ACTH-treated rats., (© 2013 Wiley Periodicals, Inc.)

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Motivation is a process that continuously changes behavior to achieve a goal and can be conceptualized as a series of steps relating to that process. Intracranial self-stimulation (ICSS) behavior is considered to consist of reward and motivational effects. Moreover, priming stimulation of ICSS behavior is known to promote motivational effects. Using the runway method and priming stimulation, rewards and motivational effects of ICSS behavior can be differentiated. We investigated whether the runway method and priming stimulation of ICSS behavior could be used to evaluate motivational effects of a drug. In the ICSS runway model, running speed was considered as a reference of motivational effect. An assessment of pharmacological drugs known to influence motivational states was also undertaken. Using our experimental methods, prominent changes were observed in running speed when animals were administered methamphetamine and nicotine. Based on our results, we conclude that the runway method may be useful for the evaluation of substances that affect motivation. This review introduces 4 types of neuronal processes involved in motivation, reward mechanisms, outlines evaluation methods, and describes motivational properties of psychoactive drugs.

It is well established that acute morphine withdrawal can be observed following opioid receptor antagonism in rodents. Glutamate receptor antagonists can attenuate the conditioning place aversion (CPA) induced by naloxone in single-dose, morphine-treated rats. Anatomically, the nucleus accumbens appears to be involved in opiate dependence. In the present study, we examined the effects of various glutamate receptor antagonists in the nucleus accumbens on naloxone-induced CPA in rats. MK-801 (an NMDA receptor antagonist), GYKI52466 (an AMPA receptor antagonist), and MCPG (a metabotropic glutamate receptor antagonist) significantly attenuated naloxone-induced CPA following microinjection into the accumbens. In contrast, none of the agents showed place conditioning ability on their own in either morphine-exposed or naïve rats. The present study suggests that glutamate receptors in the nucleus accumbens play a key role in the motivational component of withdrawal during acute morphine dependence., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Rationale: Negative motivational withdrawal from acute opiate dependence was induced by an opioid antagonist, and the withdrawal signs prevented by pretreatment with nicotine., Objectives: The present study was undertaken to examine the mechanism of nicotine-induced attenuation of withdrawal precipitated by naloxone in rats administered a single dose of morphine., Methods: Conditioned place aversion (CPA) was precipitated by naloxone in rats exposed once to morphine. Nicotinic acetylcholine receptor (nAChR) agonists were microinjected into the central amygdaloid nucleus (CeA) before naloxone was administered. Additionally, c-Fos expression in the amygdala was measured in rats exposed to α7 nAChR ligands., Results: The microinjection of nicotine (0.3 and 1.0 μg/μl) into the CeA dose-dependently inhibited naloxone-induced CPA. This inhibition of CPA was reversed by methyllycaconitine (MLA), an α7 nAChR antagonist. CPA was also significantly attenuated by the microinjection of tropisetron (3.0 μg/μl), an α7 nAChR agonist and 5-hydroxytriptamine 3 (5-HT(3)) receptor antagonist, but not by ondansetron (1.0 and 3.0 μg/μl), a 5-HT(3) receptor antagonist. The microinjection of PNU-282987 (3.0 μg/μl), a selective α7 nAChR agonist, into the CeA also inhibited CPA. Furthermore, nicotine increased c-Fos expression in the CeA, but not the medial or basolateral amygdaloid nucleus. The increase of c-Fos in the CeA was significantly inhibited by MLA., Conclusion: Nicotine-induced attenuation of CPA precipitated by naloxone is mediated by the α7 nAChR subtype, and the CeA is one of the regions of the brain involved in the effect of nicotine on acutely opiate-dependent subjects.

A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.