D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting.

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states.

Introduction: Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. Methods: All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. Results: The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Conclusion: Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

Environmental Enrichment Components Required to Reduce Methamphetamine-Induced Behavioral Sensitization in Mice: Examination of Behaviors and Neural Substrates.

Environmental enrichment (EE) involves the presentation of various sensory, physical, social, and cognitive stimuli in order to alter neural activity in specific brain areas, which can ameliorate methamphetamine (MAMPH)-induced behavioral sensitization and comorbid anxiety symptoms. No previous studies have comprehensively examined which EE components are critical for effectively reducing MAMPH-induced behavioral sensitization and anxiety. This study examined different housing conditions, including standard housing (SH, No EE), standard EE (STEE), physical EE (PEE), cognitive EE (CEE), and social EE (SEE). In the beginning, mice were randomly assigned to the different combinations of housing conditions and injections, consisting of No EE/Saline, No EE/MAMPH, STEE/MAMPH, PEE/MAMPH, CEE/MAMPH, and SEE/MAMPH groups. Then, the mice received intraperitoneal injections of 1 mg/kg MAMPH or normal saline daily for 7 days, followed by a final injection of 0.5 mg/kg MAMPH or normal saline. After behavioral tests, all mice were examined for c-Fos immunohistochemical staining. The results showed that MAMPH induced behavioral sensitization as measured by distance traveled. MAMPH appeared to induce lowered anxiety responses and severe hyperactivity. All EE conditions did not affect MAMPH-induced lowered anxiety behaviors. STEE was likely more effective for reducing MAMPH-induced behavioral sensitization than PEE, CEE, and SEE. The c-Fos expression analysis showed that the medial prefrontal cortex (i.e., cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), caudate-putamen (CPu), and hippocampus (i.e., CA1, CA3, and dentate gyrus (DG)) contributed to MAMPH-induced behavioral sensitization. The Cg1, IL, NAc, BLA, VTA, CPu, CA3, and DG also mediated STEE reductions in MAMPH-induced behavioral sensitization. This study indicates that all components of EE are crucial for ameliorating MAMPH-induced behavioral sensitization, as no individual EE component was able to effectively reduce MAMPH-induced behavioral sensitization. The present findings provide insight into the development of non-pharmacological interventions for reducing MAMPH-induced behavioral sensitization.

Examination of neuroinflammatory cytokine interleukin-1 beta expression in the medial prefrontal cortex, amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine.

A growing body of evidence has shown that abused drugs could simultaneously induce the paradoxical effect-reward and aversion. Moreover, the medial prefrontal cortex (mPFC), amygdala, and hippocampus were involved in this paradoxical effect by abused drugs. However, no research examined whether neuroinflammatory changes in the mPFC [including cingulate cortex area 1 (Cg1); prelimbic cortex (PrL); infralimbic cortex (IL)], basolateral amygdala, and hippocampus [e.g., CA1, CA2, CA3, and dentate gyrus (DG)] after morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA). The results showed that after morphine administration, the consumption of a 0.1% saccharin solution decreased; the mean time spent in the morphine-paired side compartment of the CPP box increased, indicating that morphine simultaneously induced the paradoxical effects of reward and aversion. The PrL and IL of the mPFC, the BLA of the amygdala, the CA1, CA2, CA3, and DG of the hippocampus but not the Cg1 presented hyperactive IL-1ß expression in response to morphine's aversion and reward. The mPFC, amygdala, and hippocampus may appear neuroinflammation activity following morphine-induced paradoxical effect-reward in CPP and aversion in CTA. The present data may provide a better understanding of the relationship between neuroinflammation and morphine addiction.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer's Disease in an Animal Model.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that causes cognitive impairment and other neuropsychiatric symptoms. Previously, little research has thus far investigated whether methamphetamine (MAMPH) can enhance cognitive function or ameliorate AD symptoms. This study examined whether a low dose of MAMPH can induce conditioned taste aversion (CTA) learning, or can increase plasma corticosterone levels, neural activity, and neural plasticity in the medial prefrontal cortex (mPFC) (responsible for cognitive function), the nucleus accumbens (NAc) and the amygdala (related to rewarding and aversive emotion), and the hippocampus (responsible for spatial learning). Furthermore, the excitations or lesions of the prelimbic cortex (PrL) can affect MAMPH-induced CTA learning, plasma corticosterone levels, and neural activity or plasticity in the mPFC [i.e., PrL, infralimbic cortex (IL), cingulate cortex 1 (Cg1)], the NAc, the amygdala [i.e., basolateral amygdala (BLA) and central amygdala (CeA)], and the hippocampus [i.e., CA1, CA2, CA3, and dentate gyrus (DG)]. In the experimental procedure, the rats were administered either saline or NMDA solutions, which were injected into the PrL to excite or destroy PrL neurons. Additionally, rats received 0.1% saccharin solution for 15 min, followed by intraperitoneal injections of either normal saline or 1 mg/kg MAMPH to induce CTA. A one-way ANOVA was performed to analyze the effects of saccharin intake on CTA, plasma corticosterone levels, and the expression of c-Fos and p-ERK. The results showed that the MAMPH induced CTA learning and increased plasma corticosterone levels. The mPFC, and particularly the PrL and IL and the DG of the hippocampus, appeared to show increased neural activity in c-Fos expression or neural plasticity in p-ERK expression. The excitation of the PrL neurons upregulated neural activity in c-Fos expression and neural plasticity in p-ERK expression in the PrL and IL. In summary, MAMPH may be able to improve cognitive and executive function in the brain and reduce AD symptoms. Moreover, the excitatory modulation of the PrL with MAMPH administration can facilitate MAMPH-induced neural activity and plasticity in the PrL and IL of the mPFC. The present data provide clinical implications for developing a possible treatment for AD in an animal model.

Roles of nucleus accumbens shell and core in footshock-induced stress altering behavioral sensitization by methamphetamine in acquisition and testing: Running head: stress, nucleus accumbens, and behavioral sensitization.

How the subregions of the nucleus accumbens (NAc) shell and core and stress are involved in behavioral sensitization induced by psychostimulants remains unclear. The present study manipulated methamphetamine (MAMPH) injections, lesions of the NAc shell or core, and footshock-treatment-induced stress to address this issue. The present data showed that during the acquisition phase, MAMPH injections, lesions of the NAc shell, and footshock treatments induced hyperactivity for the NAc shell. For the NAc core, MAMPH injections induced hyperactivity; however, lesions of the NAc core did not affect locomotor activity. Footshock treatments disrupted hyperactivity of behavioral sensitization. During the testing phase, MAMPH injections, lesions of the NAc shell, and footshock-treatment-induced stress facilitated hyperactivity for the NAc shell. For the NAc core, MAMPH injections and footshock-treatment-induced stress increased hyperactivity. However, the lesion of the NAc core did not affect locomotor activity. In conclusion, MAMPH injections and footshock-treatment-induced stress play an excitatory role for the NAc shell in acquisition and testing. For the NAc core, footshock-treatment-induced stress plays an inhibitory role in acquisition but an excitatory role in testing. The NAc core was not involved in MAMPH-induced behavioral sensitization in acquisition and testing. The NAc shell plays an inhibitory role in acquisition and testing phases. The present data might provide some insights for drug addiction. The results should be discussed further.