Prior studies examining the effects of cocaine on the dynorphin/kappa opioid receptor (Dyn/KOR) system primarily focus on non-contingent cocaine exposure, but the effects of self-administration, which more closely reflects human drug-taking behaviors, are not well studied. In this study we characterized the effects of escalated intravenous cocaine self-administration on the functional state of the Dyn/KOR system and its interaction with mesolimbic dopamine signaling. Rats self-administered cocaine in an extended access, limited intake cocaine procedure, in which animals obtained 40 infusions per day (1.5 mg/kg/inf) for 5 consecutive days to ensure comparable consumption levels. Following single day tests of cue reactivity and progressive ratio responding, quantitative real-time polymerase chain reaction was used to measure levels of Oprk and Pdyn transcripts in the ventral tegmental area and nucleus accumbens. Additionally, after self-administration, ex vivo fast-scan cyclic voltammetry in the NAc was used to examine the ability of the KOR agonist U50,488 to inhibit dopamine release. We found that KOR-induced inhibition of dopamine release was enhanced in animals that self-administered cocaine compared to controls, suggesting upregulated Dyn/KOR activity after cocaine self-administration. Furthermore, expression levels of Pdyn in the nucleus accumbens and ventral tegmental area, and Oprk in the nucleus accumbens, were elevated in cocaine animals compared to controls. Additionally, Pdyn expression in the nucleus accumbens was negatively correlated with progressive ratio breakpoints, a measure of motivation to self-administer cocaine. Overall, these data suggest that cocaine self-administration elevates KOR/Dyn system activity in the mesolimbic dopamine pathway.

The nucleus accumbens (NAc) is a crucial region in the reward circuit and is related to anhedonia, the pivotal symptom of major depression disorder (MDD). Deep brain stimulation (DBS) of NAc has been identified as an effective treatment for severe refractory major depression; however, the underlying mechanism of NAc-DBS in MDD treatment remains elusive. Using the chronic unpredictable mild stress (CUMS) mouse model, we found NAc-DBS rescued depression-like behaviors, and reversed high gamma oscillation reduction and neurogenesis impairment in the dorsal dentate gyrus. Inactivation of parvalbumin (PV)-positive interneurons (PVI) in the dorsal DG led to depression-like behavior and decreased adult neurogenesis. Further investigation elucidated the VTA-DG GABAergic projection and CA1-NAc projection might jointly participate in NAc-DBS therapeutic mechanism. Disinhibition of the VTA-DG GABAergic projection had an antidepressant effect, and inhibition of the CA1-NAc projection reduced the antidepressant effect of DBS-NAc. Moreover, disinhibiting the VTA-DG GABAergic projection or activating the CA1-NAc projection could increase PVI activity in the dorsal DG. These results showed PVI in the dorsal DG as an essential target in depression and NAc-DBS antidepressant mechanisms.

Many physiological functions with approximately 24-h rhythmicity (circadian rhythms) are generated by an internal time-measuring system of the circadian clock. While sleep/wake cycles, feeding patterns, and body temperature are the most widely known physiological functions under the regulation of the circadian clock, physiological regulation by the circadian clock extends to higher brain functions. Accumulating evidence suggests strong associations between the circadian clock and mood disorders such as depression, but the underlying mechanisms of the functional relationship between them are obscure. This review overviews rodent models with disrupted circadian rhythms on depression-related responses. The animal models with circadian disturbances (by clock gene mutations and artifactual interventions) will help understand the causal link between the circadian clock and depression.

The dopamine mesolimbic system is a major circuit involved in controlling goal-directed behaviors. Dopamine D2 receptors (D2R) and kappa opioid receptors (KOR) are abundant Gi protein-coupled receptors in the mesolimbic system. D2R and KOR share several functions in dopamine mesencephalic neurons, such as regulation of dopamine release and uptake, and firing of dopamine neurons. In addition, KOR and D2R modulate each other functioning. This evidence indicates that both receptors functionally interact, however, their colocalization in the mesostriatal system has not been addressed. Immunofluorescent assays were performed in cultured dopamine neurons and adult mice\'s brain tissue to answer this question. We observed that KOR and D2R are present in similar density in dendrites and soma of cultured dopamine neurons, but in a segregated manner. Interestingly, KOR immunolabelling was observed in the first part of the axon, colocalizing with Ankyrin in 20% of cultured dopamine neurons, indicative that KOR is present in the axon initial segment (AIS) of a group of dopaminergic neurons. In the adult brain, KOR and D2R are also segregated in striatal tissue. While the KOR label is in fiber tracts such as the striatal streaks, corpus callosum, and anterior commissure, D2R is located mainly within the striatum and nucleus accumbens, surrounding fiber tracts. D2R is also localized in some fibers that are mostly different from those positives for KOR. In conclusion, KOR and D2R are present in the soma and dendrites of mesencephalic dopaminergic neurons, but KOR is also found in the AIS of a subpopulation of these neurons.

Major depressive disorder is a common and serious mood illness. The molecular mechanisms underlying the pathogenesis and symptomatology of depression are poorly understood at present. Multiple neurotransmitter systems are believed to be implicated in depression. Increasing evidence supports glutamatergic transmission as a critical element in depression and antidepressant activity. In this study, we investigated adaptive changes in expression of AMPA receptors in a key limbic reward structure, the striatum, in response to an anhedonic model of depression. Prolonged social isolation in adult rats caused anhedonic/depression- and anxiety-like behavior. In these depressed rats, surface levels of AMPA receptors, mainly GluA1 and GluA3 subunits, were reduced in the nucleus accumbens (NAc). Surface GluA1/A3 expression was also reduced in the caudate putamen (CPu) following chronic social isolation. No change was observed in expression of presynaptic synaptophysin, postsynaptic density-95, and dendritic microtubule-associated protein 2 in the striatum. Noticeably, chronic treatment with the metabotropic glutamate (mGlu) receptor 5 antagonist MTEP reversed the reduction of AMPA receptors in the NAc and CPu. MTEP also prevented depression- and anxiety-like behavior induced by social isolation. These data indicate that adulthood prolonged social isolation induces the adaptive downregulation of GluA1/A3-containing AMPA receptor expression in the limbic striatum. mGlu5 receptor activity is linked to this downregulation, and antagonism of mGlu5 receptors produces an antidepressant effect in this anhedonic model of depression.

BACKGROUND: Several drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine.
METHODS: To simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p < 0.05. Ethics approval: NWU-00291-17-A5.
RESULTS: Delta-9-THC reduced OT and VP plasma levels (p < 0.0001, p = 0.0141; respectively), cocaine reduced plasma OT (p = 0.0023), while MA reduced plasma VP levels (p = 0.0001), all versus control. EFV reduced OT and VP plasma levels (p < 0.0001; OT and VP) versus control, and similar to ∆9-THC.
CONCLUSIONS: EFV markedly affects the NS in significantly reducing both plasma OT and VP equivalent to DOA. Importantly, EFV has distinct effects on peripheral OT and VP levels when assessed within the context of drug dependence. The data highlights a possible new mechanism underlying previously documented EFV-induced effects in rats, and whereby EFV may induce neuropsychiatric adverse effects clinically; also providing a deeper understanding of the suggested abuse-potential of EFV.

The vascular contributions of neurotransmitters to the hemodynamic response are gaining more attention in neuroimaging studies, as many neurotransmitters are vasomodulatory. To date, well-established electrochemical techniques that detect neurotransmission in high magnetic field environments are limited. Here, we propose an experimental setting enabling simultaneous fast-scan cyclic voltammetry (FSCV) and blood oxygenation level-dependent functional magnetic imaging (BOLD fMRI) to measure both local tissue oxygen and dopamine responses, and global BOLD changes, respectively. By using MR-compatible materials and the proposed data acquisition schemes, FSCV detected physiological analyte concentrations with high temporal resolution and spatial specificity inside of a 9.4 T MRI bore. We found that tissue oxygen and BOLD correlate strongly, and brain regions that encode dopamine amplitude differences can be identified via modeling simultaneously acquired dopamine FSCV and BOLD fMRI time-courses. This technique provides complementary neurochemical and hemodynamic information and expands the scope of studying the influence of local neurotransmitter release over the entire brain.

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

Physical exercise has been established as a low-cost, safe, and effective way to manage chronic intractable pain. We investigated the underlying mechanisms of exercise-induced hypoalgesia (EIH) using a mouse model of neuropathic pain (NPP). Epigenetic changes in activated microglia and maintained GABA synthesis in the spinal dorsal horn may contribute to EIH. Voluntary exercise (VE), a strong reward for animals, also induced EIH, which may be due in part to the activation of dopamine (DA) neurons in the ventral tegmental area (VTA). VE increases the expression of pCREB in dopaminergic neurons in the VTA, which would enhance dopamine production, and thereby contributes to the activation of the mesolimbic reward system in NPP model mice. We demonstrated that neurons in the laterodorsal tegmental and pedunculopontine tegmental nuclei, a major input source of rewarding stimuli to the VTA, were activated by exercise. Chronic pain is at least partly attributed to sedentary and inactive lifestyle as indicated by the Fear-avoidance model. Therefore, chronic pain could be recognized as a lifestyle-related disease. Physical activity/inactivity may be determined by genetic/epigenetic and neural factors encoded in our brain. The hypothalamus and reward system is closely related in the axis of food intake, energy metabolism and physical activity. Understanding the interactions between the mesolimbic DA system and the hypothalamus that sense and regulate energy balance is thus of significant importance. For example, proopiomelanocortin neurons and melanocortin 4 receptors may play a role in connecting these two systems. Therefore, in a certain sense, chronic pain and obesity may share common behavioral and neural pathology, i.e. physical inactivity, as a result of inactivation of the mesolimbic DA system. Exercise and increasing physical activity in daily life may be important in treating and preventing chronic pain, a life-style related disease.

Loud (≥70dBA) acoustic white noise improves cognitive performance in children with ADHD as well as skilled reach and rotarod performance in the spontaneously hypertensive (SH) rat model of ADHD. To investigate how acoustic noise influences the brain activity in the SH rat model of ADHD, immunohistochemical staining of two neuronal activity and plasticity markers, Ca2+/Calmodulin dependent protein kinase II (CaMKII) and ΔFosB, was evaluated in Wistar (n = 24) and SH (n = 16) rats after repeated exposure to acoustic noise or ambient silence. Other SH rats (n = 6) were treated with repeated methylphenidate (MPH). Expression of CaMKII was reduced in the tuberomammillary nucleus (TMN) of the SH rat compared to Wistar but not in the nucleus accumbens (nAc) or the dorsolateral prefrontal cortex (DL-PFC). In the TMN, the expression of CaMKII was increased by noise in both strains. ΔFosB expression was reduced in nAc, DL-PFC and the dorsolateral striatum (DLS) of the SH rat compared to Wistar. Exposure to acoustic white noise significantly increased ΔFosB expression in the nAc and DL-PFC but not in the DLS of SH rats. The results indicate that acoustic noise shifts a reduced neuronal activity in the nAc, TMN and DL-PFC in SH rats toward the normal levels of activity in outbred rats. This may explain why noise has benefit selectively in ADHD.