Mice cohabiting with familiar conspecific in chronic stress condition exhibit methamphetamine-induced locomotor sensitization and augmented consolation behavior.

Recognize and share emotions are essential for species survival, but in some cases, living with a conspecific in distress condition may induce negative emotional states through empathy-like processes. Studies have reported that stressors promote psychiatric disorders in both, who suffers directly and who witness these aversive episodes, principally whether social proximity is involved. However, the mechanisms underlying the harmful outcomes of emotional contagion needs more studies, mainly in the drug addiction-related behaviors. Here, we investigated the relevance of familiarity and the effects of cohabitation with a partner submitted to chronic stress in the anxiety-like, locomotor sensitization and consolation behaviors. Male swiss mice were housed in pairs during different periods to test the establishment of familiarity and the stress-induced anxiety behavior in the elevated plus maze. Another cohort was housed with a conspecific subjected to repeated restraint stress (1h/day) for 14 days. During chronic restraint the allogrooming was measured and after the stress period mice were tested in the open field for evaluation of anxiety and locomotor cross-sensitization induced by methamphetamine. We found that familiarity was established after 14 days of cohabitation and the anxiogenic behavior appeared after 14 days of stress. Repeated restraint stress also increased anxiety in the open field test and induced locomotor cross-sensitization in the stressed mice and their cagemates. Cagemates also exhibited increase in consolation behavior after stress sessions when compared to control mice. These results indicate that changes in drug abuse-related, consolation and affective behaviors may be precipitate through emotional contagion in familiar conspecifics.

Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging in mice to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signaling pathway decreased the number of cocaine responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

Dose Related Analgesic, Motor and Reinforcing Effects of Nalbuphine in Rats

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain.

Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.

Potential Ago2/miR-3068-5p Cascades in the Nucleus Accumbens Contribute to Methamphetamine-Induced Locomotor Sensitization of Mice

Dysregulation of microRNA (miRNA) biogenesis is involved in drug addiction. Argonaute2 (Ago2), a specific splicing protein involved in the generation of miRNA, was found to be dysregulated in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice in our previous study. Here, we determined whether Ago2 in the NAc regulates METH sensitization in mice and identified Ago2-dependent miRNAs involved in this process. We found a gradual reduction in Ago2 expression in the NAc following repeated METH use. METH-induced hyperlocomotor activity in mice was strengthened by knocking down NAc neuronal levels of Ago2 but reduced by overexpressing Ago2 in NAc neurons. Surprisingly, miR-3068-5p was upregulated following overexpression of Ago2 and downregulated by silencing Ago2 in the NAc. Knocking down miR-3068-5p, serving as an Ago2-dependent miRNA, strengthened the METH sensitization responses in mice. These findings demonstrated that dysregulated Ago2 in neurons in the NAc is capable of regulating METH sensitization and suggested a potential role of Ago2-dependent miR-3068-5p in METH sensitization.

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.