Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward.

BACKGROUND: Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. AIMS: The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. METHODS: To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. RESULTS: Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. CONCLUSIONS: Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

An N-terminal fusion allele to study melanin concentrating hormone receptor 1.

Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locus in vivo. Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus of Mchr1. Analysis of the fusion protein (mCherry MCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering the Mchr1 start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs.

Cardiac autonomic modulation during methadone therapy among heroin users: a pilot study.

BACKGROUND: Methadone therapy benefits heroin users in both the medical and psychosocial dimensions. However, both heroin and methadone have cardiac toxicity. Only limited information is available describing the changes in cardiac autonomic function of heroin users and effects of methadone therapy. We conduct the current study to explore the cardiac vagal function in heroin users as well as the impact of lapse and methadone therapy. METHODS: 80 heroin users from a methadone therapy clinic were distributed into 31 compliant and 49 incompliant patients according to whether they lapsed into heroin use within 10 days. 40 healthy control subjects were recruited from the community. Participants underwent electrocardiographic recordings and the heroin users were further investigated before and after methadone therapy. Spectral analysis of heart rate variability (HRV) was computed for cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%). RESULTS: The baseline HRV parameters found lower HF values for heroin users and lower RR interval values for patients with a recent lapse compared with the healthy control subjects. After 1h of methadone administration, heroin users who had lapsed showed a significant increase in HF but the heroin users who had not lapsed did not. CONCLUSION: Our findings suggest that heroin users show decreased cardiac vagal activity and that methadone therapy immediately facilitates vagal regulation in patients with a recent lapse. The differential patterns of autonomic alteration under methadone between those with and without lapse might offer an objective measure of lapse.

Autonomic modulation and health-related quality of life among schizophrenic patients treated with non-intensive case management.

BACKGROUND: Schizophrenia is associated with autonomic dysfunction and this may increase cardiovascular mortality. Past studies on autonomic modulation of schizophrenic patients focused on inpatients rather than individuals in a community setting, especially those receiving non-intensive case management (non-ICM). Besides, autonomic modulation and its association with health-related quality of life (HRQoL) in this population remain unexplored. METHODS: A total of 25 schizophrenic patients treated by non-ICM and 40 healthy volunteers were matched by age, gender and body mass index; smokers were excluded. Between the two groups, we compared the individuals' 5 min resting assessments of heart rate variability and their HRQoL, which was measured using EuroQoL-5D (EQ-5D). Patients with schizophrenia were assessed for psychopathology using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). We examined the relationship between heart rate variability measurements, HRQoL scores, PANSS scores, and other clinical variables among the schizophrenic patients treated by non-ICM. RESULTS: Compared to the controls, patients with schizophrenia showed a significant impairment of autonomic modulation and a worse HRQoL. Cardiovagal dysfunction among the schizophrenic patients could be predicted independently based on lower educational level and more negative symptoms. Sympathetic predominance was directly associated with anticholinergics use and EQ-5D using a visual analogue scale (EQ-VAS). CONCLUSION: Patients with schizophrenia treated by non-ICM show a significant impairment of their autonomic function and HRQoL compared to the controls. Since the sympathovagal dysfunction is associated with more negative symptoms or higher VAS score, the treatment of the negative symptoms as well as the monitoring of HRQoL might help to manage cardiovascular risk among these individuals. In addition, EQ-VAS scores must be interpreted more cautiously in such a population.