Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus

1School of Biomedical Sciences and Pharmacy, and the Centre for Translational Neuroscience and Mental Health Research, University of Newcastle,Callaghan, NSW 2308, Australia.
The Journal of Physiology (Impact Factor: 5.04). 05/2012; 590(Pt 16):3677-89. DOI: 10.1113/jphysiol.2012.230268
Source: PubMed


The hypothalamus is a critical controller of homeostatic responses and plays a fundamental role in reward-seeking behaviour. Recently, hypothalamic neurones in the perifornical/lateral hypothalamic area (PF/LHA) have also been implicated in drug-seeking behaviour through projections to extra-hypothalamic sites such as the ventral tegmental area. For example, a population of neurones that expresses the peptide orexin has been strongly implicated in addiction-relevant behaviours. To date, the effect of addictive drugs on synaptic properties in the hypothalamus remains largely unexplored. Previous studies focusing on the PF/LHA neurones, however, have shown that the orexin system exhibits significant plasticity in response to food or sleep restriction. This neuroadaptive ability suggests that PF/LHA neurones could be highly susceptible to modifications by drug exposure. Here, we sought to determine whether cocaine produces synaptic plasticity in PF/LHA neurones. Whole-cell patch-clamp techniques were used to examine the effects of experimenter-administered (passive) or self-administered (SA) cocaine on glutamatergic synaptic transmission in PF/LHA neurones. These experiments demonstrate that both passive and SA cocaine exposure increases miniature excitatory postsynaptic current (mEPSC) frequency in PF/LHA neurones. In addition, SA cocaine reduced the paired-pulse ratio but the AMPA/NMDA ratio of evoked excitatory inputs was unchanged, indicative of a presynaptic locus for synaptic plasticity. Dual-labelling for orexin and excitatory inputs using the vesicular glutamate transporter (VGLUT2), showed that passive cocaine exposure increased VGLUT2-positive appositions onto orexin neurones. Further, a population of recorded neurones that were filled with neurobiotin and immunolabelled for orexin confirmed that increased excitatory drive occurs in this PF/LHA population. Given the importance of the PF/LHA and the orexin system in modulating drug addiction, we suggest that these cocaine-induced excitatory synapse-remodelling events within the hypothalamus may contribute to persistence in drug-seeking behaviour and relapse.

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    • "Subpopulations of neurons within the PVT are excited by both orexin A and orexin B (Bayer et al., 2002; Kolaj et al., 2007), and exposure to orexin neuropeptides have been shown to increase input resistance resulting from closure of K + channels (Ishibashi et al., 2005). Interestingly, we recently showed that 7 days of cocaine exposure enhanced excitatory drive to PF/LHA orexin neurons (Yeoh et al., 2012). In addition to orexin, vasopressin has also been shown to cause state-dependent modulation of firing patterns in PVT neurons (Zhang et al., 2006). "
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    ABSTRACT: Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is likely mediated in part through the dense projections to the PVT from hypothalamic peptide transmitter systems such as orexin, and cocaine- and amphetamine-regulated transcript (CART), both of which play key roles in drug-seeking behaviour. Consistent with this proposition, we previously found that inactivation of the PVT or infusions of CART into the PVT suppressed drug-seeking behaviour in an animal model of contingent cocaine self-administration. Despite this work, very few studies have assessed the basic physiological properties of PVT neurons and how these parameters are altered by exposure to drugs such as cocaine. We set out to address these questions by employing an electrophysiological approach to record from anterior PVT (aPVT) neurons from cocaine-treated and control animals. First, we determined the excitability of aPVT neurons by injecting a series of depolarizing current steps and characterizing the resulting action potential (AP) discharge properties. Second, we investigated the effects of CART on excitatory synaptic inputs to aPVT neurons. We found that the majority of aPVT neurons exhibited tonic firing (TF), and initial bursting (IB) consistent with previous studies. However, we also identified PVT neurons that exhibited delayed firing (DF), single spiking (SS) and reluctant firing (RF). Interestingly, cocaine exposure shifted the proportion of aPVT neurons that exhibited TF. Further, application of CART suppressed excitatory synaptic drive to PVT. This finding is consistent with our previous behavioural data, which showed that CART signaling in the PVT negatively regulates drug-seeking behaviour. Together, these studies support previous anatomical evidence that the PVT can integrate reward-relevant information and provides a putative mechanism through which drugs of abuse can dysregulate this system in addiction.
    Frontiers in Behavioral Neuroscience 08/2014; 8:280. DOI:10.3389/fnbeh.2014.00280 · 3.27 Impact Factor
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    • "Surprisingly, female rats exhibited significantly greater deficits in orexin function following wheel running, suggesting that while the effects of ELS on orexin function are similar across sexes, future studies will need to consider alternative approaches to recover orexin function in female rats. These findings extend recent studies showing that the orexin system is highly plastic and is readily modified by environmental events (Yeoh et al., 2012). More broadly, this study highlights the importance of studying sex-based differences in stress-related pathology (Clayton and Collins, 2014). "
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    ABSTRACT: Early life stress (ELS) is a known antecedent for the development of mood disorders such as depression. Orexin neurons drive arousal and motivated behaviors in response to stress. We tested the hypothesis that ELS alters orexin system function and leads to an altered stress-induced behavioral phenotype in adulthood. We also investigated if voluntary exercise during adolescent development could reverse the ELS-induced changes. Male and female Wistar rats were subjected to maternal separation stress on postnatal days (PND) 2-14. A subset of animals was given access to running wheels in late adolescence (1hr/day, PND40-70). In adulthood, rats were exposed to restraint stress and then tested on the open field (OF) and elevated plus maze (EPM). Brains were processed for Fos-protein and orexin or tyrosine hydroxylase immunohistochemistry. Restraint stress stimulated Fos-protein expression in perifornical area orexin cells, the paraventricular hypothalamic nucleus, and paraventricular thalamic nuclei, but this neuronal response was dampened in male and female rats exposed to ELS. ELS also reduced exploration in the OF, without affecting EPM behavior. These neural and behavioral changes are consistent with a depressive-like phenotype. Adolescent exercise reversed the orexin and behavioral deficits in ELS males. Exercise was not protective in females, although this may be due to sex differences in running behavior. Our findings highlight the inherent plasticity of the orexin system-a trait that may lead to a state of pathological rewiring but could also be treated using non-pharmacological approaches. We also highlight a need to better understand the sex-specific changes in orexin circuits and stress-related pathology.
    Frontiers in Behavioral Neuroscience 07/2014; 8:244. DOI:10.3389/fnbeh.2014.00244 · 3.27 Impact Factor
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    • "This work showed that both experimenter- and self-administered cocaine significantly increased excitatory drive in the LH through pre-synaptic mechanisms, assessed using mEPSCs frequency, amplitude and paired pulse ratio (Yeoh et al., 2012). Consistent with our electrophysiological findings, the number of putative excitatory but not inhibitory inputs onto PFA/LH cells were significantly increased, as measured by immunolabeling for vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA transporter (VGAT; Yeoh et al., 2012). Importantly, a population of recorded neurons that were recovered with neurobiotin labeling and immunolabeled for orexin confirmed that these increases in excitatory drive occurred in orexin neurons. "
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    ABSTRACT: The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. Pivotal to our increased understanding of this pathway was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at center stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy-a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal, reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states.
    Frontiers in Neuroscience 02/2014; 8(8):36. DOI:10.3389/fnins.2014.00036 · 3.66 Impact Factor
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