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Administration of the GABAA Receptor Antagonist Picrotoxin Into Rat Supramammillary Nucleus Induces C-Fos in Reward-Related Brain Structures

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Administration of the GABAA Receptor Antagonist Picrotoxin Into Rat Supramammillary Nucleus Induces C-Fos in Reward-Related Brain Structures Shin and Ikemoto BMC Neuroscience 2010, 11:101 http://www.biomedcentral.com/1471-2202/11/101 RESEARCH ARTICLE Open Access Administration of the GABAA receptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures. Supramammillary picrotoxin and c-Fos expression Rick Shin, Satoshi Ikemoto* Abstract Background: Picrotoxin blocks GABAA receptors, whose activation typically inhibits neuronal firing activity. We recently found that rats learn to selectively self-administer picrotoxin or bicuculline, another GABAA receptor antagonist, into the supramammillary nucleus (SuM), a posterior hypothalamic structure localized anterior to the ventral tegmental area. Other drugs such as nicotine or the excitatory amino acid AMPA are also self-administered into the SuM. The SuM appears to be functionally linked with the mesolimbic dopamine system and is closely connected with other brain structures that are implicated in motivational processes, including the prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Here, we hypothesized that these brain structures are activated by picrotoxin injections into the SuM. Results: Picrotoxin administration into the SuM markedly facilitated locomotion and rearing. Further, it increased c- Fos expression in this region, suggesting blockade of tonic inhibition and thus the disinhibition of local neurons. This manipulation also increased c-Fos expression in structures including the ventral tegmental area, medial shell of the nucleus accumbens, medial prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. Conclusions: Picrotoxin administration into the SuM appears to disinhibit local neurons and recruits activation of brain structures associated with motivational processes, including the mesolimbic dopamine system, prefrontal cortex, septal area, preoptic area, lateral hypothalamic area and dorsal raphe nucleus. These regions may be involved in mediating positive motivational effects triggered by intra-SuM picrotoxin. Background recently found that rats readily learn to lever-press for Recent intracranial self-administration studies have infusions of GABAA receptor antagonists, picrotoxin or helped to define key brain structures involved in positive bicuculline [3], the excitatory amino acid AMPA [4], or motivational processes involved in approach/seeking [1]. nicotine [5] into the SuM, suggesting that activation of One such structure is the supramammillary nucleus supramammillary neurons recruits approach-related (SuM), located in the posterior hypothalamic area, just motivational processes [1]. dorsal to the mammillary body and anterior to the ven- We have also shown low systemic doses of dopamine tral tegmental area (VTA). The SuM was initially impli- receptor antagonists decrease rats’ self-administration of cated in reward-related processes by the finding that picrotoxin or AMPA into the SuM [3,4]. These findings rats learn instrumental responses to obtain brief electri- suggest that motivational effects of supramammillary cal stimulation in the vicinity of the SuM [2]. We manipulations depend on intact dopamine transmission. In addition, AMPA administration into the SuM * Correspondence: [email protected] increases extracellular dopamine concentrations in the Behavioral Neuroscience Branch, National Institute on Drug Abuse, National ventral striatum as measured by microdialysis [4]. This Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA result suggests that activation of supramammillary © 2010 Shin and Ikemoto; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Shin and Ikemoto BMC Neuroscience 2010, 11:101 Page 2 of 13 http://www.biomedcentral.com/1471-2202/11/101 neurons appears to recruit activation of the mesolimbic this manipulation will facilitate locomotor activity in dopamine system. open fields. The present study focused on effects of Conversely, some manipulations that activate VTA acute intra-SuM picrotoxin administration on locomotor dopamine neurons appear to activate supramammillary activity and c-Fos expressions in reward-related brain neurons. One manipulation that supports robust self- structures. Therefore, the study emphasized on initial administration is the cholinergic receptor agonist carba- unconditioned processes, rather than conditioned pro- chol into the posterior VTA [6], which increases extra- cesses, triggered by SuM manipulations. cellular dopamine in the ventral striatum [7], suggesting that this manipulation activates the mesolimbic dopa- Results and Discussion mine system. The administration of carbachol into the Each rat unilaterally received picrotoxin or vehicle into posterior VTA was found to robustly increase the tran- the vicinity of the SuM through a permanent guide can- scription factor c-Fos in the SuM [8]. SuM c-Fos counts nula. After a locomotor activity test, each rat was killed were positively correlated with locomotor counts for histological processes of c-Fos expression and increased by carbachol administration into the VTA, cannula placement. Each rat’s cannula placement was suggesting that SuM neurons participate in motivational verified with microscopic examination and shown in effects triggered by posterior VTA activation. These Figure 1. findings suggest that supramammillary neurons interact with the mesolimbic dopamine system. Effects of SuM picrotoxin administration on locomotor Although the SuM appears to be functionally linked activity with the dopaminergic projection from the VTA to the Unilateral administration of picrotoxin (0.3 mM in 0.3 ventral striatum, connectivity between the SuM and μl) into the SuM immediately facilitated locomotion and these regions is either absent or scarce [9-14]. Addi- rearing that then gradually decreased over the next 40 tional connectivity analysis suggests that several regions min (Figure 2). Because rats that received artificial cere- that are reciprocally connected with the SuM are also brospinal fluid into regions just outside the SuM showed reciprocally connected with the VTA [1]. These include similar locomotor/rearing counts as those receiving it the medial prefrontal cortex, septal area, preoptic area, into the SuM, the data of both groups were combined lateral hypothalamic area and dorsal raphe nucleus. together as vehicle control data. During the 60 min Moreover, these efferent and afferent regions of the observation period, the rats that received picrotoxin into SuM and VTA appear to be closely interlinked. Because the SuM traveled and reared approximately 4 times these regions have also been implicated in reward- more than those that received vehicle. These observa- related processes, these brain regions, the mesolimbic tions were verified by mixed 3 × 12 (injection manipula- dopamine system and SuM may constitute a network tion group × 5-min block) ANOVA/MANOVAs. We module that mediates approach-related motivational found significant group × block interactions, F22,34 = processes [1]. 2.72, P = 0.0042 for locomotion and F22,34 = 2.31, P = Using c-Fos as a marker for neuronal activation, we 0.013 for rearing. These results suggest that picrotoxin sought to address the following hypotheses: 1) the injections into the SuM markedly facilitate locomotion administration of GABAA receptor antagonist picrotoxin and rearing. Because the SuM is closely connected with into the SuM activates its’ local neurons, because the visceral and affective processing structures rather than GABAA receptor antagonist blocks tonic inhibition, motor processing structures and because previous stu- leading to neuronal disinhibition; 2) picrotoxin adminis- dies suggest positive motivational role of this structure, tration into the SuM activates the mesolimbic dopamine it is tempting to suggest that locomotor activity system; 3) picrotoxin administration into the SuM acti- triggered by intra-SuM picrotoxin is secondarily vates the brain regions that are involved in motivational facilitated through motivational processes, thereby processes and reciprocally connected with both SuM reflecting unconditioned motivational processes of the and VTA: medial prefrontal cortex, septum, preoptic manipulation. area, lateral hypothalamic area, and dorsal raphe nucleus. Effects of SuM picrotoxin administration on c-Fos in In addition, we examined whether intra-SuM adminis- reward related structures tration of picrotoxin facilitates locomotor activity. Posi- Figures 3, 4, 5 show c-Fos expression from the level of tive motivational manipulations such as brain the prefrontal cortex to the level of midbrain raphe stimulation reward and drugs of abuse are known to nuclei of representative rats. We also quantified c-Fos in acutely facilitate locomotor activity in rats [15,16]. selected brain regions (Figure 6) and summarized data Because our previous studies show positive motivational in Table 1. Consistent with our hypothesis that picro- effects of intra-SuM picrotoxin, we hypothesized that toxin administration into the SuM disinhibits its local Shin and Ikemoto BMC Neuroscience 2010, 11:101 Page 3 of 13 http://www.biomedcentral.com/1471-2202/11/101 neurons, we observed robust c-Fos expression in the SuM after
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