Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice

Article (PDF Available)inBehavioural brain research 218(1):152-7 · October 2010with22 Reads
DOI: 10.1016/j.bbr.2010.10.025 · Source: PubMed
Sedative-hypnotic CNS depressant drugs are widely prescribed to treat a variety of disorders, and are abused for their sedative and euphoric effects. Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains their use/abuse and may contribute to relapse in dependent individuals. Although no animal model duplicates depressant dependence, models for specific factors, like withdrawal, are useful for identifying potential neural determinants of liability in humans. Recent analyses implicate the caudolateral substantia nigra pars reticulata (clSNr) in withdrawal following acute and repeated ethanol exposures in mice, but did not assess its impact on withdrawal from other sedative-hypnotics or whether intrinsic neurons or fibers of passage are involved. Here, we demonstrate that bilateral chemical (ibotenic acid) lesions of the clSNr attenuate barbiturate (pentobarbital) and ethanol withdrawal. Chemical lesions did not affect convulsions in response to pentylenetetrazole, which blocks GABA(A) receptor-mediated transmission. Our results demonstrate that the clSNr nucleus itself rather than fibers of passage is crucial to its effects on barbiturate and ethanol withdrawal. These findings support suggest that clSNr could be one of the shared neural substrates mediating withdrawal from sedative-hypnotic drugs.


    • "This study presents clear evidence that Mpdz is a QTG for physiological dependence and associated AWD, and demonstrates that its expression within the clSNr is crucially involved. Furthermore , taken together with previous work from our lab (Chen et al. 2008Chen et al. , 2011b), this study suggests that the clSNr plays an important role as a critical modulator of AWD severity. Although our work contributes significantly to the understanding of the genetic determinants of alcohol physiological dependence and associated withdrawal, there are some limitations . "
    [Show abstract] [Hide abstract] ABSTRACT: Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference, we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared to control mice delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol enhanced convulsions differed between Mpdz shRNA and control animals, indicating that Mpdz expression in the caudolateral substantia nigra pars reticulata does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNA interference analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the caudolateral substantia nigra pars reticulata is crucially involved in risk for alcohol withdrawal.
    Full-text · Article · Aug 2014
    • "Using expression of the immediate early gene c-Fos as a marker for neuronal activation, Chen et al. (2008) found that animals congenic for the chromosome 4 QTL containing the Mpdz gene exhibited significantly less ethanol withdrawal-associated neuronal activation within the basal ganglia than background controls. This effect was particularly evident in the caudolateral region of the substantia nigra pars reticulata, where bilateral electrolytic lesions resulted in attenuation of the severity of ethanol withdrawal symptoms (Chen et al. 2011b). The mouse chromosome 4 QTL is syntenic with a region on human chromosome 9p. "
    [Show abstract] [Hide abstract] ABSTRACT: Alcohol abuse and alcoholism incur a heavy socioeconomic cost in many countries. Both genetic and environmental factors contribute to variation in the inebriating effects of alcohol and alcohol addiction among individuals within and across populations. From a genetics perspective, alcohol sensitivity is a quantitative trait determined by the cumulative effects of multiple segregating genes and their interactions with the environment. This review summarizes insights from model organisms as well as human populations that represent our current understanding of the genetic and genomic underpinnings that govern alcohol metabolism and the sedative and addictive effects of alcohol on the nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00438-013-0808-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jan 2014
    • "Within the basal ganglia circuit, the substantia nigra pars reticulata (SNr) also shows significant differential neuronal activation associated with withdrawal that is influenced by chromosome 4 QTL status. Particularly, the caudolateral SNr (clSNr) plays a critical role in withdrawal following acute and repeated alcohol exposure as well as barbiturate withdrawal (Chen et al., 2008; Chen et al., 2011). Neuroanatomic studies demonstrate the existence of direct projections from the rvCP to the clSNr. "
    [Show abstract] [Hide abstract] ABSTRACT: Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal. The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models. Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B. Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models.
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