Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice
ABSTRACT 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.
SourceAvailable from: Lauren Kruse[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.Genes Brain and Behavior 08/2014; 13(8). DOI:10.1111/gbb.12171 · 3.51 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Background Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure.Methods We assess the effects of acute ethanol withdrawal (6 hours postinjection with 4 g/kg ethanol) on 2 forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post training withdrawal exposure; foreground/background processing; training strength; and nonassociative effects) is also investigated.ResultsAcute ethanol withdrawal during training had a bidirectional effect on fear-conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses.Conclusions Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes.Alcoholism Clinical and Experimental Research 02/2015; 39(2). DOI:10.1111/acer.12614 · 3.31 Impact Factor
[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.MGG Molecular & General Genetics 01/2014; 289(3). DOI:10.1007/s00438-013-0808-y · 2.83 Impact Factor