Role of cortical alpha-2 adrenoceptors in alcohol withdrawal-induced depression and tricyclic antidepressants

Getachew, Bruk; Hauser, Sheketha R.; Csóka, Antonei B.; Taylor, Robert E.; Tizabi, Yousef

doi:10.1016/j.drugalcdep.2017.03.004

Cited by 13 publications

(13 citation statements)

References 78 publications

(92 reference statements)

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“…Whether alcohol’s effect is initiated primarily through inflammatory or neurotropic pathways and whether nicotine’s effect follows the same pattern may provide useful hints on common underpinnings of these two addictive and widely used drugs. It is also of importance to note that complex behaviors such as drug addiction and comorbid neuropsychiatric disorders such as depression may involve intricate circuitries that are not only influenced by the inflammatory or neurotrophic factors, but also a number of other neurotransmitter systems [ 38 , 39 , 40 , 41 ]. However, whether the final common denominator hinges on the neurotropic and/or inflammatory pathways remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats

Kalejaiye¹,

Getachew²,

Ferguson³

et al. 2017

J Drug Alcohol Res

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BackgroundHeavy use of alcohol is commonly associated with heavy smoking (nicotine intake). Although many factors, including mood effects of these two drugs may contribute to their co-use, the exact neurobiological underpinnings are far from clear. It is well known that chronic alcohol exposure induces neuroinflammation that may precipitate depressive-like behavior, which is considered an important factor in alcohol relapse. Nicotine, on the other hand, possesses anti-inflammatory and antidepressant effects.PurposeIn this study, we sought to determine which proinflammatory markers may be associated with the depressogenic effects of chronic alcohol and whether nicotine pretreatment may normalize these changes.Study designFor this purpose, we treated adult male Wistar rats with alcohol (1.0 g/kg, IP), nicotine (0.3 mg/kg, IP) or their combination once daily for 14 days. Two prominent proinflammatory cytokines (IL-1β and TNF-α) in two primary brain regions, namely the hippocampus and frontal cortex that are intimately involved in mood regulation, were evaluated.ResultsChronic alcohol resulted in increases in both cytokines in both regions as determined by Western blot. Nicotine completely blocked alcohol-induced effects in the hippocampus, but not in the frontal cortex. These data suggest that nicotine may mitigate the inflammatory effects of alcohol in brain-selective region. Hence, the previously observed depressogenic effects of alcohol and the antidepressant effects of nicotine may at least be partially mediated through manipulations of proinflammatory cytokines in the hippocampus.ConclusionThese findings suggest possible therapeutic potential of anti-inflammatory cytokines in combating alcohol-induced depression and/or relapse.

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Section: Discussionmentioning

confidence: 99%

Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats

Kalejaiye¹,

Getachew²,

Ferguson³

et al. 2017

J Drug Alcohol Res

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“…On day 8, approximately 24 h after the last ketamine or saline injection, the animals were sacrificed by decapitation, alternating between the groups as described previously [44]. Colons containing stools were collected, quick-frozen on dry ice and stored at − 80 °C.…”

Section: Methodsmentioning

confidence: 99%

Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties

et al. 2018

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BackgroundAppreciable evidence suggest that dysbiosis in microbiota, reflected in gut microbial imbalance plays a key role in the pathogenesis of neuropsychiatric disorders including depression and inflammatory diseases. Recently, the antidepressant properties of ketamine have gained prominence due to its fast and long lasting effects. Additional uses for ketamine in inflammatory disorders such as irritable bowel syndrome have been suggested. However, ketamine’s exact mechanism of action and potential effects on microbiome is not known. Here, we examined the effects of low dose ketamine, known to induce antidepressant effects, on stool microbiome profile in adult male Wistar rats. Animals (5/group) were injected intraperitoneally with ketamine (2.5 mg/kg) or saline, daily for 7 days and sacrificed on day 8 when intestinal stools were collected and stored at − 80 °C. DNA was extracted from the samples and the 16 S rRNA gene-based microbiota analysis was performed using 16S Metagenomics application.ResultsAt genus–level, ketamine strikingly amplified Lactobacillus, Turicibacter and Sarcina by 3.3, 26 and 42 fold, respectively. Conversely, opportunistic pathogens Mucispirillum and Ruminococcus were reduced by approximately 2.6 and 26 fold, respectively, in ketamine group. Low levels of Lactobacillus and Turicibacter are associated with various disorders including depression and administration of certain species of Lactobacillus ameliorates depressive-like behavior in animal models. Hence, some of the antidepressant effects of ketamine might be mediated through its interaction with these gut bacteria. Additionally, high level of Ruminococcus is positively associated with the severity of irritable bowel syndrome (IBS), and some species of Mucispirillum have been associated with intestinal inflammation. Indirect evidence of anti-inflammatory role of Sarcina has been documented. Hence, some of the anti-inflammatory effects of ketamine and its usefulness in specific inflammatory diseases including IBS may be mediated through its interaction with these latter bacteria.ConclusionOur data suggest that at least some of the antidepressant and anti-inflammatory effects of daily ketamine treatment for 7 days may be mediated via its interaction with specific gut bacteria. These findings further validate the usefulness of microbiome as a target for therapeutic intervention and call for more detailed investigation of microbiome interaction with central mediators of mood and/or inflammatory disorders.

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“…The control group received only air via exactly similar system. The inhalation chamber has the advantage of avoiding the stress of daily injection, easily achieving and maintaining the targeted blood alcohol concentration (BAC) vs the drinking paradigm as the animals in each chamber exhibit very similar BAC and the variability in the EtOH concentration between similarly controlled chambers is minimal [20,21,22].…”

Section: Methodsmentioning

confidence: 99%

“…To determine the concentration of alcohol in the blood (BAC) at various time points, a separate group of Wistar rats were exposed to the chambers under identical conditions. Blood was sampled by tail bleed technique every three days immediately after the end of daily EtOH exposure [22]. Briefly, tail blood (0.4ml) was collected in tubes coated with 0.2M ethylenediaminetetraacetic acid (EDTA) (Sigma-Aldrich Co., St. Louis, MO, USA) and centrifuged for 5 min at 1,500g at 4oC.…”

Section: Methodsmentioning

confidence: 99%

“…On day 8, approximately 18 h after the last alcohol exposure and drug treatment, animals were tested in an open-field activity monitoring cage (27 × 27 × 20.3 cm, Med Associates, Inc., St. Albans, VT) for 5 min where ambulatory counts representing the number of infrared beam interruptions were recorded [22]. This behavior was assessed to determine if drug treatment affected general locomotor behavior, which might impinge on forced swim test immobility assessment [9, 22]. It is important to note that no drug was on board during the behavioral tests…”

Section: Methodsmentioning

confidence: 99%

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Both Ketamine and NBQX Attenuate Alcohol-Withdrawal Induced Depression in Male Rats

Getachew

Tizabi

2018

jdar

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The co-morbidity between heavy drinking and depression can negatively influence successful cessation of alcohol use. Since ketamine, a glutamatergic NMDA receptor antagonist, has shown promise as a quick-acting antidepressant, we studied its effects specifically on alcohol withdrawal-induced depression. We also evaluated the effects of NBQX an AMPA/kainate receptor antagonist, because some of the effects of ketamine are proposed to be indirectly mediated through these receptors. Adult male Wistar rats were exposed daily to ethanol via inhalation chambers 4 h/day for 7 days (blood alcohol concentration=160 mg%), followed by daily intraperitoneal injections of ketamine (2.5 mg/kg), NBQX (5mg/kg), alone or in combination. Eighteen hours later, open field locomotor activity (OFLA) followed by forced swim test (FST) were performed. The animals were sacrificed 2 h later for evaluation of brain-derived neurotrophic factor (BDNF) in the hippocampus. Alcohol withdrawal did not affect OFLA, but caused an increase in immobility in FST, suggesting induction of "depressivelike" helplessness. Both ketamine and NBQX normalized the swimming score in FST. The combination of the two drugs, however, cancelled each other's effect. Parallel to these behavioral observations, both ketamine and NBQX normalized the reduction in hippocampal BDNF caused by alcohol withdrawal. Here also, the combination of the two drugs cancelled each other's effect. These results suggest that either NMDA or AMPA/kainate receptor antagonists, acting at least partially through hippocampal BDNF, may be of therapeutic potential in alcohol use disorder.

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Role of cortical alpha-2 adrenoceptors in alcohol withdrawal-induced depression and tricyclic antidepressants

Cited by 13 publications

References 78 publications

Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats

Alcohol-Induced Increases in Inflammatory Cytokines Are Attenuated by Nicotine in Region-Selective Manner in Male Rats

Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties

Both Ketamine and NBQX Attenuate Alcohol-Withdrawal Induced Depression in Male Rats

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