Browsing by Author "Getachew, Bruk"

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    Adolescent alcohol drinking interaction with the gut microbiome: implications for adult alcohol use disorder
    (Frontiers Media, 2024) Getachew, Bruk; Hauser, Sheketha R.; Bennani, Samia; El Kouhen, Nacer; Sari, Youssef; Tizabi, Yousef; Psychiatry, School of Medicine
    Reciprocal communication between the gut microbiota and the brain, commonly referred to as the “gut-brain-axis” is crucial in maintaining overall physiological homeostasis. Gut microbiota development and brain maturation (neuronal connectivity and plasticity) appear to be synchronized and to follow the same timeline during childhood (immature), adolescence (expansion) and adulthood (completion). It is important to note that the mesolimbic reward circuitry develops early on, whereas the maturation of the inhibitory frontal cortical neurons is delayed. This imbalance can lead to increased acquirement of reward-seeking and risk-taking behaviors during adolescence, and consequently eventuate in heightened risk for substance abuse. Thus, there is high initiation of alcohol drinking in early adolescence that significantly increases the risk of alcohol use disorder (AUD) in adulthood. The underlying causes for heightened AUD risk are not well understood. It is suggested that alcohol-associated gut microbiota impairment during adolescence plays a key role in AUD neurodevelopment in adulthood. Furthermore, alcohol-induced dysregulation of microglia, either directly or indirectly through interaction with gut microbiota, may be a critical neuroinflammatory pathway leading to neurodevelopmental impairments and AUD. In this review article, we highlight the influence of adolescent alcohol drinking on gut microbiota, gut-brain axis and microglia, and eventual manifestation of AUD. Furthermore, novel therapeutic interventions via gut microbiota manipulations are discussed briefly.
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    CB1 Receptors Regulate Alcohol-Seeking Behavior and Alcohol Self-administration of Female Alcohol-Preferring (P) Rats
    (Elsevier, 2011-02) Getachew, Bruk; Hauser, Sheketha R.; Dhaher, Ronnie; Bell, Richard L.; Oster, Scott M.; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of Medicine
    Rationale The endogenous cannabinoid (CB) system mediates a number of behaviors associated with drug-seeking and drug self-administration. In this study the effects of CB1 receptor manipulations on operant ethanol (EtOH) responding during EtOH-seeking, EtOH- relapse as well as on-going EtOH self-administration were determined. Methods Alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. After 10 weeks, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages without access to EtOH or operant chambers. Rats were then returned to the operant chambers for testing of EtOH-seeking behavior (no EtOH present) for 4 sessions. After a week in their home cages following the EtOH-seeking test, rats were returned to the operant chambers with access to EtOH and water (relapse). Rats were then maintained in the operant chambers for daily 1-hr sessions with access to 15% EtOH and water for several weeks. Results The CB1 receptor antagonist (SR141716A), at doses of 1 and 2 mg/kg, i.p. reduced EtOH-seeking and transiently reduced EtOH self-administration during relapse and maintenance. Conversely, treatment with the CB1 receptor agonist CP, 55-940, at doses of 1 and 10 μg/kg i.p., increased EtOH-seeking and EtOH self-administration during relapse. Conclusions The results of this study demonstrate that activation of CB1 receptors are involved in regulating EtOH-seeking as well as the reinforcing effects of EtOH under relapse and on-going self-administration conditions.
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    Nicotine Modulates Alcohol-Seeking and Relapse by Alcohol-Preferring (P) Rats in a Time Dependent Manner
    (Wiley, 2012-01) Hauser, Sheketha R.; Getachew, Bruk; Oster, Scott M.; Dhaher, Ronnie; Ding, Zheng-Ming; Bell, Richard L.; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of Medicine
    Background— Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at two different time points. Method— Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5 – fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hr sessions. Following 10 weeks of daily 1-hr sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected s.c. immediately or 4-hr prior to PSR or relapse testing. Results— Injections of nicotine immediately prior to testing reduced (5–10 responses PSR; 50– 60 responses relapse), whereas injections of nicotine 4-hr prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests. Discussion— The results of this study demonstrate that acute effects of nicotine on EtOH- seeking and relapse behaviors may be time-dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH whereas, with a delay of 4-hr, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine’s metabolites (i.e., cotinine, nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors.
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    Role of Glial Cells in Neuronal Function, Mood Disorders, and Drug Addiction
    (MDPI, 2024-05-30) Tizabi, Yousef; Getachew, Bruk; Hauser, Sheketha R.; Tsytsarev, Vassiliy; Manhães, Alex C.; da Silva, Victor Diogenes Amaral; Psychiatry, School of Medicine
    Mood disorders and substance use disorder (SUD) are of immense medical and social concern. Although significant progress on neuronal involvement in mood and reward circuitries has been achieved, it is only relatively recently that the role of glia in these disorders has attracted attention. Detailed understanding of the glial functions in these devastating diseases could offer novel interventions. Here, following a brief review of circuitries involved in mood regulation and reward perception, the specific contributions of neurotrophic factors, neuroinflammation, and gut microbiota to these diseases are highlighted. In this context, the role of specific glial cells (e.g., microglia, astroglia, oligodendrocytes, and synantocytes) on phenotypic manifestation of mood disorders or SUD are emphasized. In addition, use of this knowledge in the potential development of novel therapeutics is touched upon.
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    Selective breeding for high alcohol consumption and response to nicotine: locomotor activity, dopaminergic in the mesolimbic system, and innate genetic differences in male and female alcohol-preferring, non-preferring, and replicate lines of high-alcohol drinking and low-alcohol drinking rats
    (Springer, 2018-09) Deehan, Gerald A., Jr.; Hauser, Sheketha R.; Getachew, Bruk; Waeiss, R. Aaron; Engleman, Eric A.; Knight, Christopher P.; McBride, William J.; Truitt, William A.; Bell, Richard L.; Rodd, Zachary A.; Psychiatry, School of Medicine
    Rationale There is evidence for a common genetic link between alcohol and nicotine dependence. Rodents selectively bred for high alcohol consumption/responsivity are also more likely to self-administer nicotine than controls. Objectives The experiments examined the response to systemic nicotine, the effects of nicotine within the drug reward pathway, and innate expression of nicotine-related genes in a brain region regulating drug reward/self-administration in multiple lines of rats selectively bred for high and low alcohol consumption. Methods The experiments examined the effects of systemic administration of nicotine on locomotor activity, the effects of nicotine administered directly into the (posterior ventral tegmental area; pVTA) on dopamine (DA) release in the nucleus accumbens shell (AcbSh), and innate mRNA levels of acetylcholine receptor genes in the pVTA were determined in 6 selectively bred high/low alcohol consuming and Wistar rat lines. Results The high alcohol-consuming rat lines had greater nicotine-induced locomotor activity compared to low alcohol-consuming rat lines. Microinjections of nicotine into the pVTA resulted in DA release in the AcbSh with the dose response curves for high alcohol-consuming rats shifted leftward and upward. Genetic analysis of the pVTA indicated P rats expressed higher levels of α2 and β4. Conclusion Selective breeding for high alcohol preference resulted in a genetically divergent behavioral and neurobiological sensitivity to nicotine. The observed behavioral and neurochemical differences between the rat lines would predict an increased likelihood of nicotine reinforcement. The data support the hypothesis of a common genetic basis for drug addiction and identifies potential receptor targets.