Rewarding

withdrawal DR YOUSSEFSARI

In an exciting study, Dr Youssef Sari is investigating approaches to reverse the impulse to alcoholism or drug dependency by augmenting the brain’s capacity to maintain normal neurotransmitter levels and function

studies have reported that alcohol also alters an alcoholic beverage, the rats developed glutamate transport. alcohol dependence. We administered ceftriaxone to the rats every day for five days Although the neurocircuitry of the and measured their alcohol consumption. After glutamatergic system is not fully defined, it treatment with ceftriaxone, the rats consumed has been suggested that this system within the significantly less alcohol. This reduction was PFC and the NAc plays a critical role in drug associated with increased levels of expression reinforcement. Both regions receive substantial of GLT1 in brain reward regions, including the input from midbrain dopaminergic neurons, PFC and NAc. and all major drugs of abuse, including alcohol, increase forebrain dopamine transmission. We have also tested another drug, GPI-1046, that has shown to be effective in reducing Glutamatergic projections from the PFC to alcohol consumption associated with elevation the NAc are also critical in the expression of of GLT1 levels. addictive behaviors. Therefore, our studies focus on the analysis of the function of a Could you describe the mechanisms of protein called glutamate transporter-1 (GLT1) adenosine and glutamate signalling in in these two key brain reward regions. neuron-glia interactions? Could you first outline your project goals? Can you explain the role of GLT1 in Adenosine plays an important role in The prefrontal cortex (PFC) in the brain is the developing therapeutics for the treatment regulating the activity of neurons and moderator for decision making. In addicts, of alcohol abuse and dependence? controlling neurotransmitters, including the PFC is very active and releases – in gamma-aminobutyric acid (GABA), glutamate particular and at the slightest provocation – a We have found that elevation of the expression and dopamine. Alcohol has been shown to neurotransmitter called glutamate. We aim of GLT1 was associated with a reduction in increase extracellular adenosine levels, which to investigate the role of the glutamatergic alcohol consumption and attenuation of in turn regulates the ataxic and hypnotic/ system in the central reward regions of the relapse to alcohol drinking behavior in rats. sedative effects of alcohol. Adenosine brain that are involved in alcohol dependence, GLT1 might therefore be considered as a signalling is also involved in the homeostasis and ultimately seek to develop drugs that can potential therapeutic target for the treatment of major inhibitory (GABA) and excitatory successfully treat alcohol addiction. of alcohol abuse and dependence. (glutamate) neurotransmission through neuron-glial interactions. These interactive What evidence is there to suggest that many Other researchers have tested more than 1,040 mechanisms regulate the effect of alcohol aspects of alcohol and drug dependence approved drugs to determine those which and sleep. Furthermore, adenosine exerts its involve changes in glutamate transmission? might be effective at removing glutamate from function through several adenosine receptors the space between neurons. It turns out that and regulates glutamate levels in the brain, Neuroadaptations of the glutamatergic a β-lactam antibiotic – ceftriaxone – increases which modulate alcohol dependence and system play a key role in alcohol tolerance, the expression of GLT1 and decreases the sleep patterns. dependence and withdrawal. The selective amount of extracellular glutamate available effects of alcohol include inhibition of to activate addictive behaviors. This drug has What will be the next steps for your glutamatergic neurotransmission by alteration been used to treat meningitis and is in phase III research? of N-methyl-D-aspartate (NMDA) receptors. clinical trial for the treatment of amyotrophic One of the effects of chronic alcohol exposure lateral sclerosis (ALS). Now that we have shown the effectiveness of is the up-regulation of NMDA receptors that ceftriaxone in reducing addictive behaviors, are part of the compensatory mechanism, What did you discover during your we are working to create synthetic analogues. which results from chronic inhibition of examination of alcohol-preferring (P) rats? Ceftriaxone is an antibiotic and it would glutamatergic neurotransmission. In addition, be advantageous to have therapeutic the effects of alcohol withdrawal are associated P rats naturally prefer drinking alcohol to compounds that do not have the antibiotic with increased extracellular glutamate levels plain water and so we used this model to form. There are other compounds that in the striatum of alcohol-dependent rats and measure the effectiveness of ceftriaxone in activate GLT1. We are currently investigating enhanced NMDA sensitivity in the nucleus reducing alcohol cravings and consumption. the signalling pathways involved in the accumbens (NAc). Importantly, a number of After five weeks of a constant free choice of mechanism of action of these drugs. WWW.RESEARCHMEDIA.EU 15 DR YOUSSEF SARI

Alcohol dependency: the sobering reality

Studies at the University of Toledo have identified that the compulsion to indulge in harmful behaviors can be modulated by adjusting the expression of fundamental neuron-glia messaging proteins in the brain – research that could have important implications for alcoholism

ALCOHOLISM IS WIDELY recognised as that the alcohol causes GLT1 to fail to properly as alcohol, cocaine, methamphetamine, a disease rather than a lifestyle choice – a fulfil its role. This proposal has been validated heroin and nicotine (Goldstein and Volkow, perception first put forward by the Alcoholics in several recent projects in Sari’s laboratory, 2002),” Sari elaborates. Anonymous organisation in the 1930s. The in which he has determined that treatment of perception that alcoholism is a physical disease addicted rats with an antibiotic – ceftriaxone, In 2009, Sari tested the hypothesis that, since rests on the evidence that, despite widespread which elevates GLT1 levels (Rothstein el al., an increase in glutamate transmission triggers knowledge of the damaging effects of excessive 2005) – causes a significant reduction in alcohol dopamine to engender relapse behavior, the drinking on health – from life-threatening consumption, and inhibits relapse into cocaine elevation of GLT1 levels in the PFC and NAc liver disease to impaired brain function – the or alcohol dependency behaviors (Sari et al., regions of the brain should prevent relapse nature of an alcoholic’s addiction is such 2009; Sari et al., 2011; Qrunfleh et al., 2013). into cocaine use by reducing the extracelullar that, presented with the opportunity to drink, glutamate levels. Indeed, Sari and colleagues he/she will most often succumb. Emerging found that ceftriaxone treatment attenuates THE NATURE OF DEPENDENCY evidence suggests that physiological changes relapse to cocaine seeking behavior (Sari et are responsible for the formation of addiction The burden of alcohol dependency is massive. al., 2009). to and dependency on alcohol and other It afflicts nearly 14 million people and is drugs, though such changes do not arise from responsible for around 79,000 deaths annually Though the neurochemistry is different in disease (Krystal et al., 2003). A key source of in the US alone. On a global scale, the World alcohol and cocaine addiction, glutamate plays dependency is thought to be alcohol-induced Health Organization (WHO) attributes 2.5 a similar role in both cases. Sari deduced that the changes to the transport of glutamate, an million deaths annually to the disease: “Alcohol amino acid that is responsible for messaging dependency is defined by four characteristics: between neurons in the brain (Smith, 1997). craving, or the strong need to drink; loss of control, or not being able to stop; dependence, Z Dr Youssef Sari, Assistant Professor of or having withdrawal symptoms such as Pharmacology at the University of Toledo in seizures, nausea and sweating after stopping; Ohio, USA, is exploring the role of the main and tolerance, or requiring greater quantities Z glutamate transporter, glutamate transporter to obtain the same effect,” Sari explains. 1 (GLT1) – an integral membrane protein – in alcohol dependency. The role of GLT1 is to clear The prefrontal cortex (PFC) and nucleus Z glutamate from clefts between synapses by accumbens (NAc) regions in the brain receive taking it up and sequestering it. Sari’s hypothesis substantial input from midbrain dopamine is that normal glutamatergic transmission neurons, and all major drugs of abuse, in central reward regions of the brain thus including cocaine, are known to increase $18 modulates the intake of alcohol or drugs such as forebrain dopamine transmission (Kalivas, billion+ cocaine, and that perturbations of this system 2004). However, dopamine involvement result in substance abuse and dependency. in relapses into drug abuse relies on an increase in glutamate, the primary driver Dysfunction in the glutamatergic excitatory of PFC neurons. “The importance of these system is known to be involved in glutamatergic projections from the PFC to the Economic burden of sleep neurodegenerative diseases. As there are NAc and the ventral tegmental area have been disorders related to alcohol parallels between the effects of alcohol on the observed in neuroimaging studies performed dependency in the US alone brain and some neurodegenerative diseases during craving periods in several different such as Huntington’s disease, Sari proposes paradigms, for commonly abused drugs such 16 INTERNATIONAL INNOVATION INTELLIGENCE THE ROLE OF GLT1 IN THE Key MODULATION OF ALCOHOL-DRINKING BEHAVIOR IN P RATS Publications OBJECTIVES To investigate the potential therapeutic role of glutamate transporter 1 (GLT1) on alcohol-drinking behavior with a genetically selected high alcohol-consuming rat line: Goldstein RZ, Volkow ND (2002) Drug the alcohol-preferring (P) rat. addiction and its underlying neurobiological KEY COLLABORATORS findings from his study with cocaine-addicted basis: neuroimaging evidence for the rats provided a solid foundation for targeting involvement of the frontal cortex. Dr Doo-Sup Choi, Mayo Clinic, Rochester GLT1 in alcohol dependency. In recent Am J Psychiatry 159:1642-1652. Dr James Leighton, Columbia University, projects, Sari’s lab has examined the effects of New York ceftriaxone and another drug, GPI-1046, that Kalivas PW (2004) Glutamate systems raises GLT1 levels in alcohol-preferring (P) rats in cocaine addiction. Dr George Rebec, Indiana University (Sari et al., 2011; Sari and Sreemantula, 2012): Curr Opin Pharmacol 4:23-29. Dr Bryan Yamamoto, University of Toledo “Increasing the expression of GLT1 in the brain of a rat exposed to alcohol reduced the levels Krystal JH, Petrakis IL, Mason G, Trevisan L, Dr Richard Bell, Indiana University of extracellular glutamate available to activate D’Souza DC (2003) N-methyl-D-aspartate neurons in central reward regions of the brain, glutamate receptors and alcoholism: reward, Dr Paul Rosenberg, Harvard Medical School and thus decreased the craving initiated by it,” dependence, treatment, and vulnerability. Dr Jeffery Rothstein, Johns Hopkins he observes. Pharmacol Ther 99:79-94. University

Nam HW, McIver SR, Hinton DJ, Thakkar MM, FUNDING ADJUSTING THE EFFECTS OF ALCOHOL Sari Y, Parkinson FE, Haydon PG, Choi DS National Institutes of Health In a further review of the implication of (2012) Adenosine and glutamate signaling (Grant no. R01AA019458). adenosine and glutamate in alcoholism and in neuron-glial interactions: implications in sleep disorders, Sari and his collaborators alcoholism and sleep disorders. CONTACT discussed the importance of neuron-glia Alcohol Clin Exp Res 36:1117-1125. Dr Youssef Sari signalling between glutamate and adenosine, Assistant Professor of Pharmacology which plays a critical role in proper brain Qrunfleh AM, Alazizi A, Sari Y (2013) function and regulates the effects of alcohol Ceftriaxone, a beta-lactam antibiotic, University of Toledo on coordination and wakefulness (Nam et attenuates relapse-like ethanol-drinking College of Pharmacy al., 2012). Alcohol increases extracellular behavior in alcohol-preferring rats. & Pharmaceutical Sciences adenosine levels, which decreases glutamate Journal of psychopharmacology. Department of Pharmacology neurotransmission; equally, glutamate Health Science Campus, Mail Stop 1015 increases the release of adenosine. Rothstein JD, Patel S, Regan MR, Haenggeli 3000 Arlington Avenue, HEB283C C, Huang YH, Bergles DE, Jin L, Dykes Hoberg Toledo, OH 43614, USA Importantly, the team reported that alteration M, Vidensky S, Chung DS, Toan SV, Bruijn LI, of glial transporters, GLT1 and equilibrative Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam T +1 419 383 1507 nucleoside transporter 1 (ENT1) occurred with antibiotics offer neuroprotection by increasing E [email protected] exposure to alcohol (Sari et al., 2013 in press). glutamate transporter expression. Researchers found that astrocyte-dependent Nature 433:73-77. DR YOUSSEF SARI received his doctorate purinergic signalling additionally appeared to in neuroscience from Pierre and Marie Curie have an impact on dependent behavior and Sari Y, Sakai M, Weedman JM, Rebec GV, Bell University, Institute of Neuroscience (Paris, Sari feels that this needs further clarification. RL (2011) Ceftriaxone, a beta-lactam antibiotic, France) and subsequently held postdoc However, Ceftriaxone administration restored reduces ethanol consumption in alcohol- and faculty research positions at Indiana GLT1 and ENT1 levels to normal and Sari and his preferring rats. Alcohol Alcohol 46:239-246. University. Sari holds a faculty position team found that the risk of excessive glutamate at the level of Assistant Professor of clearing was low. Sari Y, Smith KD, Ali PK, Rebec GV (2009) Pharmacology at the University of Toledo, Upregulation of GLT1 attenuates cue-induced College of Pharmacy and Pharmaceutical The team has established that ceftriaxone reinstatement of cocaine-seeking behavior in Sciences, Toledo, Ohio, USA. His research administration in P rats is long-lasting, being rats. J Neurosci 29:9239-9243. focuses on the role of GLT1 in alcohol- effective after five weeks of alcohol drinking drinking behavior using compounds and lasting up to 10 days post-treatment Sari Y, Sreemantula SN (2012) targeting this transporter. Sari is also testing (Sari et al., 2011). They have also ascertained Neuroimmunophilin GPI-1046 reduces ethanol compounds for the treatment of diseases that ceftriaxone administration can stop the consumption in part through activation involving oxidative stress. rats from relapsing into drinking alcohol, but of GLT1 in alcohol-preferring rats. that it does not interfere with less harmful Neuroscience 227:327-335. compulsions (Qrunfleh et al., 2013). To Sari, therefore, proper glutamate transport Sari Y, Sreemantula SN, Lee R, Choi D-S (2013, provides protection against deleterious in press) Ceftriaxone treatment affects the addictions and targeting GLT1 expression levels of GLT1 and ENT1 as well as ethanol is clearly the way forward: “A focus on the intake in alcohol-preferring rats. glutamatergic system as a prime candidate for mediating drug and alcohol dependence is Smith TL (1997) Regulation of glutamate the key to paving the path for new treatment uptake in astrocytes continuously exposed to of such addictions,” he forecasts. ethanol. Life Sci 61:2499-2505. WWW.RESEARCHMEDIA.EU 17