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Cocaine Interaction with Dopamine Transporter in the Prefrontal Cortex and Beyond

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Cocaine Interaction with Dopamine Transporter in the Prefrontal Cortex and Beyond Central Journal of Substance Abuse & Alcoholism Bringing Excellence in Open Access Review Article *Corresponding author Ezio Carboni, Department of Biomedical Sciences, University of Cagliari, Via Ospedale 72, 09126, Cagliari, Cocaine Interaction with Italy, Email: Submitted: 18 March 2017 Accepted: 28 February 2018 Dopamine Transporter in the Published: 28 February 2018 ISSN: 2373-9363 Prefrontal Cortex and Beyond Copyright © 2018 Carboni et al. Ezio Carboni1,2*, Elena Carboni3, and Dragana Jadzic1 OPEN ACCESS 1Dept. of Biomedical Sciences, University of Cagliari, Italy 2Neuroscience Institute, National Research Council of Italy - CNR, Italy Keywords 3Unit of Pediatrics, University Magna Graecia of Catanzaro, Italy • Cocaine • Monoamine transporters Abstract • Prefrontal cortex • Nucleus accumbens Although the relevant research investment in understanding the mechanism of action of • Bed nucleus of stria terminalis cocaine and its role in altering brain circuits and behaviour, an efficacious therapy for cocaine addiction has not been found yet. Thus, cocaine use, dependence, abuse and addiction are still a relevant health, social, and economical problem. Cocaine interacts with three different monoamine transporters and increases the extracellular level of dopamine, norepinephrine and serotonin in many brain areas as well in periphery. The aim of this review is to evaluate the interaction of cocaine with the dopamine transporter (DAT) but also with the norepinephrine transporter (NET) and the serotonin transporter (SERT) in several brain areas. In addition, it will be discussed some of the receptor interaction the are involved in the complex alteration of brain circuitry that in turns produces the feeling and the behaviours sought by addicted. The areas that will be considered are: i) the prefrontal cortex (PFC), being the area in which the process of decision making is elaborated; ii) the NAcc shell because its involvement in the reinforcing and motivational properties of cocaine; iii) the bed nucleus of stria terminal is (BNST), due to its involvement in the stress response and in the relapse of cocaine consumption. It will be also considered the effect of prenatal exposure to cocaine and the target role of monoamine transporters in the search of a therapy for cocaine addiction. ABBREVIATIONS Substance Abuse and mental health Service Administration). In addition, the prevalence of acute coronary syndrome (ACS) NAcc: Nucleus Accumbens; DAT: Dopamine Transporter; associated with cocaine use increased from about 6 % in 2001 to NET: Norepinephrine Transporter; SERT: Serotonin Transporter; 22 % in 2008 and interestingly, more than 25 % of hospitalized PFC: Prefrontal Cortex; mPFC: medial Prefrontal Cortex; BNST: were younger than thirty [3]. Number of deaths from cocaine use Bed Nucleus of Stria Terminalis; VTA: Ventral Tegmental Area; is also increasing (2014) after a decline in 2010 [2,4]. LC: Locus Coeruleus; DRN: Dorsal Raphe Nucleus; PNCE: Prenatal Cocaine Exposure; GD: Gestational Day; PD: Postnatal Day Generally speaking, people begin to use drugs of abuse for recreational purposes, when the novelty seeking behaviour INTRODUCTION prevails over a prudent conservative behaviour, often under the Although the relevant research investment in understanding the mechanism of action of cocaine and its role in altering motivated by the reinforcing property of abuse substances, leads toinfluence dependence of a challenging and addiction. environment. Cocaine useThe didrepeated not differentiate exposition, from other substances until the seventies, when its use became pharmacologicalbrain circuits and tools behaviour, to prevent an efficacious abuse or therapy to treat for cocaine popular among businessmen, art-performers and other people addiction ishas probably not been due found to the yet. complexity Failure in of finding its interaction suitable who deal with high demanding roles, for improving their with brain circuits that are involved in the process of the decision formation. Thus, cocaine use, dependence, abuse and addiction effectivenessThus, if alcohol, and self-confidence. cannabis or heroin were regularly abused are still a relevant health, social, and economical problem. to ‘escape from everyday life’, cocaine was frequently used Even though the prevalence of cocaine use among high to reach better performances in demanding activities as well school seniors is much lower than alcohol use or smoking [1,2], as social life. Later on, this type of use spread among lower emergency room visits for cocaine consumption are twice as classes because of the increasing number of drug dealers and much as for heroin or marijuana consumption (Thedea.org/US the consequent drop of drug prices. Again, cocaine was often Cite this article: Carboni E, Carboni E, Jadzic D (2018) Cocaine Interaction with Dopamine Transporter in the Prefrontal Cortex and Beyond. J Subst Abuse Alcohol 6(1): 1074. Carboni et al. (2018) Email: Central Bringing Excellence in Open Access used to enhance performances and, as a result, more violent DOPAMINE RECEPTORS AND COCAINE EFFECTS crimes were accomplished under its effect [5]. Hence, although Even if we consider that cocaine monoamine reuptake cocaine shares many features with many other drugs of abuse, blockade is the primary mechanism of its action, we have to we believe that its peculiar motivational properties have a take into account that the higher synaptic levels of monoamine crucial role in cocaine addiction. In particular, cocaine ability to will produce a plethora of effects by interacting with multiple be self-administered by experimental animals and its property types of receptors. Thus, one may wonder which receptors to stimulate dopamine transmission in the nucleus accumbens mediate cocaine effects and in which brain area they play their (NAcc) [6-8], allows its inclusion in the large group of addictive substances. Yet, the peculiar use among addicted people suggests vast number that do not allow an exhaustive evaluation in this that the neurobiological mechanisms and the alteration of paragraph.role. We will Although consider numerous here a few studies significant on dopamine reports, out receptors of their brain circuits observed in animal models should be evaluated the results are still unsatisfactory [16-18]. Nonetheless, these into clinical practice. The aim of this review is to evaluate the studieshad the contributedaim to find toan aefficacious better understanding therapy for ofcocaine the mechanisms addiction, with caution, along with the translation of research findings interaction of cocaine with the dopamine transporter (DAT) of cocaine effects. As regards dopamine D2 receptors, it has been but also with the norepinephrine transporter (NET) and the reported that vulnerability to the reinforcing effects of cocaine is serotonin transporter (SERT) in several brain areas, in addition, higher when D2 receptor number is reduced [19], and that chronic the relative consequences that generate the complex alteration cocaine exposure reduces their number in monkeys and humans in brain circuitry that in turns produces the feeling and the [20] while, in general, blockade of D2 receptors can reduce the behaviours sought by addicted will be discussed. The areas that strength of cocaine reinforcing effects [21]. Among D2 receptors will be considered are: i) the prefrontal cortex (PFC), being the a minority are autoreceptors and their role is somehow different. area in which the process of decision making is elaborated; ii) In fact, Bello et al. [22], have showed that mice with the selective the NAcc shell because its involvement in the reinforcing and loss of D2 autoreceptors exhibits increased place preference motivational properties of cocaine; iii) the bed nucleus of stria for cocaine. Thus we could hypothesize that an individual has terminalis (BNST), due to its involvement in the stress response a higher vulnerability for cocaine due to existence of increased and in the relapse of cocaine consumption. dopamine transmission and due to possibly reduced number of D2 receptors and in particular to autoreceptor function reduction. COCAINE MECHANISM OF ACTION: MONOAMINE Therefore cocaine, by increasing synaptic dopamine levels TRANSPORTERS should also increase stimulation of D2 receptor. On this basis, Understanding cocaine mechanism of action is apparently with D2 antagonists while a therapy based on dopamine agonists have suggested that the primary site of cocaine action is the shouldit is very better unlikely reproduce that a the subject effects will of cocaine.find acceptable Unfortunately, a therapy the presynaptican easy task. DAT Earlier [9]. studiesBeing DATon geneticallythe main modifiedmechanism mice of therapy for cocaine addiction, based either on dopamine agonists synaptic dopamine removal, cocaine blockade of DAT increases or antagonists, is not adequate [16,18,23]. Furthermore, D3 the extracellular dopamine concentration, thus strengthening receptors are also involved in cocaine addiction (see [24] for a the effects mediated by dopamine. In particular, the increase dopamine and results fully occupied when D1 or D2 are occupied short review). Peculiarly, this receptor has a higher affinity for a distinctive mark of drugs of abuse in rodents and in humans only by about 25 % [25]. They are located in limbic areas and may [10,11].of extracellular Therefore dopamine it appears in obviousspecific thatbrain cocaine areas (i.e.is rewarding NAcc) is mediate motivational and emotional
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