Special Issue "Drug Abuse Targets"

Guest Editor
Dr. Juan J. Canales
Behavioural Neuroscience, Department of Psychology, The University of Canterbury, PB 8140, Christchurch, New Zealand
Website: http://www.psyc.canterbury.ac.nz/people/canales.shtml
E-Mail: juan.canales@canterbury.ac.nz
Interests: neuroscience; neuropsychopharmacology; drug addiction; adult neurogenesis; hippocampus; memory

Dear Colleagues,

The development of more efficacious pharmacological interventions in drug addiction remains a major challenge. The pharmacological treatment of drug addiction is intended to help patients stop compulsive drug seeking and taking, ameliorate the symptoms of drug withdrawal and reduce the likelihood of relapse. Recent advances into the neurobiology and neuropharmacology of drug addiction have led to the identification of new targets and molecules that are currently under investigation as potential leads for developing specific therapeutics, including vaccines, novel monoamine transport inhibitors, dopamine agonists, cannabinoids, and compounds acting at trace amine associated receptors. This special issue is devoted to reviewing the present state of the science in neuropharmacology and medication development for drug addiction, and to identifying promising areas for future research.

Dr. Juan J. Canales
Guest Editor

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• drug abuse and addiction
• neurotoxicity
• neuropsychopharmacology
• animal models
• monoamines
• monoamine transporters
• dopamine receptors

Type of Paper: Review
Title: Methylenedioxymethamphetamine (MDMA, 'ecstasy'): Neurotoxicity versus Neuromodulation
Authors: Elena Puerta and Norberto Aguirre
Affiliation: Department of Pharmacology, University of Navarra, School of Medicine, c/Irunlarrea 1, 31008 Pamplona, Spain; E-Mail: popi@unav.es (N.A.)
Abstract: The ring-substituted amphetamine analogue, 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), is widely abused as a recreational drug. Among its psychological effects MDMA usually produces emotional openness and empathy what makes it different from other traditional stimulants such as cocaine or amphetamine. Of interest, single or repeated injections of MDMA can cause long-lasting deficits in neurochemical and histological markers of the serotonergic function in the brain of different animal species and humans. Great efforts have been made during the last two decades trying to decipher the chain of biochemical events responsible for the serotonergic deficits caused by MDMA and still, nowadays, we do not have a clear picture of the situation. For many years we were all very confident that reactive oxygen species (ROS) were responsible for such deficits and it was the source of ROS the only matter of scientific debate. Moreover, since the first published work in 1987 reporting the long-term 5-HT depletions caused by MDMA in rats, we all assumed that such deficits were indicative of neurotoxicity. However, recent studies indicate that MDMA causes regulatory changes in the expression of some serotonergic markers that had been used as an index of neurotoxicity. Evidences supporting neurotoxicity or neuromodulation will be reviewed.

Type of Paper: Review
Title: Drug Abuse and Adult Neurogenesis
Author: Vicente Hernandez-Rabaza
Affiliation: University of Valencia-General Foundation & Red de Trastornos Adictivos (RETICS) Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE) Polígono de la Coma s/n, Paterna 46980 Valencia, Spain; E-Mail: vitehernandez@yahoo.es
Abstract: The constant production of new neurons in the adult mammalians brain is referred to as adult neurogenesis. This process represents a recent discovery that has been described to occur only in two brain regions: the olfactory bulbs and the hippocampus. We have current evidence indicating that a damaged adult neurogenesis could negative affect different cognitive abilities and mood states. Among the many detrimental factors affecting adult neurogenesis, the abuse of drugs has been pointed as one of the most relevant. Different experimental protocols and treatments have been used to demonstrate that drugs such as psychomotor stimulants, alcohol and psychedelic compounds alter the progenitor rate, the survival or the maturation of the new adult neurons. The new challenge, the current research is facing is to establish a relationship between the cellular alterations in the neurogenic process and the acquisition of addictive behavior and induction of drug-induced cognitive deficits described in humans abusers. Particularly, neurogenesis in the hippocampus has sparked off a great interest as a potential substrate for the cognitive and emotional abnormalities that become apparent during the drug addiction process. However, the harmful effects of drugs are produced at multiple physiological and anatomical levels, and the consequences that specifically result from reduced hippocampal neurogenesis remain to be elucidated.

Type of Paper: Review
Title: Psychostimulant Drugs and Neuroplasticity
Author: Emilio Fernandez-Espejo
Affiliation: Departamento de Fisiología Médica, Facultad de Medicina, Universidad de Sevilla, 41009 Seville, Spain; E-Mail: efespejo@us.es
Abstract: Drugs of abuse induce plastic changes in the brain that seem to underlie addictive phenomena. These plastic changes can be structural (morphological) or synaptic (biochemical), and most of them take place in the mesolimbic and mesostriatal circuits. Repeated exposure to psychostimulants induces morphological changes such as increase in the number of dendritic spines, changes in the morphology of dendritic spines, and altered cellular coupling through new gap junctions. Arc mRNA and Arc protein, markers for neuritic outgrowth, have been reported to be upregulated in the dorsal striatum after chronic cocaine, and downregulation of mielin-related genes takes place in the nucleus accumbens of human cocaine abusers. Repeated exposure to psychostimulants also induces various synaptic adaptations, that include up- or down-regulation of D1, D2 and D3 dopamine receptors, changes in subunits of G proteins, increased adenylyl cyclase activity, cyclic AMP and protein kinase A in the nucleus accumbens, increased tyrosine hydroxylase enzyme activity, increased calmodulin and activated CaMKII in the ventral tegmental area, and increased delta-Fos-beta, c-Fos and AP-1 binding proteins. Most of these changes are transient, suggesting that more lasting plastic brain adaptations should take place. In this context, protein synthesis inhibitors block the development of sensitization to cocaine, and pups younger than 3 weeks old, which are too immature to develop neural networks, do not become sensitized to psychostimulants. These evidences suggest that rearrangement of neural networks must develop for the long-lasting plasticity required for addiction and drug sensitization to occur.

Type of Paper: Review
Title: Neuronal Nicotinic Receptors as New Targets for Amphetamine Derivatives
Authors: David Pubill, Sara Garcia-Ratés, Jordi Carmarasa and Elena Escubedo
Affiliation: Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda. Joan XXIII s/n, 08028 Barcelona, Spain; E-Mail: d.pubill@ub.edu (D.P.)
Abstract: Amphetamine derivatives such as methamphetamine (MA) and 3,4- methylenedioxymethamphetamine (MDMA, ecstasy) are drugs widely abused in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As for neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research from our group has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits MA- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by MA and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found.

Type of Paper: Review
Title: The Endocannabinoid System as Pharmacological Target Derived from its Role in Homeostasis and Reward
Authors: Maria-Paz Viveros, Francisco-Javier Bermudez-Silva F, Ana B. Lopez-Rodriguez and Edward J. Wagner
Affiliation: Departamento de Fisiología (Fisiología Animal II) Facultad de Biología, Universidad Complutense 28040 Madrid Spain; E-Mail: pazviver@bio.ucm.es (M.-P.V.)
Abstract: The endocannabinoid system (ECS) has been implicated in many physiological functions including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We will introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the Gi/o-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN) and bulimia nervosa (BN) are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbance. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We will present and discus data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we will discus recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzimatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH) as a particularly interesting potential target. Since a disregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug-withdrawal states, this is an area of relevance to also explore adjuvant treatments for improving these adverse emotional reactions.

Type of Paper: Review
Title: Targeting Trace Amine-Associated Receptors in the Treatment of Drug Addiction
Authors: Antonio Ferragud, Clara Velázquez-Sánchez, Florent Revel, Marius C. Hoener and Juan J. Canales
Affiliation: Behavioural Neuroscience, Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; E-Mails: juan.canales@canterbury.ac.nz (J.J.C.); antonio.ferragud@uv.es (A.F.)
Abstract: Since the discovery, over a decade ago, of the so-called trace amine-associated receptors (TAAR), a family of G-protein-coupled receptors which are non-selectively activated by some endogenous trace amines, the interest in characterizing their biological and behavioural functions has increased remarkably. Although their physiological function has been controversial and remains so, growing evidence suggests that these receptors may play an important role in the regulation of monoaminergic transmission. In particular, TAAR1, which is activated by a broad spectrum of classic biogenic amines as well as amphetamine-related psychostimulants, has been shown to be anatomically positioned to modulate dopamine neurons in mesolimbic system, and it is therefore feasible to assume they make a contribution toward the acute and long-term effects of psychostimulants drugs in the brain. We will review recent evidence in support of this assumption. We propose that pharmacological manipulations of TAAR1 may be used to antagonise/minimise the effects of psychomotor stimulants, and may constitute new leads for preventing/correcting the long-tem neuroadaptations underlying relapse to drug seeking behaviour. Although more studies are needed to better understand the physiology and behavioural pharmacology of TAAR1 receptors, they stand out as a promising new target for the development of effective medications for stimulant addiction.

Type of Paper: Review
Title: Orexin Receptor Targets for Anti-Relapse Medication Development
Authors: Luyi Zhou, Wei-Lun Sun and Ronald E. See
Affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC, USA; E-Mail: seere@musc.edu (R.E.S.)
Abstract: Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a clear target for ongoing drug development. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of relapse and the potential for orexin receptors as targets for anti-relapse medication approaches.

Type of Paper: Review
Title: Neural Changes Developed During the Extinction of Cocaine Self-Administration Behavior
Authors: Emilio Ambrosio, Miguel Miguéns, Nuria del Olmo, Alejandro Higuera-Matas and Carmen García-Lecumberri
Affiliation: Psychobiology Department, School of Psychology, UNED, C/Juan del Rosal no. 10, 28040 Madrid, Spain; E-Mail: eambrosio@psi.uned.es (E.A.)
Abstract: The high rate of recidivism in cocaine addiction after prolonged periods of abstinence is an important clinical problem that probably requires a better understanding of the neurobiological process that might be involved in this phenomenon. The aim of this review is to discuss the evidences obtained to date on the neurobiological changes that occur during the maintenance of cocaine abstinence. Particularly, we will focus on data provided by self-administration paradigms, as well as by withdrawal studies after chronic cocaine administration, on the dopaminergic, opioidergic, glutamatergic, cholinergic, serotoninergic and CRF systems. Most of these works suggest that cocaine absence induces the development of modifications in regulatory elements of these neurotransmitter systems that might contribute to establish an increased vulnerability to cocaine relapse. Genetic differences in the neuroadaptive response to cocaine absence also are aspects that should be consider for having a comprehensive view of this subject. Similarly, the importance of differences related to contingent versus non-contingent presentation of environmental in presence of cocaine and its effects during the extinction will be analyzed. The results discussed in this work might help to develop more effective therapeutic approaches for cocaine relapse.