Current Drug Abuse Reviews

ISSN: 1874-4737 - Volume 1, 2008

Current Drug Abuse Reviews
Volume 1, Number 2, June 2008

Contents


Editorial : Pp. 112-113
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Long-Term Consequences of Adolescent Cannabis Exposure on the Development of Cognition, Brain Structure and Function: An Overview of Animal and Human Research Pp. 114-123
Gerry Jager and Nick F. Ramsey
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The Genetic Components of Alcohol and Nicotine Co-Addiction: From Genes to Behavior Pp.124-134
Isabel R. Schlaepfer, Nicole R. Hoft and Marissa A. Ehringer
[Abstract] [Purchase Issue/Articles]


Policy and Health Implications of Using the U.S. Food and Drug Administration Product Design Approach in Reducing Tobacco Product Risk Pp. 135-141
Michael Givel
[Abstract] [Purchase Issue/Articles]


Smoking Cessation for Adolescents: A Review of Pharmacological and Psychosocial Treatments Pp. 142-154
Ty S. Schepis and Uma Rao
[Abstract] [Purchase Issue/Articles]


Use of Caffeine and Nicotine in People with Schizophrenia Pp. 155-161
Jill M. Williams and Kunal K. Gandhi
[Abstract] [Purchase Issue/Articles]


“My Drink is Larger than Yours”? A Literature Review of Self-Defined Drink Sizes and Standard Drinks Pp. 162-176
Loraine Devos-Comby and James E. Lange
[Abstract] [Purchase Issue/Articles]


Hepatitis C Treatment in Patients with Drug Addiction: Clinical Management of Interferon-Alpha-Associated Psychiatric Side Effects Pp. 177-187
Martin Schaefer and Stefan Mauss
[Abstract] [Purchase Issue/Articles]


Potential Role of ADAMTS13 in the Progression of Alcoholic Hepatitis Pp.188-196
Masahito Uemura, Yoshihiro Fujimura, Tomomi Matsuyama, Masanori Matsumoto, Masatoshi Ishikawa, Hiromichi Ishizashi, Seiji Kato, Tatsuhiro Tsujimoto, Masao Fujimoto, Hitoshi Yoshiji, Chie Morioka and Hiroshi Fukui
[Abstract] [Purchase Issue/Articles]

Recent Developments in the Treatment of Alcoholic Chronic Pancreatitis Pp.197-202
Tatsuhiro Tsujimoto, Hideto Kawaratani, Hitoshi Yoshiji, Masahito Uemura and Hiroshi Fukui
[Abstract] [Purchase Issue/Articles]


“Speed” Warps Time: Methamphetamine’s Interactive Roles in Drug Abuse, Habit Formation, and the Biological Clocks of Circadian and Interval Timing Pp. 203-212
Lauren L. Williamson, Ruey-Kuang Cheng, Mikel Etchegaray and Warren H. Meck
[Abstract] [Purchase Issue/Articles]


Modafinil: A Useful Medication for Cocaine Addiction? Review of the Evidence from Neuropharmacological, Experimental and Clinical Studies Pp. 213-221
Jose Martínez-Raga, Carlos Knecht and Sonsoles Cepeda
[Abstract] [Purchase Issue/Articles]


Do Pharmacological Approaches that Prevent Opioid Tolerance Target Different Elements in the Same Regulatory Machinery? Pp. 222-238
Javier Garzón, María Rodríguez-Muñoz and Pilar Sánchez-Blázquez
[Abstract] [Purchase Issue/Articles]


Role of Mu and Delta Opioid Receptors in Alcohol Drinking Behaviour Pp. 239-252
Milagros Méndez and Marcela Morales-Mulia
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Abstracts


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Editorial: Smoking and Drinking Go Hand in Hand

Smoking and drinking often occur simultaneously. When drinking, the urge to smoke increases and vice versa. This is commonly observed in pubs, where the majority of visitors smokes and drinks alcohol. When asking these drinkers, the majority acknowledges that they smoke more cigarettes during the drinking session than they would do on other occasions without alcohol consumption.

Fig. 1 illustrates the relationship between alcohol consumption and smoking among 500 Dutch students [1]. The presented data are typically found in surveys on drinking and smoking habits. Students that consume more alcohol also smoke more cigarettes. In addition, the percentage of smokers steadily increases from abstainers to excessive drinking groups.



Fig. (1). Drinking and smoking of 500 Dutch students [1].
The number of daily cigarettes and weekly number of alcoholic drinks are displayed.

Among alcoholics, 90% also meet the criteria for nicotine dependence [2]. Smokers, especially those who are nicotine dependent, have a higher risk of alcohol dependence [3], and dependency-related problems are more severe in those who smoke more cigarettes [4].

Although many studies have examined the individual effects of nicotine and alcohol on cognitive and psychomotor performance, surprisingly few studies examined the effects of co-administration on human behavior. A study by Michel and Battig [5] showed that in female smokers nicotine accelerated processing speed in a visual information processing task, whereas alcohol significantly slowed processing speed. However, when administering tobacco and alcohol together, no significant difference was found from pre-drug baseline performance. Kerr and colleagues [6] also reported opposite effects of nicotine (improvement) and alcohol (impairment) on tests of memory scanning, tracking, psychomotor performance and choice reaction time tests. Co-use of nicotine and alcohol attenuated these effects and overall performance did not differ greatly from the non-drug condition. These studies support the idea that, when consumed in a moderate fashion, the co-use of tobacco seems to reverse the cognitive effects caused by alcohol consumption.

Kouri and colleagues [7] showed that those who smoked before a drinking session wanted to drink more alcohol than those who did not smoke. Also, smoking before the drinking session resulted in higher subjective feelings of intoxication, and alcohol’s euphoric effects were reported at lower blood alcohol concentrations. Experiments in which participants were pre-treated with the nicotine receptor antagonist mecamylamine [8, 9] showed the opposite effects. Participants who received mecamylamine were less euphoric during drinking when compared those who consumed alcohol without this treatment. From a different angle, the relationship between smoking and drinking was also established in smokers who were pre-treated with alcohol [10]. Those who consumed alcohol before smoking reported a significantly higher rate of smoking satisfaction than those who did not consume alcohol. In sum, there is much evidence that smoking and drinking reinforce each other and that this is established by enhancing their rewarding effects.

In this issue of CURRENT DRUG ABUSE REVIEWS, Schlaepfer and colleagues discuss the substantial scientific evidence of a common genetic vulnerability to alcohol and nicotine addictions. The authors conclude that neuronal nicotinic acetylcholine receptors (nAChRs) genes may have a role in mediating behaviors that are the risk factors for alcohol and nicotine dependence. Also, nAChRs play an important mediating role in the dopaminergic reward system mediating the pleasurable feelings of reward when drinking alcohol and smoking.

A review by Dr Scepis discusses various pharmacological and non-pharmacological ways to help adolescent quit smoking. Smoking cessation remains extremely difficult and many smokers fail to stop. Relapse is common even after several times of smoking cessation. A recent meta-analysis on smoking cessation attempts among adolescent current smokers reveiled that their lifetime cessation attempt prevalence was 71% (range 28-84%). More than half had made multiple attempts and the median prevalence of relapse was 92% within 1 year [11].

Many governments and organizations try to convince smokers to quit and inform smokers about the negative health consequences of smoking. Various warning labels including text or pictures on cigarette packages are in use to inform smokers. In this issue of CURRENT DRUG ABUSE REVIEWS, Dr Givel reviews the product design approach of the U.S. Food and Drugs Administration.

Future studies should continue to examine the causes and effects of co-use of nicotine and alcohol. New treatments or ways to reduce their use should be developed, taking into account that both addictions are often related.

REFERENCES

[1] Verster JC. Alcohol hangover frequency, severity and interventions among Dutch college students. Alcoholism: Clin Exp Res 2006; 30 (supplement to #6): 157A.

[2] Batel P, Pessione F, Maitre C, Rueff B. Relationship between alcohol and tobacco dependencies among alcoholics who smoke. Addiction 1995; 90: 977-80.

[3] John U, Meyer C, Rumpf H-J, Hapke U. Probabilities of high-risk drinking, abuse or dependence estimates on grounds of tobacco smoking and nicotine dependence. Addiction 1998; 98: 805-814.

[4] Daeppen JB, Smith TL, Danko GP, et al. Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. Alcohol Alcohol 2000; 35:171-75.

[5] Michel C, Battig K. Separate and combined psychophysiological effects of cigarette smoking and alcohol consumption. Psychopharmacology 1989; 7: 65-73.

[6] Kerr JS, Sherwood N, Hindmarch I. Separate and combined effects of the social drugs in psychomotor performance. Psychopharmacology 1991; 104: 113-19.

[7] Kouri EM, McCarthy EM, Faust AH, Lucas SE. Pretreatment with transdermal nicotine enhances some of ethanol’s acute effects in men. Drug Alcohol Depend 2004; 75: 55-65.

[8] Blomqvist O, Hernandez-Avila CA, Van Kirk J, Rose JE, Kranzler HR. Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res 2002; 26: 326-31.

[9] Chi H, De Wit H. Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcohol Clin Exp Res 2003; 27: 780-86.

[10] Rose JE, Brauer LH, Behm FM, Cramblett M, Calkins K, Lawhon D. Potentiation of nicotine reward by alcohol. Alcohol Clin Exp Res 2002; 26: 1930-31.

[11] Banjcej C, O’Loughlin J, Platt RW, Paradis G, Gervais A. Smoking cessation attempts among adolescent smokers: a systematic review of prevalence studies. Tob Control 2007; 16 (6): e8.


Joris C. Verster
(Editor-in-Chief)
Utrecht Institute for Pharmaceutical Sciences (UIPS)
Section Psychopharmacology (W038A)
Faculty of Science
Utrecht University
P.O. Box 80082
3508 TB Utrecht
The Netherlands
E-mail: J.C.Verster@uu.nl


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Long-Term Consequences of Adolescent Cannabis Exposure on the Development of Cognition, Brain Structure and Function: An Overview of Animal and Human Research
Gerry Jager and Nick F. Ramsey

Over the last decade there has been a steady increase in the prevalence of frequent cannabis use among teenagers, accompanied by a decrease in age of first use. Evidence from both animal and human studies suggests that the severity of the effects of cannabis use on cognitive development is dependent on the age when cannabis use begins. One possible explanation is that those who begin cannabis use early in adolescence are more likely to become heavily dependent. It is plausible that chronic cannabis abuse will then interfere with educational and vocational training. From a more biological perspective, however, use of cannabis during critical developmental periods in the still maturing brain may induce persistent alterations in brain structure and brain function. Therefore, the effects of frequent cannabis use during adolescence could be different from and more serious than during adulthood, an issue increasingly recognized in the field of cannabis research. In this paper we review the relevant animal and human literature on long-term effects of frequent exposure to cannabis during adolescence on the development of cognition, brain structure and function, and discuss implications, methodological and conceptual issues, and future prospects.


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The Genetic Components of Alcohol and Nicotine Co-Addiction: From Genes to Behavior
Isabel R. Schlaepfer, Nicole R. Hoft and Marissa A. Ehringer

Co-occurrence of alcohol and nicotine addiction in humans is well documented and there is good evidence that common genes may contribute to both disorders. Although genetic factors contributing to tobacco and alcohol problem use have been well established through adoption, twin and family studies, specific genes remain to be identified and their mode of action elucidated. Recent work from human genetics studies has provided evidence that neuronal nicotinic acetylcholine receptors (nAChR) genes may have a role in mediating early behaviors that are risk factors for alcohol and nicotine dependence, such as age of initiation and early subjective responses to the drugs. Converging evidence suggests that the dopaminergic system is likely to be important in mediating the pleasurable feelings of reward when activated by nicotine and /or alcohol consumption. The nAChRs are important components of the dopaminergic reward system because some of the receptors have been shown to activate the release of dopamine, and mice lacking genes for specific nAChR gene subunits show altered behavioral responses to nicotine and alcohol. Furthermore, complex interactions between other neurotransmitter circuits including GABA, glutamate and serotonin may be modulated by nAChRs, leading researchers to study genes involved in neurobiology shared by different drugs. Future studies aimed at understanding the variation among these genes, and their corresponding functional implications, will help elucidate how natural variants in nicotinic receptor genes contribute to these common co-morbid disorders.


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Policy and Health Implications of Using the U.S. Food and Drug Administration Product Design Approach in Reducing Tobacco Product Risk
Michael Givel

Purported risk or harm reduction through product design change of cigarettes has occurred in three phases in the U.S. The first phase from the 1940s to the early 1960s included a gradual rise in filtered cigarettes. The second phase, which began in the early 1960s in response to the landmark 1964 U.S. Surgeon General’s report that linked smoking with lung cancer and other diseases, included the introduction of purportedly low tar and nicotine cigarettes. Subsequent research found that both filters and low tar and nicotine cigarettes were ineffective approaches to reducing health risks associated with smoking. Despite this, these product design changes were used in tobacco industry marketing campaigns to allay consumer health concerns and stabilize tobacco markets and sales. Since 2004, a new risk or harm reduction phase has occurred with the backing by Philip Morris as well as major U.S. health groups of U.S. Food and Drug Administration legislation that would require disclosure of tobacco ingredients, ban misleading health claims, prohibit or reduce harmful ingredients, and require prior approval of tobacco design, performance changes, and modified risk tobacco products. However, current scientific literature indicates that there is no scientific consensus and little evidence on what tobacco ingredients are linked to particular morbidities and mortalities and at what levels. This will allow the tobacco industry to implicitly or explicitly claim their products are “safer.” Instead, health advocates should advocate for scientifically proven policy measures such as smoke free public places or higher tobacco taxes that control and reduce tobacco markets and consumption.


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Smoking Cessation for Adolescents: A Review of Pharmacological and Psychosocial Treatments
Ty S. Schepis and Uma Rao

Unlike the vast literature on smoking cessation in adults, research in adolescents has gained significant attention only within the last decade. Even with this increase in focus, research into pharmacological aids for smoking cessation in adolescents (e.g., nicotine replacement therapy, bupropion) is a more recent phenomenon and has produced only modest results. While more extensive, much of the research on behaviorally- or psychosocially-based adolescent smoking cessation interventions has been limited by a lack of control for contact time, biochemical verification of self-reported abstinence, and/or a theoretical focus for the interventions. The MEDLINE, PubMed, PSYCInfo, EMBASE, ERIC, CINHAL, Cochrane CENTRAL and Systematic Review databases were searched for articles relevant to adolescent smoking cessation treatment. After briefly examining the adolescent smoking cessation research prior to 2000, more recent developments in pharmacological aids and psychological treatment will be reviewed. Investigations have made progress in elucidating efficacious treatments for adolescent smokers, but much work remains to be done in both pharmacological and non-pharmacological areas of treatment. With the current state of the literature as a guide, future directions for research into smoking cessation for adolescents will be proposed.


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Use of Caffeine and Nicotine in People with Schizophrenia
Jill M. Williams and Kunal K. Gandhi

There are numerous reports of increased use of both caffeine and nicotine in schizophrenia. Clinical effects of these substances are important and may complicate the interpretation of schizophrenia symptoms and antipsychotic medication side effects. Use of caffeine and nicotine is often linked, with smokers using more caffeine due to interacting metabolic effects. Studies of neurobiology reveal evidence of specific brain changes in schizophrenia that are impacted by nicotine and caffeine and suggest self-medication effects. Interestingly both substances are linked to altered inhibitory mechanisms in brain functioning. Few studies have examined both simultaneously which is critical given their metabolic and symptomatic interactions. This paper reviews use of caffeine and nicotine in people with schizophrenia and gives recommendations for their further study.


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“My Drink is Larger than Yours”? A Literature Review of Self Defined Drink Sizes and Standard Drinks
Loraine Devos-Comby and James E. Lange

National health offices define drink sizes to establish guidelines for alcohol use. International variations exist in the limits and drink sizes recommended. Surveys assessing drinking levels rely on the notion of standard drink when enquiring about participants’ alcohol consumption and international comparisons are difficult because of the various definitions of one standard drink. Surveys are based on the assumption that respondents know and understand the concept of standard drink and are able to use it. We reviewed studies examining participants’ knowledge and understanding of the notion of standard drinks as well as their ability to pour standard drinks. Across studies, participants’ drink sizes typically contained greater volumes of alcohol than one standard drink. This suggests that levels of alcohol consumption have been underestimated in previous research. The magnitude of this over-sizing effect varied based on types of drinks, vessel sizes, drinking habits, and research methods. Indeed, the effect was the greatest for mixed drinks and spirits, followed by wine and beer. It also increased with vessel size and was affected by respondents’ drinking experience. Using photographs of vessels as representations of usual drinks exhibited the strongest discrepancy compared to tasks using actual vessels; and paradigms involving pouring real alcohol seemed to lead to greater effects than those using water or colored water. Lastly, evidence suggests that these misperceptions could be corrected and that such correction may reduce drink sizes. Implications of these findings are discussed and recommendations for researchers, health promotion campaigns and policy makers are made.


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Hepatitis C Treatment in Patients with Drug Addiction: Clinical Management of Interferon-Alpha-Associated Psychiatric Side Effects
Martin Schaefer and Stefan Mauss

60-90% of patients with intravenous drug abuse are chronically infected with the hepatitis C virus (HCV). Antiviral treatment with pegylated interferon-alfa (IFN-α) plus ribavirin is often complicated by psychiatric adverse events, significantly affecting patients adherence. Depression, anxiety, fatigue and irritability as typical IFN-α associated side effects occur in 30-80% during antiviral treatment of hepatitis C. Patients with drug addiction were shown to have an increased risk to discontinue HCV-treatment early in the first three treatment months, where most neuropsychiatric side effects appear. Especially vegetative side effects in the first few weeks (”flu-like syndrome”) can be misunderstood as withdrawal symptoms, followed by a relapse in drug or alcohol abuse. As a consequence methadone substitution treatment was found to be the best therapeutic setting. In addition side effect management should be intensified during first three months of HCV-treatment. Most data for the management of specific IFN-α associated side effects are available for depressive syndromes. Antidepressants (especially serotonin-reuptake-inhibitors) such as citalopram were shown to significantly reduce IFN-α associated depressive symptoms. A pre-emptive treatment with antidepressants should be considered at least for patients with additional psychiatric risk factors before interferon-based therapy is started. Because data from prospective controlled trials are lacking, management of other side effects such as sleep disturbances, irritability, psychotic syndromes, mania, suicidal thoughts and delirious syndromes should follow general psychiatric treatment recommendations. Overall, the psychiatric adverse event profile of interferon-based therapy for HCV-infected patients with drug addiction is considerable and requires active management and knowledge about psychiatric medical therapy.


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Potential Role of ADAMTS13 in the Progression of Alcoholi Hepatitis
Masahito Uemura, Yoshihiro Fujimura, Tomomi Matsuyama, Masanori Matsumoto, Masatoshi Ishikawa, Hiromichi Ishizashi, Seiji Kato, Tatsuhiro Tsujimoto, Masao Fujimoto, Hitoshi Yoshiji, Chie Morioka and Hiroshi Fukui

Alcoholic hepatitis (AH) is a potentially life-threatening complication of alcohol abuse. The severe form of AH, severe alcoholic hepatitis (SAH), is characterized by multiorgan failure (MOF) with manifestations of acute hepatic failure and is associated with high morbidity and mortality. However, the pathogenesis of SAH in addition to AH remains to be elucidated. Recent advances showed that ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) is closely related to thrombotic thrombocytopenic purpura, a multiorgan disorder. Decreased activity of plasma ADAMTS13 (ADAMTS13:AC) leads to the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and subsequent platelet clumping and/or thrombi under high shear stress, resulting in microcirculatory disturbances. Immunological studies and in situ hybridization have indicated that ADAMTS13 is produced exclusively in hepatic stellate cells (HSCs). Plasma ADAMTS13:AC was extremely low in fatal SAH cases, and enhanced UL-VWFM production with deficient ADAMTS13:AC may contribute to the progression of MOF through microcirculatory distur-bances in SAH and AH. Considering that ADAMTS13 is synthesized in HSCs and its substrate, UL-VWFM, is produced in transformed vascular endothelial cells, the imbalance between ADAMTS13:AC and VWF:Ag in AH patients might also involve sinusoidal microcirculatory disturbances and subsequent liver injury. It will be necessary to clarify the mechanism of the decrease in plasma ADAMTS13:AC in association with pro-inflammatory cytokinemia, an ADAMTS13 inhibitor and the production of ADAMTS13 in HSCs. The determination of ADAMTS13:AC and its substrate will give us new insights into the pathophysiology of acute alcoholic liver injury and help to elucidate additional therapeutic strategies for this disease.


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Recent Developments in the Treatment of Alcoholic Chronic Pancreatitis
Tatsuhiro Tsujimoto, Hideto Kawaratani, Hitoshi Yoshiji, Masahito Uemura and Hiroshi Fukui

Chronic pancreatitis is a progressive inflammatory condition characterized by repeated attacks of abdominal pain, and the destruction and fibrosis of the pancreatic parenchyma which causes to reduced exocrine and endocrine functions. Alcohol is the most common cause of chronic pancreatitis. Although abstinence is usually considered a prerequisite for successful treatment of alcoholic chronic pancreatitis, we often encounter patients who have repeated attacks from the compensated stage through the transitional stage. In alcoholic chronic pancreatitis, continued alcohol consumption causes changes in the digestive hormones and vagal nerve function that induce the pancreatic acinar cells to oversecrete protein, increasing the protein concentration and viscosity of the pancreatic juice. This induces protein sedimentation from the pancreatic juice and formation of protein plugs within the pancreatic duct, triggering repeated attacks of acute pancreatitis. The treatment of alcoholic chronic pancreatitis includes alleviation of symptoms, particularly abdominal pain, elimination of trigger factors, prevention of recurrence and disease progression, adjuvant therapies for pancreatic exocrine and endocrine failure. Recently, the main constituent proteins in these protein plugs have been identified, enabling trials of several therapies, such as the administration of secretin formulations and endoscopic removal. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for the pancreatic acinar cells, inducing them to secrete pancreatic juice of low viscosity. In this review, we summarize the most recent thoughts about alcoholic chronic pancreatitis, and the new treatments, and in particular, we present our findings concerning the efficacy of bromhexine hydrochloride in the treatment of this disease.


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“Speed” Warps Time: Methamphetamine’s Interactive Roles in Drug Abuse, Habit Formation, and the Biological Clocks of Circadian and Interval Timing
Lauren L. Williamson, Ruey-Kuang Cheng, Mikel Etchegaray and Warren H. Meck

The indirect dopamine (DA) agonist methamphetamine (MAP) is evaluated in terms of its impact on the speed of temporal processing across multiple time scales involving both interval and circadian timing. Behavioral and neuropharmacological aspects of drug abuse, habit formation, neurotoxicity, and the potential links between interval and circadian timing are reviewed. The view that emerges is one in which the full spectrum of MAP-induced effects on timing and time perception is both complex and dynamic in as much as it involves DA-glutamate interactions and gene expression within cortico-striatal circuitry spanning oscillation periods ranging from milliseconds to multiple hours. The conclusion is that the psychostimulant properties of MAP are very much embedded within the context of temporal prediction and the anticipation of reward.


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Modafinil: A Useful Medication for Cocaine Addiction? Review of the Evidence from Neuropharmacological, Experimental and Clinical Studies
Jose Martínez-Raga, Carlos Knecht and Sonsoles Cepeda

Cocaine addiction is a chronic relapsing disorder associated with severe medical and psychosocial complications. However, there are no approved medications for cocaine dependent individuals. Modafinil, a medication that differs chemically and pharmacologically from other central nervous system stimulants, has been suggested to be potentially useful for this complex disorder. The present paper aims to critically review the published evidence from laboratory and clinical studies on modafinil for cocaine addiction, including discussion of its pharmacological characteristics and how it may relate with cocaine neurobiology. Whilst its exact mechanism of action remains to be elucidated, different neurotransmitter systems have been implicated, including modulation on dopamine, glutamate/GABA, noradrenaline and the hypocretin/orexin system, but it is possible that modafinil acts by a synergistic combination of mechanisms. With a favourable pharmacokinetic profile, it appears to have a low abuse potential. Laboratory and clinical studies provide consistent, albeit preliminary, evidence of the potential usefulness of modafinil for cocaine dependent patients. Not only there is no evidence of pharmacokinetic interactions between modafinil and cocaine, but in addition cocaine induced euphoria and cardiovascular effects appear to be attenuated by modafinil. Furthermore, modafinil has been shown to decrease cocaine self-administration. In addition, modafinil treated patient are more likely to achieve protracted abstinence than placebo treated patients. However, further research is needed to confirm these findings.


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Do Pharmacological Approaches that Prevent Opioid Tolerance Target Different Elements in the Same Regulatory Machinery?
Javier Garzón, María Rodríguez-Muñoz and Pilar Sánchez-Blázquez

In the nervous system, the interaction of opioids like heroin and morphine with the G protein-coupled Muopioid receptor (MOR) provokes the development of tolerance to these opioids, as well as physical dependence. Tolerance implies that higher doses of these drugs must be consumed in order to obtain an equivalent sensation, a situation that contributes notably to the social problems surrounding recreational opioid abuse. The mechanisms that promote opioid tolerance involve a series of adaptive changes in the MOR and in the post-receptor signalling elements. Pharmacological studies have consistently identified a number of signalling proteins relevant to morphine-induced tolerance, including the delta-opioid receptor (DOR), protein kinase C (PKC), protein kinase A (PKA), calcium/calmodulin-dependent kinase II (CaMKII), nitric oxide synthase (NOS), N-methyl-D-aspartate acid glutamate receptors (NMDAR), and regulators of G-signalling (RGS) proteins. Thus, it is feasible that these treatments which diminish morphine tolerance target distinct elements within the same regulatory machinery. In this scheme, the signals originated at the agonist-activated MORs would be recognised by elements such as the NMDARs, which in turn exert a negative feedback on MOR-evoked signalling. This process involves DOR regulation of MORs, MOR-induced activation of NMDARs (probably via the regulation of Src, recruiting PKC and Gα subunits) and the NMDAR-mediated activation of CaMKII. The active CaMKII promotes the sequestering of morphine-activated Gβγ dimers by phosducin-like proteins (PhLP) and of Gα subunits by RGS proteins and tolerance to opioids like morphine develops. Future efforts to study these phenomena should focus on fitting additional pieces into this puzzle in order to fully define the mechanism underlying the desensitization of MORs in neural cells.


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Role of Mu and Delta Opioid Receptors in Alcohol Drinking Behaviour
Milagros Méndez and Marcela Morales-Mulia

The dopaminergic mesolimbic system plays a key role in the mechanisms of reinforcement elicited by alcohol (ethanol) and other drugs of abuse. Numerous lines of evidence indicate that ethanol reinforcement mechanisms involve, at least partially, the ethanol-induced activation of the endogenous opioid system. Ethanol may alter opioidergic transmission at different levels, including the biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. Several studies suggest that mu and delta opioid receptors play a major role in ethanol reinforcement and dependence. These studies implicate enkephalins and β-endorphin as physiological mediators of ethanol’s actions in the brain. In this review we describe the pharmacological characteristics of opioid receptors and their distribution in brain, as well as the major functions of their endogenous ligands. Thereafter, we present evidence supporting the participation of mu and delta opioid receptors in ethanol reinforcement mechanisms and high alcohol drinking behaviour. The use of opioid receptor agonists and antagonists, as well as ethanol-preferring selected rodents and knockout mice, has contributed to understand the role of mu and delta receptors in these processes. The effects of ethanol on binding of selective ligands to opioid receptors in different experimental models are also reviewed. The relevance of opioid receptors in human alcoholism is further evidenced by the association of mu receptor polymorphisms with ethanol dependence. The clinical implication of these findings is discussed regarding the differential responses observed in some alcoholic patients to treatment with opioid receptor antagonists such as naltrexone.