Current Drug Abuse Reviews - Volume 2, Issue 2, 2009

The effects of alcohol on driving ability have been thoroughly investigated during the past 50 years. Experimental studies have consistently shown that alcohol impairs cognitive and psychomotor performance in a dose-dependent manner including various driving related skills and abilities [1]. Driving simulator tests and driving tests in real traffic confirmed these findings. Epidemiological evidence and roadside studies revealed that people who drive under the influence (DUI) of alcohol are at increased risk of becoming involved in traffic accidents. The relationship between blood alcohol concentration (BAC) and traffic accident risk is illustrated in Fig. (1) (left figure). The data comes from a landmark study performed in the 1960s by Borkenstein and colleagues [2]. Many studies have followed and underlined the relationship between BAC and accident risk. During the past decade, many countries have lowered their legal BAC limits for driving a car and successfully reduced the number of alcohol-related traffic accidents.

This review summarizes evidence on negative affect among drinking drivers. Elevations in negative affect, including depressed mood, anxiety and hostility, have long been noted in convicted drinking drivers, and recent evidence suggests an association between negative affect and driving after drinking in the general population. Previous efforts to understand the significance of this negative affective state have ranged from suggestions that it may play a causal role in drinking driving to suggestions that it may interfere with response to treatment and remedial interventions. Recent studies have uncovered an important paradox involving negative affect among convicted drinking drivers (hereafter DUI offenders). DUI offenders with high levels of negative affect recidivated more frequently following a DUI program than did those reporting no or minimal negative affect. However, when a brief supportive motivational intervention was added to the program, offenders with high negative affect levels showed lower recidivism rates than did those with no or minimal negative affect. The review includes studies from the general literature on alcohol treatment in which the same negative affect paradox was reported. In an attempt to understand this paradox, we present a conceptual model involving wellestablished psychological processes, with a focus on salient discrepancy, the crucial component of cognitive dissonance. In this model, negative affect plays an important role in motivating both continued high-risk drinking as well as therapeutic change. This model suggests that links between motivational states and negative affective processes may be more complex than previously thought. Implications for intervention with DUI offenders are discussed.

A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol- seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), α-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.

Despite the availability of currently approved medications and various psychosocial therapies, alcohol abuse and dependence are increasingly prevalent in the United States, and carry a significant socioeconomic burden. Recently, the novel anti-epileptic topiramate has shown great promise as a new treatment for this disorder. The objective of this review is to discuss the limitations of the currently available options for treating alcohol dependence, to review the results of clinical trials assessing the efficacy of topiramate in treating alcohol dependence, and to describe the pharmacological characteristics and mechanisms of action of topiramate as related to this indication. We systematically reviewed Medline, EMBASE, Cochran Reviews and PsycINFO search terms included combinations of the terms “pharmacotherapy” “topiramate”, “alcoholism” and “alcohol dependence.” Searches were last updated 24 October 2008. Currently approved treatments include disulfiram, naltrexone tablets and injection, and acamprosate. Of these, naltrexone has shown the most benefit, however the effect size is small and may reach its most promising potential when combined with medical management. Alternatively, through multiple mechanisms of action, topiramate in clinical trials has demonstrated safety and efficacy in decreasing both craving and withdrawal symptoms and increasing quality of life measures among alcoholdependent individuals. The findings of this review suggest that topiramate is a promising new option for the treatment of alcohol dependence, and may offer substantial benefits over currently approved medications. While the manufacturer will not pursue approval of an indication for the treatment of alcohol dependence, the drug will soon be available generically, making it more affordable for a greater proportion of the public.

Neuropsychological dysfunction, ranging from mild cognitive symptoms to dementia has been a consistent part of the clinical picture of HIV/AIDS. However, advances in clinical management, particularly antiretroviral (ARV) treatment, have mitigated the neuropsychological effects of HIV and revised the pattern and nature of cognitive deficits, which are observed in HIV-infected individuals. The attendant improvements in mortality and morbidity have led to a need for programs and interventions that sustain healthy behavior and prevent a resurgence of HIV transmission risk. Psychiatric risk factors, particularly substance use, which often contribute to initial acquisition of HIV, still require attention. These risk factors may also exacerbate neuropsychological dysfunction and compromise adherence to prevention recommendations and treatment. Specifically, a more complete understanding of the effects of substance abuse on the progression of HIV related cognitive decline can inform evaluation and management of HIV seropositives with concurrent substance use disorders. This review provides an overview of the neuropsychology of HIV and substance abuse and the extant research that has examined the effects of both HIV disease and substance use on neuropsychological functioning and implications for treatment and future research.

Methylphenidate hydrochloride (MPH) is one of the most widely available prescription stimulants. In response to an increase in stimulant treatment for Attention-Deficit/Hyperactivity Disorder, the prescription and production rates of MPH have increased dramatically in the past two decades. Given that college students and adolescents might be attracted to MPH for its attention-focusing, weight loss, or euphoric effects, there is concern that the rise in therapeutic use of MPH might also coincide with a rise in illicit (non-medical) use. After a dramatic increase in the 1990s, recent large-scale surveys of high-school students suggest that rates of illicit MPH use are either holding steady, or even decreasing in this population. Across studies, annual usage rates for secondary school students are below 5%, and lifetime usage rates remain below 7%. Among college students, self-reported rates range from 1.5% to 31% among the various surveys, with the most nationally representative study estimating annual illicit MPH usage at about 4%. Although more research is needed to corroborate findings, this review was able to begin developing a profile of individuals who might be more likely to illicitly use MPH. Among college students, available evidence suggests illicit MPH users were more likely to be white, male, affiliated with a formally organized fraternity, and more likely to use other illicit and illegal substances. The majority of college students reported that the primary reason for use was to improve academic performance. Future studies should provide more information on the motivations and subtypes of illicit MPH, especially repeated users and those diagnosed with ADHD. Research on prevention of illicit MPH or other stimulants used to treat ADHD would make major contributions to the literature.

The co-occurrence of drug addiction in adults with attention deficit hyperactivity disorder (ADHD) is very common, but its etiology remains largely unknown. Therefore, animal models to study this kind of psychiatric comorbidity are needed. The Spontaneously Hypertensive Rat (SHR) strain shows neurochemical and behavioral characteristics which make it a suitable model of ADHD. Compared with their normotensive controls (Wistar-Kyoto) and with some other rat strains, SHR rats drink more ethanol and are more sensitive to its anxiolytic/stimulant effects. They also show increased sensitivity to psychostimulants, opioids and cannabinoids. Furthermore, chronic treatment with methylphenidate, the first-choice drug to treat ADHD, during adolescence, changes the ethanol intake and the behavioral effects of cocaine in adult SHR rats. Regarding sex differences, females are more sensitive to psychostimulants and drink more ethanol than males, an important condition because in adulthood, more females suffer from ADHD than males. Taken together, the reviewed findings indicate that the SHR strain is a promising tool for studies on drug addiction and, possibly, its relationship with ADHD.

Understanding and preventing relapse to drug use is one of the most difficult challenges faced by clinicians and practitioners in the struggle to help people remain abstinent. In this paper, we review basic preclinical research on forced abstinence periods that identify the neural substrates involved and neural adaptations that occur after a drug-free period. Our attention focuses on forced abstinence after self-administration because of its promise for translational research in the development of candidate medications to reduce relapse. This model requires subjects (often rats) to initially acquire drug self-administration. However, rather than extinguishing behavior with daily drug-free sessions as in the reinstatement model of drug seeking, subjects are removed from the self-administration situation and do not receive any exposure to the drug. Notably, the integrity of the drug-taking behavior and the drug-associated cues in the drug-taking environment are preserved because they are not experienced in the absence of the drug. Research shows time dependent increases in drugseeking following forced abstinence periods. More so, neural substrates and adaptations within the mesocorticolimbic system and the nigrostriatal system have been identified that contribute to increased drug seeking following abstinence. From a translational perspective, behavioral and pharmacological treatment of substance use disorder often starts during this initial abstinence period (either forced or voluntary). The forced abstinence model simulates some of the features of this treatment situation and thus allows for the study of potential treatments that alter relapse of drug-seeking behaviors along with the accompanying neurobiological changes.

Although dopamine is implicated in the development of addiction, it is unclear how specific dopamine release patterns are involved with drug seeking. Addictive drugs increase tonic dopamine levels on the order of minutes, as well as phasic dopamine release events that occur on a subsecond time scale. Phasic dopamine release is associated with the initiation of goal-directed behaviors, and has been shown to promote drug seeking. Prior experience with addictive drugs modulates the synaptic and intrinsic properties of dopamine neurons, affects the pattern of dopamine neuron firing and release, and alters dopamine-dependent behaviors related to drug addiction. In this review, we synthesize the known drugdependent changes to the dopamine system along with the established functions of phasic dopamine release in order to provide a framework for conceptualizing the role of phasic dopamine release in drug addiction. Because drug addiction is commonly thought to involve changes in brain circuits important for natural reinforcement, we first present the role of phasic dopamine release in appetitive and goal-directed behaviors in the context of contemporary theories regarding the function of dopamine. Next, we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience increases the contrast, or ‘signal to noise’, of phasic dopamine release to basal dopamine levels in response to drug-related stimuli, which could result in aberrant associations between cues and reinforcers that contribute to the development of addiction.