The contribution of genetics to addiction therapy approaches

Addictions, including alcohol dependence, which is the focus of this article, are complex genetic diseases. Recently, several individual genes that contribute to the risk for alcohol dependence have been identified, and more are expected to be in the near future. Among these are genes encoding alcohol and aldehyde dehydrogenases and GABA(A) receptor subunits. These reveal pathways of vulnerability and provide targets for rational drug design. It is likely that response to particular therapies is also a complex trait influenced by genetics, but studies to explore this are just beginning. We discuss some studies on bromocriptine, naltrexone, and serotonergic agents. Adding a genetic component to treatment trials could greatly help to understand the biological basis of variations in the efficacy of therapies and, in the future, could lead to individualized choices of therapy.     

Medical treatment of the adolescent drug abuser. An opportunity for rehabilitative intervention.

Illnesses related to both the pharmacologic properties of abused substances and their methods of administration often bring the teenager to medical attention and may provide sufficient motivation for the adolescent to seek help beyond the acute problem. Successful treatment of an overdose reaction, an abstinence syndrome, or any other medical complication of drug abuse may give the physician a unique opportunity to begine further evalution for future care.     

Mitoepigenetics and drug addiction

Being the center of energy production in eukaryotic cells, mitochondria are also crucial for various cellular processes including intracellular Ca²⁺ signaling and generation of reactive oxygen species (ROS). Mitochondria contain their own circular DNA which encodes not only proteins, transfer RNA and ribosomal RNAs but also non-coding RNAs. The most recent line of evidence indicates the presence of 5-methylcytosine and 5-hydroxymethylcytosine in mitochondrial DNA (mtDNA); thus, the level of gene expression – in a way similar to nuclear DNA – can be regulated by direct epigenetic modifications. Up to now, very little data shows the possibility of epigenetic regulation of mtDNA. Mitochondria and mtDNA are particularly important in the nervous system and may participate in the initiation of drug addiction. In fact, some addictive drugs enhance ROS production and generate oxidative stress that in turn alters mitochondrial and nuclear gene expression. This review summarizes recent findings on mitochondrial function, mtDNA copy number and epigenetics in drug addiction.     

Neuroproteomics of the synapse and drug addiction

Proteomic analyses of brain tissues are becoming an integral component of neuroscientific research. In particular, the essential role of the synapse in neurotransmission and plasticity has brought about extensive efforts to identify its protein constituents. Recent studies have used a combination of subcellular fractionation and proteomic techniques to identify proteins associated with different components of the synapse. Thus, a coherent map of the synapse proteome is rapidly emerging, and a timely review of these data is warranted. In the first part of this review, neuroproteomic techniques that have been used to analyze the synapse proteome are described. We then summarize the results from several recent proteomic analyses of mammalian synapses and discuss the similarities and differences in their profiling of synaptic proteins. Important advances in this field of research include the use of proteomics to analyze synaptic function and drug effects on synaptic proteins. This article presents an overview of proteomic analyses of the phosphorylation states of synaptic proteins and recent applications of neuroproteomic techniques to the study of drug addiction. Finally, we discuss the challenges in comparing proteomic studies of drug addiction and the future directions of this field in furthering our understanding of the molecular mechanisms underlying synaptic function and drug addiction.     

Anti-relapse medications: Preclinical models for drug addiction treatment

Addiction is a chronic relapsing brain disease and treatment of relapse to drug-seeking is considered the most challenging part of treating addictive disorders. Relapse can be modeled in laboratory animals using reinstatement paradigms, whereby behavioral responding for a drug is extinguished and then reinstated by different trigger factors, such as environmental cues or stress. In this review, we first describe currently used animal models of relapse, different relapse triggering factors, and the validity of this model to assess relapse in humans. We further summarize the growing body of pharmacological interventions that have shown some promise in treating relapse to psychostimulant addiction. Moreover, we present an overview on the drugs tested in cocaine or methamphetamine addicts and examine the overlap of existing preclinical and clinical data. Finally, based on recent advances in our understanding of the neurobiology of relapse and published preclinical data, we highlight the most promising areas for future anti-relapse medication development.     

Dynorphin and the pathophysiology of drug addiction

Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/kappa-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.     

Current treatment approaches in the nonoperative and operative management of adolescent idiopathic scoliosis

Idiopathic scoliosis is the most common type of lateral curvature of the spine, accounting for about 65% of adolescent patients with structural scoliosis. The treatment goal is to prevent moderate curves from becoming severe, because severe curves, in adults, may not only lead to serious medical and physical complications, but also cause significant cosmetic deformities. Fortunately, early detection, through school screening programs, has led to successful nonoperative management of idiopathic scoliosis. In those instances in which nonoperative management is not an option, surgical correction is available. Surgery prevents curve progression and offers the patient a significant correction of the cosmetic deformity. This article will review both treatment approaches in the management of adolescent idiopathic scoliosis.     

Caring for the adolescent drug user.

Adolescence as a social and individual process provides a challenge to the teenager with subsequent situational and maturational crises. The discomfort of change promotes alleviation, and in the limited resource of the adolescent, this may involve drug use. The physician must understand the adolescent and his adolescence in order to effectively intervene. This may be accomplished through a systematic evaluation of the problem, the teenager, and subsequently himself.