Neuroadaptations Involved in Long-Term Exposure to ADHD Pharmacotherapies: Alterations That Support Dependence Liability of These Medications

Abstract

INTRODUCTIONSubstance dependence is one of the most established physiological states following chronic exposure to an addictive drug. It is characterized by a cluster of physio-behavioral and cognitive phenomena which include the persistent desire or unsuccessful efforts to cut down substance abuse, unrestrained drug taking despite harmful consequences, higher priority given to drug use than to other social, recreational activities and obligations, tolerance to the drug's euphorigenic effects and a physical withdrawal state (International Classification of Diseases (ICD)-10).Measuring the dependence liability of a certain substance is a challenging task as some components of dependence cannot be gauged objectively in the laboratory. Pro-addictive behaviors such as tolerance and withdrawal can be well studied in animal subjects and they have provided us with important information on the effects of drugs on health and longterm consequences of substance use. However, it is diffi cult to measure the cognitive aspect of dependence (such as drug craving, loss of control and persistent drug use), although this is slowly being addressed by recent neuroimaging techniques Repeated administration of addictive drugs causes cellular and molecular changes believed to be the mechanism of pro-addictive behaviors. Neuroadaptations also take place with repeated administration of amphetamine, methylphenidate and atomoxetine, drugs for Attention Defi cit Hyperactivity Disorders (ADHD), and it is speculated that these changes may serve as markers to demonstrate the dependence liability of these therapies. In this review, we enumerate the neuroadaptive changes in molecules associated with neuronal signaling and plasticity, as well as neuronal morphology wrought by repeated administration of ADHD medications. We provide the current perspective on the dependence liability of these therapies, and also suggest of some factors that need to be considered in future investigations, so that what is drawn from animal studies would be better consolidated with those known clinically. (Maganti, 2004). On the other hand, a number of studies have emerged and those investigations center on the molecular and cellular changes in the brain associated with chronic

Methylphenidate treatment in the spontaneously hypertensive rat: influence on methylphenidate self-administration and reinstatement in comparison with Wistar rats

“…Catheter patency was ensured by infusing each catheter with 0.1 ml of thiopental sodium (10 mg/kg) a day before commencing experiments 1 and 2 (see the following Discussion). A complete description of the methods can be found in our previous studies (dela Peña et al 2010Peña et al , 2011b. Fig.…”

“…Thus, the number of rats per group was reduced to n=8 animals only. Surgical procedures, checking for catheter patency and post-surgical care are outlined in our previous studies (dela Peña et al 2010Peña et al , 2011b). Experiment 1.…”

“…The dose of 2-mg/kg methylphenidate was chosen as it produces clinically relevant levels of methylphenidate in the plasma (Gerasimov et al 2000). After acclimatization, rats were reduced to 85% of their free-feeding body weights and trained to press a lever for a contingent sucrose pellet reward (dela Peña et al 2010(dela Peña et al , 2011b. It was important to ensure that methylphenidate treatment does not affect responding for sucrose pellets such that drug administration took place at the end of each session 3 or 5 h before lights are turned off.…”

“…Finally, we evaluated the ability of methylphenidate to reinstate previously extinguished drugseeking behavior, a condition that may model relapse and drug addiction (for review, see Epstein et al 2006). In view of the controversial data regarding the effects of long-term methylphenidate treatment in animal models, we used the Wistar rat, strain used to represent the "normal" genetically heterogeneous population, as controls in this study (dela Peña et al 2010(dela Peña et al , 2011b.…”

Chronic Methylphenidate Effects on Brain Gene Expression: An Exploratory Review

“… 29 , 85 MP studies indicate a general upregulation of the PSD proteins, due to an increase in neurotransmitters within the synapses. 29 , 86 Furthermore, within the PSD family there are two important families of proteins. These include the membrane-associated guanylate kinase (MAGUK) and the Shank families (see Table 2 ).…”