The aim of this study was to evaluate the association between stimulant treatment and the risk for substance abuse among young adults with a childhood diagnosis of attention- deficit/hyperactivity disorder (ADHD).
Subjects included 295 research-identified ADHD incidence cases treated with psychostimulant medication and 84 ADHD cases not treated with psychostimulants. These subjects are from a 1976-1982 population-based birth cohort, retrospectively, followed from birth until emigration, death, or last follow-up (mean = 17.2 years of follow-up). Medical and school records were reviewed for documented substance abuse and psychostimulant treatment. The association was evaluated using logistic regression models.
Socioeconomic characteristics at birth, and comorbidities, were similar between treated and untreated ADHD cases. Sixty (20.3%) of treated ADHD cases had documented substance abuse compared to 23 (27.4%) of cases not treated (OR = 0.7; 95% CI = 0.4-1.2). Among treated ADHD boys, 21.8% had substance abuse compared to 36.4% not-treated ADHD boys (OR = 0.5; 95% CI = 0.3-0.9). Among treated ADHD girls, 15.2% had substance abuse compared to 10.3% not-treated ADHD girls (OR = 1.5; 95% CI = 0.4-6.1).
While these results cannot demonstrate cause and effect, our findings indicate that psychostimulant treatment of childhood ADHD is associated with reduced risk for later substance abuse among boys with ADHD.
"We reiterate, however, that this observation does not indicate lack of reinforcing effects of repetitive amphetamine treatment in SHRs, as CPP and self-administration data did not show decrement (see dela Peña et al. 2012b), but rather similarity in the behavioral responses of drug-naı¨ve and amphetamine-treated SHRs to amphetamine. Of note, despite years of clinical studies, it is still unresolved whether or not stimulant therapy increases risk of developing substance dependence (including psychostimulant dependence; Fischer and Barkley 2003; Groenman et al. 2013; Katusic et al. 2005; Kollins 2008b; Lambert and Hartsough 1998). Nevertheless, considering the objectives of the study, we assayed gene expression changes in the brain of amphetamine-treated SHRs which showed amphetamine CPP and self-administration in order to provide some information on the potential molecular effects of chronic amphetamine use or abuse in individuals with ADHD. "
[Show abstract][Hide abstract] ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD), the most commonly diagnosed neurobehavioral disorder of childhood, is usually treated with psychostimulants (e.g., amphetamine). Little is known about the neuronal and behavioral consequences of chronic amphetamine use or abuse in individuals with ADHD. Of all ADHD animal models, the spontaneously hypertensive rat (SHR) is the most validated and widely used. Here, we analyzed striatal transcriptomes in amphetamine-pretreated SHRs (5 mg/kg, i.p. for 7 days [twice daily]), which showed a conditioned place preference to and self-administration of amphetamine. Microarray analyses revealed increased mRNA expression of 55 genes (>1.65-fold increase), while 17 genes were downregulated (<0.6-fold) in the striatum of SHRs. The main functional categories overrepresented among the differentially expressed genes in the striatum include those involved in transcription (e.g., Cebpb, Per2), genes associated with angiogenesis (e.g., Kdr, Klf5), cell adhesion (e.g., Col11a1, Ctgf), apoptosis (e.g., Nfkbia, Perp) and neuronal development (e.g., Egr2, Nr4a3). In conclusion, we dissected the striatal transcriptional responses to the reinforcing effects of repeated amphetamine treatment in the SHR model of ADHD. Future studies should determine the influence of these altered transcripts on amphetamine reinforcement in amphetamine-treated SHRs, and the clinical relevance of the present findings with regard to amphetamine use/abuse in ADHD individuals.
Archives of Pharmacal Research 08/2014; 38(5). DOI:10.1007/s12272-014-0470-x · 2.05 Impact Factor
"All experiments were performed in accordance with the Principles of Laboratory Animal Care (NIH) and the Animal Care and Use Guidelines of Sahmyook University, Korea. Experiments were conducted in male rats only based on earlier clinical findings that stimulant therapy only influences the development of substance misuse in males, but not female subjects (Katusic et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Background:
High novelty seeking has been assumed to predict vulnerability to use addictive drugs. Notably, it is also a symptom associated with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to identify whether spontaneously hypertensive rats (SHRs), putative animal models of ADHD, display individual differences in novelty-seeking behavior, and whether high novelty-seeking SHRs show enhanced sensitivity to the reinforcing effect of methylphenidate, the most commonly prescribed stimulant ADHD medication.
First, we established that SHRs show higher levels of novelty-seeking behavior than their normotensive control strain, Wistar Kyoto (WKY) rats. Novelty seeking was measured in two tests: open field test in a novel test arena, and novel object preference tests. Thereafter, SHRs were classified into high responders (HR) or low responders (LR), high novelty-preferring (HNP) or low novelty-preferring (LNP) rats, based on individual scores in the two behavioral assays. Methylphenidate self-administration was assessed thereafter.
SHRs showed higher levels of novelty-seeking behavior than WKY rats. HR/LR and HNP/LNP subgroups were identified. HR and LR rats showed comparable rates of methylphenidate self-administration. However, HNP SHRs worked more for methylphenidate infusions than their LNP counterparts.
We showed some evidence on inter-individual variations in novelty seeking in SHRs. Importantly, we demonstrated enhanced sensitivity of HNP SHRs to the reinforcing effect of methylphenidate, indicating a "drug-vulnerable" SHR subpopulation. These findings are important as they may provide basis for a potential screening tool to identify a subset of ADHD patients (i.e. high novelty seekers) who may be at risk for misusing/abusing methylphenidate.
"Along this line, among the patients with ADHD that are more vulnerable to develop SUD later in life are those who have comorbid CD or ODD. Additionally, there is evidence that co-occurrence of ADHD and CD symptoms contributes in an epistatic manner to a more severe form of SUD as compared to ADHD or CD alone (Flory et al., 2003; Katusic et al., 2005; Klein et al., 2012; Kollins, 2008). More recently, there has been growing interest in studying the role of post-transcriptional regulatory elements in the susceptibility to different complex disorders. "
[Show abstract][Hide abstract] ABSTRACT: Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inappropriate and impaired levels of hyperactivity, impulsivity and inattention. Around 75% of adults with ADHD show comorbidity with other psychiatric disorders such as disruptive behavior disorders or substance use disorders (SUDs). Recently, there has been growing interest in studying the role of microRNAs (miRNAs) in the susceptibility to complex disorders. Interestingly, converging evidence suggests that single nucleotide polymorphisms (SNPs) within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. We evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD (266 and 396 subjects with and without comorbid SUD, respectively), 403 subjects with SUD without life-time diagnosis of ADHD and 485 sex-matched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3' region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. Our results provide preliminary evidence for the contribution of two sequence variants at the miR-183-96-182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2013; 23(11). DOI:10.1016/j.euroneuro.2013.07.002 · 4.37 Impact Factor
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