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New York: McGraw-Hill purchase 160 mg super p-force oral jelly otc, 1996: treatment of obsessive-compulsive disorder 160 mg super p-force oral jelly. Open trial of fluoxetine interactions of psychotropic drugs. Int J Psychol Med 1991;21: in obsessive-compulsive disorder. J Int Clin Psychopharmacol 1994;14: ment of obsessive-compulsive disorder: an open clinical trial. Am J Psychiatry 1996;153: blind, placebo-controlled study of fluoxetine inpatients with 311–320. Psychopharmacology in the medically sented at the Annual Meeting of the American Psychiatric Asso- ill. Principles of medical psychia- ciation, New York, May 1996. Efficacy of drug treatment in obses- adolescents with obsessive-compulsive disorder (Letter). Am J sive-compulsive disorder: a meta-analytic review. Int Clin Psycho- pulsive disorders: preliminary clinical experience. Fluvoxamine trial of fluoxetine and placebo in children and adolescents with versus clomipramine in the treatment of obsessive-compulsive obsessive-compulsive disorder. J Am Acad Child Adolesc Psychia- disorder: a multi-center, randomized, double-blind, parallel try 1992;31:1062–1069. Fluvoxamine versus to fluoxetine in the treatment of children and adolescents with clomipramine for obsessive-compulsive disorder: a double-blind obsessive-compulsive disorder. Sertraline in children ment of obsessive-compulsive disorder. Br J Psychiatry 1996; and adolescents with obsessive-compulsive disorder: a multicen- 169:468–474. Clomipramine versus fluoxetine 1752–1756 (published erratum appears in JAMA 2000;8: in obsessive-compulsive disorder: a retrospective comparison of 283(10):1293). Riddle MA, Reeve EA, Yaryura-Tobias side effects and efficacy. Fluvoxamine for children and adolescents with obses- 122–124. A review of the efficacy of selective seroto- trial. J Am Acad Child Adolesc Psychiatry 2001;40(2):222–229. Arch Gen Psychiatry 1985;42(10): toms after discontinuation of clomipramine in patients with 977–983. A double-blind der Psychopharmacol Bull 1980;16(3):61–63. Treatment of child- ment in children and adolescents with obsessive-compulsive dis- hood obsessive-compulsive disorder with clomipramine and order. Long-term follow-up of Psychopharmacol Bull 1988;24(1):93–95. Child and adolescent obsessive-compulsive disor- 1994;151:441–442. Childhood obsessive- Child Adolesc Psychiatr Clin North Am 1999;8(3):599–616. Psychopharmacologic sive-compulsives: from theory to treatment. In: Mavissakalian treatment of child and adolescent obsessive-compulsive disor- M, Turner SM, Michelson L, ed.
As noted generic super p-force oral jelly 160mg on-line, a shared property of addictive drugs is to promote dopamine release in multiple forebrain regions discount super p-force oral jelly 160mg on-line, including the NAc, but also including the dorsal striatum, amygdala, and hippocampus, in which dopamine release can act as a reinforcement signal, thus controlling learning processes (39,40). As drug use con- tinues, tolerance may occur, leading to dosage escalation. Depending on the drug, somatic dependence and/or emo- tional–motivational dependence my sustain drug seeking and drug use in attempts to avoid the aversive state of with- drawal. The emotional–motivational aspects of tolerance and dependence may largely occur within the mesocorticoli- mbic circuitry itself, but molecular adaptations occur in other circuits as well in a drug-specific manner reflecting the location of the target molecules for the given drug. Sen- sitization to some drug effects may occur, a phenomenon that is especially well documented for psychostimulants. Sensitization may act, inter alia, to increase the incentive salience of the drug, and thereby contribute to compulsive drug use (41). At the same time, multiple memory systems are affected by drugs of abuse (42)and, undoubtedly con- tribute to sustaining active drug use and late relapses (37). What follows are examples of different molecular processes that contribute to different aspects and stages of substance use disorders. These illustrations have been chosen based on the depth of available information, and likely relevance to the clinical situation in humans. Adaptations That Produce Tolerance and Somatic Dependence to Opiates FIGURE 96. Mechanism of opiate tolerance and dependence Opiates and ethanol produce somatic dependence and with- in the locus ceruleus: Acute administration of opiates increases drawal because their targets are expressed on cells and cir- outward K current, thereby hyperpolarizing locus ceruleus cells cuits that regulate bodily functions such as autonomic activ- (top). With chronic opiate use the cAMP signaling system is up- regulated, leading to PKA-dependent phosphorylation of the ity. Tolerance and dependence are generally thought to Na channel. In this state, the channel is more active, allowing represent homeostatic adaptations that compensate for Na ions to flow into the cell, increasingly the intrinsic excitability overstimulation by a drug or neurotransmitter. Up-regulation of the cAMP system also increases CREB Ser133 phosphorylation and CRE-dependent gene transcription. The molecular adaptations probably responsible for some aspects of tolerance and somatic dependence are best understood signaling mechanisms in opiate receptor-bearing cells (Fig. With repeat administration of mu agonist opiates such The locus ceruleus (LC), located in the dorsal pons, is as morphine or heroin, both tolerance and dependence the major noradrenergic nucleus of the brain and regulates emerge. There is a significant somatic component to heroin arousal, attention, and vigilance. It is involved in responses dependence as manifest by the classic heroin somatic with- to stress, and together with other noradrenergic cell groups drawal syndrome. It had initially been hypothesized that plays a role in regulation of the autonomic nervous system. Thus, despite continued op- turned out to be the case; rather opiate tolerance and depen- iate exposure, LC firing rates gradually return to their basal dence appear to be caused by adaptation in postreceptor levels. At this point, administration of an opioid receptor Chapter 96: Molecular and Cellular Biology of Addiction 1373 antagonist, such as naloxone or naltrexone, causes a dra- mice exhibited markedly reduced signs of withdrawal in- matic increase in LC firing rates. In animals, the period cluding complete absence of sniffing and ptosis (44,45). Opiate-induced syndrome, and drugs, such as the 2-adrenergic receptor up-regulation of PKA does not involve CREB and may be agonist clonidine, which inhibit LC firing, attenuate with- mediated posttranslationally. When the regulatory subunits are bound erance and dependence depend on the cyclic AMP (cAMP) by cAMP, the catalytic subunits are free to phosphor late pathway. In the LC, as in most other cell types, -opioid substrate proteins. However, free catalytic subunits of PKA receptor activation inhibits the cAMP pathway via Gi acti- are highly vulnerable to proteolysis, whereas inactive sub- vation and stimulates an inwardly rectifying K current by units bound to regulatory subunits are proteolysis-resistant. As the number of enzyme the actions of agonist opiates on these K and Na molecules increases, the kinase activity can be more readily channels expressed by LC neurons decrease the excitability activated by the low levels of cAMP. With long-term opiate administration, however, a homeostatic compensatory re- Adaptations That May Produce Tolerance sponse occurs: key components of the cAMP pathway be- and Somatic Dependence on Ethanol come up-regulated in LC neurons; thus, for example there Like opiates, ethanol produces somatic dependence and are increased concentrations of adenylyl cyclase and protein withdrawal, although the clinical syndrome is quite distinct, kinase A. This up-regulation increases the intrinsic excitabil- and potentially more dangerous.
Any pathophysiologic theory about ADHD must address Others argue that the diagnosis of ADHD in adults is both the large pharmacotherapy literature about the disorder purchase super p-force oral jelly 160mg free shipping. These investigators point to longitudi- The mainline treatments for ADHD are the stimulant med- nal studies of children with ADHD purchase 160mg super p-force oral jelly visa, studies of clinically ications methylphenidate, pemoline, and dextroampheta- referred adults, family-genetic studies, and psychopharma- mine. These compounds are safe and effective for treating cologic studies. Longitudinal studies have found that as ADHD in children, adolescents, and adults (8,9). Studies of clinically referred ness, hyperactivity, and impulsivity, stimulants also improve associated behaviors, including on-task behavior, academic performance, and social functioning in the home and at school. In adults, occupational and marital dysfunction tend Stephen V. Farone: Pediatric Psychopharmacology Unit, Child Psychia- try Service, Massachusetts General Hospital; Harvard Medical School; Massa- to improve with stimulant treatment. There is little evidence chusetts Mental Health Center; Harvard Institute of Psychiatric Epidemiology of a differential response to methylphenidate, pemoline, and and Genetics, Boston, Massachusetts. The average response rate for each is Joseph Biederman: Pediatric Psychopharmacology Unit, Child Psychia- try Service, Massachusetts General Hospital; Harvard Medical School, Boston, 70%. Stimulants enhance social skills at home and in school. Solanto suggested that stimulants may also activate uational cues and to modulate the intensity of their behav- presynaptic inhibitory autoreceptors and may lead to re- ior. They also show improved communication, greater duced dopaminergic and noradrenergic activity (21). The responsiveness, and fewer negative interactions. Neuro- maximal therapeutic effects of stimulants occur during the psychological studies show that stimulants improve vigi- absorption phase of the kinetic curve, within 2 hours after lance, cognitive impulsivity, reaction time, short-term ingestion. The absorption phase parallels the acute release memory, and learning of verbal and nonverbal material in of neurotransmitters into synaptic clefts, a finding providing children with ADHD. A plausible model for the effective anti-ADHD agents. TCAs include secondary and effects of stimulants in ADHD is that, through dopami- tertiary amines with a wide range of receptor actions, effi- nergic or noradrenergic pathways, these drugs increase the cacy, and side effects. Secondary amines are more selective inhibitory influences of frontal cortical activity on subcorti- (noradrenergic) with fewer side effects. TCAs have found either a moderate or robust response rate Human studies of the catecholamine hypothesis of of ADHD symptoms (8–10). These studies show anti- ADHD that focused on catecholamine metabolites and en- ADHD efficacy for imipramine, desipramine, amitriptyline, zymes in serum and cerebrospinal fluid produced conflict- nortriptyline, and clomipramine. Perhaps the best summary of this litera- studies show that TCAs produce moderate to strong effects ture is that aberrations in no single neurotransmitter system on ADHD symptoms. In contrast, neurocognitive symp- can account for the available data. Of course, because studies toms are do not respond well to TCA treatment. Because of neurotransmitter systems rely on peripheral measures, of rare reports of sudden death among TCA-treated chil- which may not reflect brain concentrations, we cannot ex- dren, these drugs are not a first-line treatment for ADHD pect such studies to be completely informative. Neverthe- and are only used after carefully weighing the risks and less, although such studies do not provide a clear profile of benefits of treating or not treating a child who does not neurotransmitter dysfunction in ADHD, on balance, they respond to other agents. One approach has been the are rarely used because of their potential for hypertensive use of 6-hydroxydopamine to create lesions in dopamine crisis, several studies suggested that monoamine oxidase in- pathways in developing rats. Because these lesions created hibitors may be effective in juvenile and adult ADHD (14). Disruption of catecholaminergic showed efficacy in a controlled study of adults with ADHD transmission with chronic low-dose N-methyl-4-phenyl- (15) and in an open study of children with ADHD (16). In this latter work, TCAs, there is only weak evidence that either 2-noradren- MPTP administration to monkeys caused cognitive impair- ergic agonists or serotonin reuptake inhibitors effectively ments on tasks thought to require efficient frontal-striatal combat ADHD (17). A controlled clinical trial showed that neural networks. These cognitive impairments mirrored transdermal nicotine improved ADHD symptoms and those seen in monkeys with frontal lesions (26,27).
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