Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex.
ABSTRACT Impulsivity is a key symptom of attention-deficit hyperactivity disorder (ADHD). The use of the norepinephrine reuptake inhibitor, atomoxetine, to treat ADHD suggests that the activity of the norepinephrine transporter (NET) may be important in regulating impulsive behavior. Many ADHD patients receive chronic drug treatment during adolescence, a time when frontal brain regions important for impulse control are undergoing extensive development.
The current study aimed to determine the effects of chronic atomoxetine treatment during adolescence in rats on two distinct forms of impulsivity in adulthood and whether any behavioral changes were accompanied by alterations in mRNA or protein levels within the frontal cortices.
Rats received daily injections of saline or atomoxetine (1 mg/kg) during adolescence (postnatal days 40-54). Two weeks later, animals were trained to perform either the delay-discounting test or the five-choice serial reaction time task (5CSRT).
Adolescent atomoxetine treatment caused a stable decrease in selection of small immediate rewards over larger delayed rewards (impulsive choice) in adulthood, but did not affect premature responding (impulsive action) in the 5CSRT. Chronic atomoxetine treatment also altered the ability of acute atomoxetine to modulate aspects of impulsivity, but did not change the response to d-amphetamine. Ex vivo analysis of brain tissue indicated that chronic atomoxetine decreased phosphorylation of CREB and ERK in the orbitofrontal cortex and decreased mRNA for BDNF and cdk5.
These data suggest that repeated administration of atomoxetine in adolescence can lead to stable decreases in impulsive choice during adulthood, potentially via modulating development of the orbitofrontal cortex.
- SourceAvailable from: Jose Javier Miguel-Hidalgo[show abstract] [hide abstract]
ABSTRACT: Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 07/2007; 6(3):219-33. · 3.77 Impact Factor
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ABSTRACT: Atomoxetine is a noradrenaline-specific reuptake inhibitor used clinically for the treatment of childhood and adult attention deficit hyperactivity disorder (ADHD). Studies in human volunteers and patient groups have shown that atomoxetine improves stop-signal reaction time (SSRT) performance, an effect consistent with a reduction in motor impulsivity. However, ADHD is a heterogeneous disorder and it is of interest to determine whether atomoxetine is similarly effective against other forms of impulsivity, as well as the attentional impairment present in certain subtypes of ADHD. The present study examined the effects of atomoxetine on impulsivity using an analogous SSRT task in rats and two additional tests of impulsivity; delay discounting of reward and the five-choice serial reaction time task (5CSRTT), the latter providing an added assessment of sustained visual attention. Atomoxetine produced a significant dose-dependent speeding of SSRT. In addition, atomoxetine produced a selective, dose-dependent decrease in premature responding on the 5CSRTT. Finally, on the delay-discounting task, atomoxetine significantly decreased impulsivity by increasing preference for the large-value reward across increasing delay. These findings conclusively demonstrate that atomoxetine decreases several distinct forms of impulsivity in rats. The apparent contrast of these effects with stimulant drugs such as amphetamine and methylphenidate, which generally act to increase impulsivity on the 5CSRTT, may provide new insights into the mechanisms of action of stimulant and nonstimulant drugs in ADHD.Neuropsychopharmacology 05/2008; 33(5):1028-37. · 8.68 Impact Factor
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ABSTRACT: A single exposure to cocaine rapidly induces the brief activation of several immediate early genes, but the role of such short-term regulation in the enduring consequences of cocaine use is poorly understood. We found that 4 h of intravenous cocaine self-administration in rats induced a transient increase in brain-derived neurotrophic factor (BDNF) and activation of TrkB-mediated signaling in the nucleus accumbens (NAc). Augmenting this dynamic regulation with five daily NAc BDNF infusions caused enduring increases in cocaine self-administration, and facilitated relapse to cocaine seeking in withdrawal. In contrast, neutralizing endogenous BDNF regulation with intra-NAc infusions of antibody to BDNF subsequently reduced cocaine self-administration and attenuated relapse. Using localized inducible BDNF knockout in mice, we found that BDNF originating from NAc neurons was necessary for maintaining increased cocaine self-administration. These findings suggest that dynamic induction and release of BDNF from NAc neurons during cocaine use promotes the development and persistence of addictive behavior.Nature Neuroscience 09/2007; 10(8):1029-37. · 15.25 Impact Factor