Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms

The habenular nuclear complex is a major influence on brainstem cell groups that influence attention, but its role in attentional performance has not previously been explored. The present study investigated how habenula lesions affect attentional function as assessed by the 5-choice serial reaction time task (5-CSRTT) in male Lister-Hooded rats. Rats were pretrained in the 5-CSRTT before receiving discrete bilateral lesions of the habenula or a sham procedure. In test sessions immediately following recovery from surgery, lesioned rats showed a marked increase in premature responding. Over the course of testing this increase of premature responding declined in magnitude. In contrast, choice accuracy showed no impairment during the earliest postsurgery test sessions but progressively deteriorated over the course of testing. These opposite time courses strongly imply that different mechanisms mediate these two effects of the habenula lesion. Differential effects of drug treatment on these effects further supported this view. Thus, D-amphetamine (0.2 mg/ kg s.c.) increased premature responding without affecting choice accuracy. On the other hand, haloperidol (0.01-0.03 mg/kg i.p.) decreased premature responding without significantly affecting choice accuracy. The results are consistent with the view that elevated premature responding in habenula-lesioned animals is mediated by increased dopaminergic activity, whereas impaired choice accuracy is not. Implications of these findings for the hypothesis that habenula dysfunction is involved in cognitive symptoms of schizophrenia are discussed.

Section: Discussionmentioning

confidence: 92%

Bilateral Lesions of the Habenula Induce Attentional Disturbances in Rats

Lecourtier

Kelly

2004

“…Other human and animal studies DA modulates responses to positive/negative rewards, salient events and arousal-producing stimuli (Everitt et al, 2000;Liberzon et al, 2003;Horvitz, 2000) CSF HVA levels are related to impulsivity in BPD (Coccaro, 1998;Chotai et al, 1998); to self-injurious and violent behavior (Winchel and Stanley, 1991;Soderstrom et al, 2001) DA receptor activity in the DLPFC modulates working memory and cognition (Arnsten et al, 1994;Goldman-Rakic, 1996;Arnsten and Goldman-Rakic, 1998) DA modulates emotional responses mediated by the amygdala-VTA-PFC circuits (Horvitz, 2000) DA dysfunction is involved in drug addiction (Modell et al, 1993;Volkow and Fowler, 2000) PCP-induced cognitive impairment correlates with DA levels in the DLPFC (Jentsch et al, 1997) Stress alters DA activity in the amydala and PFC (Finlay and Zigmond, 1997;Doherty and Gratton, 1999) DA mediates aggression and attack in rats (Wade et al, 2000;Vukhac et al, 2001) DA modulates cognitive processes at NMDA receptors (Williams and Goldman-Rakic, 1995) DA modulates conditioned fear responses (Guarraci et al, 1999) DA stimulates impulsive behavior in rats (Harrison et al, 1997) D1 agonist dilhydrexidine enhances cognitive performance and stimulates Ach release in the PFC (Steele et al, 1997;Schneider et al, 1994) Microdialysates of the PFC and the NAC suggest DA dysfunction is a risk factor for impulsivity (Van Erp and Miczek, 2000;Dalley et al, 2002) DA dysfunction in the DLPFC is related to cognitive impairment in SCZ, SPD, and normal subjects (Goldberg et al, 2003;Siever et al, 2002) DAFdopamine; CSF HVAFspinal fluid homovanillic acid; DLPFCFdorsolateral prefrontal cortex; PCPFphencylclidine; VTAFventral tegmental area; PFCFprefrontal cortex; AchFacetylcholine; NACFnucleus accumbens; SCZFschizophrenia; SPDFschizotypal personality disorder.…”

Section: The Effects Of Dopamine In Human and Animal Studiesmentioning

confidence: 99%

Section: Da Dysfunction and Impulsive Behaviors In Animalsmentioning

confidence: 99%

“…Aggressive and impulsive behaviors in rodents are modulated, in part, by DA activity at D1 and D2 receptors (Harrison et al, 1997;Vukhac et al, 2001). Dopamine-stimulated impulsive responses in rats are increased by central 5-HT depletion (Harrison et al, 1997). Microdialysates of the NAC and the medial PFC collected during behaviors measuring impulse control suggest that both DA and 5-HT dysfunction are risk factors of impulsivity (Van Erp and Miczek, 2000;Dalley et al, 2002).…”

Section: Da Dysfunction and Impulsive Behaviors In Animalsmentioning

confidence: 99%

See 1 more Smart Citation

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

Friedel

2004

123

Research on the biological basis of borderline personality disorder (BPD) has focused primarily on the serotonin model of impulsive aggression. However, there is evidence that dopamine (DA) dysfunction may also be associated with BPD. Pertinent research and review articles, identified by Medline searches of relevant topics, books, references from bibliographies, and conference proceedings from 1975 to 2003, were reviewed. Evidence of DA dysfunction in BPD derives from the efficacy of traditional and atypical antipsychotic agents in BPD, and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder. In addition, human and animal studies indicate that DA activity plays an important role in emotion information processing, impulse control, and cognition. The results of this review suggest that DA dysfunction is associated with three dimensions of BPD, that is, emotional dysregulation, impulsivity, and cognitive-perceptual impairment. The main limitation of this hypothesis is that the evidence reviewed is circumstantial. There is no study that directly demonstrates DA dysfunction in BPD. In addition, the therapeutic effects of antipsychotic agents observed in BPD may be mediated by non-DA mechanisms of action. If the stated hypothesis is correct, DA dysfunction in BPD may result from genetic, developmental, or environmental factors directly affecting specific DA pathways. Alternatively, DA dysfunction in BPD may be a compensatory response to alterations in the primary neural systems that control emotion, impulse control, and cognition, and that are mediated by the brain's main neurotransmitters, glutamate, and GABA, or in one or more other neuromodulatory pathways such as serotonin, acetylcholine, and norepinephrine.

“…The 5CSRTT assesses aspects of impulse control as well as attentional performance, speed of responding and motivation (Carli et al, 1983;Robbins, 2002). Harrison et al (1997a) showed that global 5-HT depletion increases premature responding on the 5CSRTT with concurrent decreases in omissions and latency to make a correct response. Intracerebral administration of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or specific lesions of serotonergic forebrain projections also increase impulsivity as well as impair attentional accuracy (Carli and Samanin, 1992;Jakala et al, 1992;Harrison et al, 1997a, b;Puumala and Sirviö, 1998;Winstanley et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Opposing Roles for 5-HT2A and 5-HT2C Receptors in the Nucleus Accumbens on Inhibitory Response Control in the 5-Choice Serial Reaction Time Task

Robinson

Dalley

Theobald

et al. 2007

130

110

Serotonin (5-HT) is thought to play an important role in the regulation of behavioral inhibition. Studies manipulating 5-HT function in the rodent brain indicate that 5-HT receptors regulate distinct forms of impulsive behavior, including impulsive responding in the 5-choice serial reaction time task (5CSRTT). The present study investigates the loci of effects mediated by 5-HT 2A and 5-HT 2C receptors in attention and inhibitory response control using microinfusions targeted at the nucleus accumbens (NAc), prelimbic cortex (PL) and infralimbic cortex (IL). Rats were implanted with bilateral guide cannulas and received infusions of the selective 5-HT 2A receptor antagonist M100907 (0.1 and 0.3 mg) or selective 5-HT 2C receptor antagonist SB242084 (0.1 and 0.5 mg) immediately prior to testing. The results show that intra-NAc infusions of M100907 significantly decrease impulsive responding on the 5CSRTT and at the highest dose increased omissions as well. By contrast, infusions of SB242084 into the NAc selectively and dose-dependently increased impulsivity. Neither M100907 nor SB242084 significantly altered impulsive responding following either intra-PL or intra-IL administration. However, SB242084 significantly decreased omissions following intra-PL administration (0.5 mg only). These data reveal opposing effects on impulsivity following 5-HT 2A and 5-HT 2C blockade in the NAc. Our results suggest that the NAc, but not the PL or IL, is implicated in the mediation of the effects of M100907 and SB242084 on inhibitory response control during baseline 5CSRTT performance.