Deficits in Impulse Control Associated with Tonically-elevated Serotonergic Function in Rat Prefrontal Cortex

128

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.

Section: Discussionmentioning

confidence: 99%

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

128

110

“…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%

“…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%

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

Friedel

2004

120

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.

“…Furthermore, recent studies with human volunteers have found that ATD increases impulsive and aggressive behavior, although these effects appear to depend on individual differences in impulsive personality traits (Cherek and Lane, 1999;LeMarquand et al, 1999;Dougherty et al, 1999;Bjork et al, 2000;Marsh et al, 2002;Crean et al, 2002). Findings from studies with clinical human populations are corroborated by an extensive number of animal studies, which suggest that impulsive choice in delaydiscounting paradigms and premature responding in choice reaction-time tasks implicate changes in the 5-HT system (Wogar et al, 1993;Harrison et al, 1997a, b;Puumala and Sirvio, 1998;Koskinen et al, 2000;Mobini et al, 2000;Dalley et al, 2002;Passetti et al, 2003;Winstanley et al, 2003;Liu et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

Tryptophan Depletion Disrupts the Motivational Guidance of Goal-Directed Behavior as a Function of Trait Impulsivity

Cools

Blackwell

Clark

et al. 2005

140

145

Serotonin (5-HT) is well known to affect the motivational properties of stimuli predictive of rewards as well as the inhibitory control of behavior. Here, central 5-HT depletion was induced by the acute tryptophan (TRP) depletion (ATD) procedure in young healthy volunteers to examine the role of 5-HT in motivated action and prepotent response inhibition. A novel reaction-time task, tailored to individual differences in general cognitive speed, was employed to measure the guidance of behavior by motivationally relevant signals predictive of reinforcement likelihood, while the stop-signal reaction-time task was used to measure response inhibition. Following the TRP-balancing control drink, cues predictive of high-reinforcement certainty induced faster, but less accurate responses compared with cues predictive of lower reinforcement certainty. Depletion of central 5-HT modulated this coupling between motivation and action by slowing responses and increasing accuracy as a function of incentive certainty. These effects of ATD on motivated action correlated highly with individual differences in the personality trait of Nonplanning Impulsiveness (Barratt Impulsivity Scale (BIS-11)), so that strongest effects on motivated action were observed in high-impulsive individuals. By contrast, ATD left unaltered the ability to inhibit prepotent responses. Our findings may have implications for a variety of neuropsychiatric disorders including impulsive aggressive disorders and depression.