5‐HT2A and D2 receptor blockade increases cortical DA release via 5‐HT1A receptor activation: a possible mechanism of atypical antipsychotic‐induced cortical dopamine release

In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Disruption of the Prepulse Inhibition of the Startle Reflex in Vasopressin V1b Receptor Knockout Mice: Reversal by Antipsychotic Drugs

Egashira

Tanoue

Higashihara

et al. 2005

“…In addition, the D1 agonist dihydrexidine releases acetylcholine in the PFC and enhances cognitive performance in rats (Steele et al, 1997) and in monkeys (Schneider et al, 1994), effects blocked by SCH 23390. Of interest in this regard is the recent finding that atypical, but not traditional antipsychotic drugs increase cortical acetylcholine release in the PFC with no effect in the nucleus accumbens or striatum (Ichikawa et al, 2002).…”

Section: Da Dysfunction and Impulsive Behaviors In Animalsmentioning

confidence: 99%

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.

“…Moreover 5-HT 1A agonists are known to increase cortical DA efflux without affecting striatal DA efflux (Arborelius et al, 1993;Rollema et al, 2000). Ichikawa et al (2001) recently hypothesized that simultaneous blockade of 5-HT 2A and DA D 2 receptors causes an increase in cortical DA efflux by facilitating 5-HT 1A agonist activity by endogenous 5-HT. It may thus be suggested that, by directly activating 5-HT 1A receptors, SSR181507 is functionally equivalent to atypical antipsychotics that indirectly achieve this effect.…”

Section: Mesocorticolimbic Selectivity and Atypical Antipsychotic Promentioning

confidence: 99%

“…Recent preclinical and clinical data have suggested that combining antagonist activity at DA D 2 receptors with agonist activity at 5-HT 1A receptors might offer a promising alternative to schizophrenia treatment (see Meltzer and McGurk, 1999;Millan, 2000;Ichikawa et al, 2001;Bantick et al, 2001 for reviews).…”

Section: Introductionmentioning

confidence: 99%

SSR181507, A Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist. I: Neurochemical and Electrophysiological Profile

Claustre

Peretti

Brun

et al. 2003

monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT 1A receptors (K I ¼ 0.8, 0.2, and 0.2 nM for human D 2 , D 3 , and 5-HT 1A , respectively). In vivo, SSR181507 inhibited [ 3 H]raclopride binding to D 2 receptors in the rat (ID 50 ¼ 0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D 2 antagonist and 5-HT 1A agonist properties in the same concentration range in vitro (IC 50 ¼ 5.3 nM and EC 50 ¼ 2.3 nM, respectively, in the GTPgS model) and in the same dose range in vivo (ED 50 ¼ 1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D 2 receptor antagonism and 5-HT 1A agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.