title: Lifelong disturbance of serotonin transporter functioning results in fear learning deficits: Reversal by blockade of CRF1 receptors.
abstract: The inability to associate aversive events with relevant cues (i.e. fear learning) may lead to maladaptive anxiety. To further study the role of the serotonin transporter (SERT) in fear learning, classical fear conditioning was studied in SERT knockout rats (SERT(-/-)) using fear potentiation of the startle reflex. Next, fear acquisition and concomitant development of contextual conditioned fear were monitored during training. To differentiate between developmental and direct effects of reduced SERT functioning, effects of acute and chronic SSRI treatment were studied in adult rats. Considering the known interactions between serotonin and corticotropin-releasing factor (CRF), we studied the effect of the CRFR1 antagonist CP154,526 on behavioral changes observed and determined CRF1 receptor levels in SERT(-/-) rats. SERT(-/-) showed blunted fear potentiation and enhanced contextual fear, which resulted from a deficit in fear acquisition. Paroxetine treatment did not affect acquisition or expression of fear-potentiated startle, suggesting that disturbed fear learning in SERT(-/-) results from developmental changes and not from reduced SERT functioning. Although CRF1 receptor levels did not differ significantly between genotypes, CP154,526 treatment normalized both cue- and contextual fear in SERT(-/-) during acquisition, but not expression of fear-potentiated startle. The disrupted fear acquisition and concomitant increase in contextual conditioned fear-potentiated startle fear in SERT(-/-) resembles the associative learning deficit seen in patients with panic disorder and suggests that normal SERT functioning is crucial for the development of an adequate fear neuro-circuitry. Moreover, the normalization of fear acquisition by CP154,526 suggests a role for central CRF signaling in the generalization of fear.
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Brain Center Rudolf Magnus, Utrecht University, The Netherlands. Electronic address: e.y.bijlsma@uu.nl.
authors: Elisabeth Y
authors: EY
authors: Bijlsma
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Brain Center Rudolf Magnus, Utrecht University, The Netherlands.
authors: Hendrikus
authors: H
authors: Hendriksen
authors: Department of Experimental Psychology and Psychopharmacology, Utrecht University, The Netherlands.
authors: Johanna M P
authors: JM
authors: Baas
authors: Institut de Recherches Servier, Croissy-sur-Seine, France.
authors: Mark J
authors: MJ
authors: Millan
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Brain Center Rudolf Magnus, Utrecht University, The Netherlands.
authors: Lucianne
authors: L
authors: Groenink
mesh_terms: D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D055786:Gene Knockout Techniques; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D007859:Learning Disabilities / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055647:Rats, Transgenic; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D000099052:CRF Receptor, Type 1
chemical_list: C101628:CP 154526; D018377:Neurotransmitter Agents; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; C482440:Sert1 protein, rat; D017374:Paroxetine; D000099052:CRF Receptor, Type 1
keywords: Anxiety; CP154,526; Fear-potentiated startle; Knockout; Light-enhanced startle; Prepulse inhibition