title: Distinct effects of haloperidol in the mediation of conditioned fear in the mesolimbic system and processing of unconditioned aversive information in the inferior colliculus.
abstract: Chemical and electrical stimulation of the inferior colliculus (IC) causes defensive behavior. Electrical stimulation of the IC at the escape threshold enhances dopamine (DA) release in the prefrontal cortex. Intra-ventral tegmental area injections of quinpirole at doses that act presynaptically reduce the release of DA in the terminal fields of the mesolimbic system and clearly reduce conditioned fear in several animal models of anxiety. However, little is known about the involvement of DA in the mediation of unconditioned fear, such as the reactivity to acute stressors. The present study investigated the neural substrates mediated by DA transmission associated with emotional changes triggered by the activation or inhibition of D2 receptors during conditioned and unconditioned fear. We examined the effects of systemic or local injections of the DA-receptor antagonist and agonist haloperidol and quinpirole, respectively, into the IC in rats subjected to fear-potentiated startle, a Pavlovian paradigm that uses loud sounds as the unconditioned stimulus and light previously paired with footshock as the conditioned stimulus. We also assessed auditory-evoked potentials (AEPs) recorded from electrodes implanted in the IC. Intraperitoneal haloperidol administration dose-dependently enhanced AEPs induced by loud tones and inhibited fear-potentiated startle. Intra-IC injections of quinpirole left AEPs unchanged, suggesting that an optimal level of postsynaptic D2 receptors in the IC may regulate the transmission of aversive information through the midbrain tectum. These findings provide evidence of opposing DA-mediated mechanisms in fear/anxiety processes that depend on the area under study. The activity of the neural substrates of conditioned fear was attenuated by haloperidol, whereas midbrain neural substrates of unconditioned fear were enhanced. Thus, DA appears to regulate unconditioned fear at the midbrain level, likely by reducing the sensory gating of aversive events and reducing conditioned fear by acting at more rostral levels of the brain.
authors.affiliation: Laboratory of Neuropsychopharmacology, FFCLRP, Universidade de São Paulo, Campus USP, Ribeirão Preto, SP 14049-901, Brazil; Instituto de Neurociencias e Comportamento, Avenida do Café, 2450, Ribeirão Preto, SP 14050-000, Brazil.
authors.forename: S
authors.initials: S
authors.lastname: Muthuraju
authors.affiliation: Laboratory of Neuropsychopharmacology, FFCLRP, Universidade de São Paulo, Campus USP, Ribeirão Preto, SP 14049-901, Brazil; Instituto de Neurociencias e Comportamento, Avenida do Café, 2450, Ribeirão Preto, SP 14050-000, Brazil; Departamento de Psicologia, Uni-FACEF, 14401-135 Franca, SP, Brazil.
authors.forename: M J
authors.initials: MJ
authors.lastname: Nobre
authors.affiliation: Laboratory of Neuropsychopharmacology, FFCLRP, Universidade de São Paulo, Campus USP, Ribeirão Preto, SP 14049-901, Brazil; Instituto de Neurociencias e Comportamento, Avenida do Café, 2450, Ribeirão Preto, SP 14050-000, Brazil.
authors.forename: V M N
authors.initials: VM
authors.lastname: Saito
authors.affiliation: Laboratory of Neuropsychopharmacology, FFCLRP, Universidade de São Paulo, Campus USP, Ribeirão Preto, SP 14049-901, Brazil; Instituto de Neurociencias e Comportamento, Avenida do Café, 2450, Ribeirão Preto, SP 14050-000, Brazil. Electronic address: mbrandao@usp.br.
authors.forename: M L
authors.initials: ML
authors.lastname: Brandao
mesh_terms: D000818:Animals; D002375:Catalepsy / Q000139:chemically induced; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology*; D007245:Inferior Colliculi / Q000187:drug effects* / Q000502:physiology; D008297:Male; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D006220:Haloperidol
keywords: auditory-evoked potentials; conditioned aversion; dopamine; fear-potentiated startle; inferior colliculus; unconditioned fear