Conditioned fear is modulated by D-2 receptor pathway connecting the ventral tegmental area and basolateral amygdala

Laboratório de Psicobiologia, Faculdade de Filosofia, Ciências e Letras, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Neurobiology of Learning and Memory (Impact Factor: 3.65). 10/2010; 95(1):37-45. DOI: 10.1016/j.nlm.2010.10.005
Source: PubMed


Excitation of the mesocorticolimbic pathway, originating from dopaminergic neurons in the ventral tegmental area (VTA), may be important for the development of exaggerated fear responding. Among the forebrain regions innervated by this pathway, the amygdala is an essential component of the neural circuitry of conditioned fear. The functional role of the dopaminergic pathway connecting the VTA to the basolateral amygdala (BLA) in fear and anxiety has received little attention. In vivo microdialysis was performed to measure dopamine levels in the BLA of Wistar rats that received the dopamine D(2) agonist quinpirole (1 μg/0.2 μl) into the VTA and were subjected to a fear conditioning test using a light as the conditioned stimulus (CS). The effects of intra-BLA injections of the D(1) antagonist SCH 23390 (1 and 2 μg/0.2 μl) and D(2) antagonist sulpiride (1 and 2 μg/0.2 μl) on fear-potentiated startle (FPS) to a light-CS were also assessed. Locomotor performance was evaluated by use of open-field and rotarod tests. Freezing and increased dopamine levels in the BLA in response to the CS were both inhibited by intra-VTA quinpirole. Whereas intra-BLA SCH 23390 did not affect FPS, intra-BLA sulpiride (2 μg) inhibited FPS. Sulpiride's ability to decrease FPS cannot be attributed to nonspecific effects because this drug did not affect motor performance. These findings indicate that the dopamine D(2) receptor pathway connecting the ventral tegmental area and the basolateral amygdala modulates fear and anxiety and may be a novel pharmacological target for the treatment of anxiety.

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    • "Although the precise neural circuitry of DA transmission involved in aversive states remains unclear, pharmacological and neurochemical studies appear to implicate prefrontal cortex [40], [41] and nucleus accumbens DA terminals in the response to acute stressors [42]–[49]. With regard to DA's mediation of conditioned fear, an increase in DA metabolism in the mesolimbic system is correlated with conditioned fear, and a decrease in DA activity in the basolateral amygdala causes a reduction of the expression of conditioned fear responses [19], [20], [34], [50], [51]. In fact, intraperitoneal injections of low doses of the D2 receptor agonist quinpirole act at autoreceptors on VTA neurons, slowing DA release at their terminals and also causing a reduction of conditioned fear responses [19], [34], [51]. "
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    ABSTRACT: Background A reduction of dopamine release or D2 receptor blockade in the terminal fields of the mesolimbic system clearly reduces conditioned fear. Injections of haloperidol, a preferential D2 receptor antagonist, into the inferior colliculus (IC) enhance the processing of unconditioned aversive information. However, a clear characterization of the interplay of D2 receptors in the mediation of unconditioned and conditioned fear is still lacking. Methods The present study investigated the effects of intra-IC injections of the D2 receptor-selective antagonist sulpiride on behavior in the elevated plus maze (EPM), auditory-evoked potentials (AEPs) to loud sounds recorded from the IC, fear-potentiated startle (FPS), and conditioned freezing. Results Intra-IC injections of sulpiride caused clear proaversive effects in the EPM and enhanced AEPs induced by loud auditory stimuli. Intra-IC sulpiride administration did not affect FPS or conditioned freezing. Conclusions Dopamine D2-like receptors of the inferior colliculus play a role in the modulation of unconditioned aversive information but not in the fear-potentiated startle response.
    PLoS ONE 08/2014; 9(8):e104228. DOI:10.1371/journal.pone.0104228 · 3.23 Impact Factor
    • "The basolateral complex of the amygdala is one of the most potent modulators of the mechanisms that are responsible for the emotional memory system in animal models (Simmons et al., 2007). Studies have also determined that the dopamine transmission in the basolateral complex of the amygdala during fear conditioning plays a key role in the formation, retrieval, and expression of emotional memory (Bissière et al., 2003; Fadok et al., 2010; de Oliveira et al., 2011). Previous studies have demonstrated that valproic acid increased the extracellular dopamine levels in the medial prefrontal cortex and hippocampus; this is a mechanism that is believed to improve cognition in patients with schizophrenia (Ichikawa and Meltzer, 1999; Ichikawa et al., 2005; Huang et al., 2006). "
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    ABSTRACT: Valproic acid, an established antiepileptic and antimanic drug, has recently emerged as a promising emotion-stabilizing agent for patients with psychosis. Although dopamine transmission in the amygdala plays a key role in emotional processing, there has been no direct evidence about how valproic acid acts on the dopaminergic system in the brain during emotional processing. In the present study, we tested the effect of valproic acid on a trait marker of vulnerability to emotional stress in psychosis, which is excess dopamine release in response to a fear-conditioned stimulus (CS) in the basolateral complex of the amygdala of methamphetamine-sensitized rats. Extracellular dopamine was collected from the amygdala of freely moving methamphetamine-sensitized rats by in vivo microdialysis and was measured using high-performance liquid chromatography. During microdialysis, valproic acid was intraperitoneally injected followed by CS exposure. Valproic acid treatment decreased baseline levels of dopamine and also attenuated the excess dopamine release in response to the CS in the amygdala of methamphetamine-sensitized rats. The results prove that valproic acid inhibits spontaneous dopamine release and also attenuates excess dopaminergic signaling in response to emotional stress in the amygdala. These findings suggest that the mechanisms of the emotion-stabilizing effect of valproic acid in psychosis involve modulation of dopaminergic transmission in emotional processing.
    European journal of pharmacology 02/2014; 730(1). DOI:10.1016/j.ejphar.2014.01.020 · 2.53 Impact Factor
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    • "The prefrontal cortex (PFC), which has an essential role in working memory and executive function, has a more limited role in fear inhibition and extinction, rather than acquisition (Morgan and LeDoux 1995; Braver et al. 2001). MPH, a high affinity dopamine transporter (DAT) and norepinephrine transporter (NET) inhibitor (Han and Gu 2006), modulates behavior via increased monoamine neurotransmission (Kuczenski and Segal 1997, 2002; Lazzaro et al. 2010; de Oliveira et al. 2011; Johansen et al. 2011). We also tested diverse monoamine transporter inhibitors that have been used to treat ADHD, atomoxetine (ATM, NET inhibitor), bupropion (BPN, DAT inhibitor), and citalopram (CIT, SERT inhibitor), on fear learning (Fone and Nutt 2005). "
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    ABSTRACT: Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01-10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1-10 mg/kg, i.p.), bupropion (0.5-20 mg/kg, i.p.), and citalopram (0.01-10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.
    Learning & memory (Cold Spring Harbor, N.Y.) 01/2014; 21(2):82-9. DOI:10.1101/lm.033613.113 · 3.66 Impact Factor
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