5-HT2 and D1-mechanisms of the basolateral nucleus of the amygdala enhance conditioned fear and impair unconditioned fear

Laboratório de Psicobiologia, Faculdade Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo (USP), 14040-901 Ribeirão Preto, SP, Brasil.
Behavioural Brain Research (Impact Factor: 3.03). 03/2007; 177(1):100-8. DOI: 10.1016/j.bbr.2006.10.031
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The inferior colliculus (IC) is involved in processing of auditory information, but also integrates acoustic information of aversive nature. In fact, chemical stimulation of the IC with semicarbazide (SMC) - an inhibitor of the GABA synthesizing enzyme glutamic acid decarboxylase - has been found to cause defensive behavior in an open-field test and functions as an unconditioned stimulus in the place conditioned aversion test (PCA). A question has arisen regarding whether the basolateral nucleus of the amygdala (BLA) is involved in the acquisition of the aversive information ascending from the IC and whether dopaminergic and serotoninergic mechanisms of the BLA regulate this process. Recent evidence has shown that inactivation of the BLA with muscimol inhibits the PCA and causes an increase in the aversiveness of the chemical stimulation of the IC. Based on this, we examined the effects of ketanserin and SCH-23390, antagonists of the 5HT(2) and D(1) receptors, respectively, on the conditioned and unconditioned fear elicited by IC stimulation with SMC. The results obtained confirm the crucial role of 5-HT(2)- and D(1)-mechanisms of the BLA on conditioned fear in that ketanserin and SCH-23390 injections into the BLA caused a reduction in the PCA. On the other hand, ketanserin and SCH-23390 injections into the BLA enhanced the aversiveness of the IC injections of SMC. These findings suggest that while 5-HT(2) and DA(1) mechanisms in the BLA appear to facilitate the conditioned fear they inhibit the unconditioned fear triggered by IC activation.

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Available from: Victor Alejandro Molina, Apr 23, 2015
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    • "High numbers of D1 receptors are located within caudate putamen (CPu), nucleus accumbens (NAc), and substantia nigra pars reticulata (SNr) with a less dense distribution in the amygdaloid regions [5]. Evidences suggest that D1 receptors in the CPu, NAc, and SNr facilitate motivated behavior [6, 7], while those in the amygdala are more involved in affective behavior [8, 9]. "
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    ABSTRACT: The aim of this study was to explore effects on anxiety-like behavior of D1 dopamine receptor agonist, SKF-38393, and of D1 dopamine receptor antagonist, SCH-23390, given alone or in combination with a low dose of 17 β -estradiol (17 β -E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17 β -E2 (5.0 μ g/rat, s.c.), SKF-38393 (0.1 mg/kg, i.p.), SCH-23390 (0.1 mg/kg, i.p.), SKF-38393 plus 17 β -E2, or SCH-23390 plus 17 β -E2. The animals were tested in the black and white model (BWM) and the open field test (OFT). SCH-23390 (0.1 mg/kg, i.p.) alone or in a combination with a low dose of 17 β -E2 (5.0 μ g/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment with SCH-23390 and 17 β -E2 profoundly increased anxiolytic-like effect of single substances exerted per se. Coadministration of SCH-23390 with 17 β -E2 increased frequency of rearing and grooming in OVX rats in OFT. SKF-38393 (0.1 mg/kg, i.p.) treatment failed to alter anxiety-like behavior in OVX rats in the BWM. The results of the present study suggest that 17 β -E2 and SCH-23390 interact to exert anxiolytic-like action and that each of these drugs can potentiate effects of each other.
    02/2014; 2014:847821. DOI:10.1155/2014/847821
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    • "These receptors modulate a complex array of animal behaviors in various models including anxiety (Kennett et al., 1994), impulsivity (Hadamitzky et al., 2009), and working memory (Terry et al., 2005). And BLA 5-HT2-like receptors specifically regulate anxiety-like behaviors (Zangrossi and Graeff, 1994), impulsive decision making (Hadamitzky and Koch, 2009), and conditioned aversion (Macedo et al., 2007). Given that acute ethanol is often considered an aversive stimulus in naïve animals (Phillips et al., 2005), complex interactions between anxiety, impulsive decision making, and conditioned behaviors may drive BLA-dependent modulation of operant behaviors directed at either drug or natural rewards. "
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    ABSTRACT: The lateral/basolateral amygdala (BLA) forms an integral part of the neural circuitry controlling innate anxiety and learned fear. More recently, BLA dependent modulation of self-administration behaviors suggests a much broader role in the regulation of reward evaluation. To test this, we employed a self-administration paradigm that procedurally segregates "seeking" (exemplified as lever-press behaviors) from consumption (drinking) directed at a sweetened ethanol solution. Microinjection of the nonselective serotonin type-2 receptor agonist, alpha-methyl-5-hydroxytryptamine (α-m5HT) into the BLA reduced lever pressing behaviors in a dose-dependent fashion. This was associated with a significant reduction in the number of response-bouts expressed during non-reinforced sessions without altering the size of a bout or the rate of responding. Conversely, intra-BLA α-m5HT only modestly effected consumption-related behaviors; the highest dose reduced the total time spent consuming a sweetened ethanol solution but did not inhibit the total number of licks, number of lick bouts, or amount of solution consumed during a session. In vitro neurophysiological characterization of BLA synaptic responses showed that α-m5HT significantly reduced extracellular field potentials. This was blocked by the 5-HT2A/C antagonist ketanserin suggesting that 5-HT2-like receptors mediate the behavioral effect of α-m5HT. During whole-cell patch current-clamp recordings, we subsequently found that α-m5HT increased action potential threshold and hyperpolarized the resting membrane potential of BLA pyramidal neurons. Together, our findings show that the activation of BLA 5-HT2A/C receptors inhibits behaviors related to reward-seeking by suppressing BLA principal neuron activity. These data are consistent with the hypothesis that the BLA modulates reward-related behaviors and provides specific insight into BLA contributions during operant self-administration of a sweetened ethanol solution.
    Frontiers in Integrative Neuroscience 01/2014; 8:5. DOI:10.3389/fnint.2014.00005
    • "Also, the medial nucleus, which as described above is adjacent to the SFA and is sensitive to androgens, has in rodents been implicated in emotional stress responses, but not physical stress responses, while the CMA shows an opposite pattern (Ebner et al., 2004). Recent rodent data moreover show that the functions of the amygdala subregions are not only dissociated, but that the BLA is even capable of reducing CMA output (Macedo et al., 2007; Tye et al., 2011). Together, a selective effect of testosterone on the fear response and the distinct roles of amygdala subregions in fear processing imply that fear reduction induced by testosterone is consistent with increased activation of the SFA or BLA. "
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    ABSTRACT: Data from both rodents and humans show that testosterone reduces fear. This effect is hypothesized to result from testosterone's down regulating effects on the amygdala, a key region in the detection of threat and instigator of fight-or-flight behavior. However, neuroimaging studies employing testosterone administration in humans have consistently shown increased amygdala responsivity. Yet, no study to date has investigated specifically how testosterone affects the amygdala response to fearful emotional expressions. Such stimuli signal the presence of environmental threat and elicit robust amygdala responses that have consistently been associated with anxious traits. In the present study, we therefore used functional magnetic resonance imaging combined with a single administration of 0.5 mg testosterone in 12 healthy women to assess testosterone's effects on amygdala responses to dynamic fearful (and happy control) faces. Our results show that both stimuli activate the amygdala. Notably, testosterone increased the amygdala response to both stimuli, and to an equal degree. Thus, testosterone appears not to reduce fear by attenuating the amygdala response toward signals of threat. Data further show that testosterone selectively increases activation of the superficial amygdala (SFA) and, to a lesser extent, the basolateral amygdala (BLA). No effect was found in the central nucleus, which is involved in the generation of autonomic fear responses. Both the SFA and BLA are considered input regions, and enhanced activation by testosterone might reflect the role of this hormone in adaptive responding to socially relevant stimuli. Furthermore, literature on the distinct roles of the SFA and BLA in fear processing show that increased activation of these subregions of the amygdala is consistent with a fear reducing effect of testosterone.
    Psychoneuroendocrinology 06/2013; 38(6):808–817. DOI:10.1016/j.psyneuen.2012.09.005 · 4.94 Impact Factor
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