The effects of intra-amygdaloid infusions of a D₂ dopamine receptor antagonist on Pavlovian fear conditioning.

Guarraci, Fay A.; Frohardt, Russell J.; Falls, William A.; Kapp, Bruce S.

doi:10.1037/0735-7044.114.3.647

Cited by 137 publications

(89 citation statements)

References 20 publications

(26 reference statements)

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“…A similar pattern of results has been obtained with muscimol infusion into the amygdala (Helmstetter and Bellgowan, 1994;Muller et al, 1997). Finally, normal conditioned fear during testing was found in rats that received behaviorally effective infusions of a protein kinase inhibitor or a dopamine antagonist before testing, but not conditioning, into the amygdala (Goosens et al, 2000;Guarraci et al, 2000); of the local anesthetic bupivacaine before conditioning, but not testing, into the nucleus accumbens (Haralambous and Westbrook, 1999); or of a dopamine agonist or antagonist before conditioning, but not testing, into the medial prefrontal cortex (Pezze et al, 2002a;2003). Thus, even though generalization over different drugs (Castellano and McGaugh, 1990) and brain regions (Phillips and LePiane, 1981) has to be made with caution, there is no clear evidence of drug infusions into single brain sites inducing state dependency of conditioned fear, while several findings argue against this possibility.…”

Section: State Dependencysupporting

confidence: 64%

Dorsal hippocampus and classical fear conditioning to tone and context in rats: Effects of local NMDA‐receptor blockade and stimulation

2003

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ABSTRACT:Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 g/side) or of NMDA (0.7 g/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

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Section: State Dependencysupporting

confidence: 64%

Dorsal hippocampus and classical fear conditioning to tone and context in rats: Effects of local NMDA‐receptor blockade and stimulation

2003

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“…In general, local blockade of D2-like receptors with pharmacological agents disrupts fear learning and memory (Guarraci et al 2000;Greba et al 2001). Our results indicate that this is also true for systemic D2 injections (Fig.…”

Section: Discussionmentioning

confidence: 99%

Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice

Ponnusamy¹,

Nissim²,

Barad³

2005

Learn. Mem.

121

101

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Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear conditioning mice with three pairings of a white noise conditional stimulus (CS) with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction. We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls. Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.Extinction of conditioned fear in mammals is an important preclinical model of behavior therapy, one of the most effective treatments for human anxiety disorders (Wolpe 1969;Craske 1999). Despite the efficacy of behavior therapy for human anxiety disorders, extinction-like treatments require repeated cue exposures and are vulnerable to reversal by a number of environmental factors. Thus, a deeper understanding of the synaptic mechanisms of extinction may permit the development of adjunctive medications to facilitate extinction learning, and perhaps, to make it more permanent.Anxiety disorders affect about 16% of the American population and include panic disorder (PD, 1.7%), obsessivecompulsive disorder (OCD, 2.3%), post-traumatic stress disorder (PTSD, 3.6%), generalized anxiety disorder (GAD, 2.8%), social phobia (2%), and simple phobias (8%) (US-Surgeon-General 1999). The rate of PTSD may well go higher in the context of current wars and terrorist acts. Given the enormous burden of such anxiety disorders, we are fortunate in having a reasonable animal model for the acquisition of some of these fears, that is, classically conditioned fear, and an even better animal model of an effective treatment method for those disorders, extinction of conditioned fear.Pavlovian, or classical, fear conditioning has long been an important model both of associative learning and of the etiology of human anxiety (Watson and Rayner 1920;Eysenck 1979;Wolpe and Rowan 1988). Temporal pairing of a neutral conditional stimulus (CS) with an aversive unconditional stimulus (US) generates robust conditional fear responses upon subseque...

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“…Based on results from a wide array of pharmacological studies, McGaugh and colleagues (McGaugh, 1989(McGaugh, , 2000McGaugh and Cahill, 1997; proposed that interactions of opioid, GABA, noradrenergic, and cholinergic neurochemical systems in the amygdala modulate aversive learning. Recently, pre-training intra-amygdalar infusions of the dopamine (D2) receptor antagonist eticlopride have been shown to markedly attenuate conditioned freezing, indicating that amygdaloid dopamine transmission also contributes to the formation of fear memories (Guarraci et al, 2000;Nader and LeDoux, 1999). Dopamine has also been shown to gate LTP induction in lateral amygdala by suppressing thalamo-amygdalo feedforward inhibition (Bissierre et al, 2003).…”

Section: Evidence From Pharmacological Studiesmentioning

confidence: 99%

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

Kim

Jung

2006

Neuroscience & Biobehavioral Reviews

516

438

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Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular-molecular mechanisms of fear conditioning. Converging lines of evidence indicate that the amygdala is necessarily involved in the acquisition, storage and expression of conditioned fear memory, and long-term potentiation (LTP) in the lateral nucleus of the amygdala is often proposed as the underlying synaptic mechanism of associative fear memory. Recent studies further implicate the prefrontal cortexamygdala interaction in the extinction (or inhibition) of conditioned fear. Despite these advances, there are unresolved issues and findings that challenge the validity and sufficiency of the current amygdalar LTP hypothesis of fear conditioning. The purpose of this review is to critically evaluate the strengths and weaknesses of evidence indicating that fear conditioning depend crucially upon the amygdalar circuit and plasticity. KeywordsFear conditioning; Amygdala; Prefrontal cortex; LTP; NMDA Fear is considered a defensive mechanism that evolved because of its evolutionary success in protecting animals from danger. While fear to certain kinds of stimuli is innately hardwired (e.g. a loud noise evoking fear in newborn infants, a cat inducing fear in naïve laboratory-reared rats), fear can also be acquired rapidly and lastingly to different stimuli allowing animals to respond adaptively to new or changing environmental situations. In the laboratory setting, Pavlovian or classical fear conditioning has become the par excellence task for studying the anatomical, cellular and molecular bases of fear memory formation in the brain.

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The effects of intra-amygdaloid infusions of a D₂ dopamine receptor antagonist on Pavlovian fear conditioning.

Cited by 137 publications

References 20 publications

Dorsal hippocampus and classical fear conditioning to tone and context in rats: Effects of local NMDA‐receptor blockade and stimulation

Dorsal hippocampus and classical fear conditioning to tone and context in rats: Effects of local NMDA‐receptor blockade and stimulation

Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice

Neural circuits and mechanisms involved in Pavlovian fear conditioning: A critical review

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