Research reportAmygdaloid D1 dopamine receptor involvement in Pavlovian fear conditioning
Introduction
Recent research suggests that the mesencephalic dopaminergic system is activated by stressful events. For example, dopamine-containing neurons in the ventral tegmental area (VTA) demonstrate enhanced firing rates in response to presentations of conditioned fear-arousing stimuli 18, 37. Furthermore, immobilization stress selectively increases Fos protein in VTA dopamine-containing neurons [10] and footshock stress increases dopamine metabolism in the VTA [11]. The amygdala has been identified as a site of dopamine release in response to stressful events since footshock and conditioned fear-arousing stimuli increase dopamine metabolism in this structure 7, 21.
The extant literature strongly suggests that the amygdala is a critical component of the neural circuitry essential for conditioned fear since various manipulations of the amygdala disrupt the acquisition and/or expression of conditioned fear 9, 22, 23, 25, 26. Furthermore, neurons within the amygdala demonstrate associative responses to presentations of conditioned fear-arousing stimuli 30, 32. Finally, the extensive descending projections of the amygdala, particularly, the projections of the amygdaloid central nucleus, to a variety of brainstem areas offer an anatomical substrate for the expression of several responses indicative of fear 9, 22, 33.
The well-documented role of the amygdala in conditioned fear and the substantial dopaminergic innervation of the amygdala 2, 11, 12 suggest a contribution of the mesoamygdaloid dopaminergic system to the acquisition and/or expression of conditioned fear. Surprisingly, little effort, however, has been devoted to investigating this contribution. Nevertheless, evidence has accumulated indicating that dopamine activation is involved in conditioned fear. For example, Davis [8] has demonstrated that systemic administration of SCH 23390, a D1-receptor antagonist, or raclopride, a D2-receptor antagonist, attenuates fear-potentiated startle. This finding is consistent with the recent report that VTA lesions block fear-potentiated startle, whereas electrical stimulation of the VTA facilitates acoustic startle [5]. However, the forebrain terminal region(s) where dopamine exerts its effects were not revealed using these techniques. For this reason, we have been investigating the role of the mesoamygdaloid dopaminergic system in conditioned fear using a well-defined model of Pavlovian fear conditioning in the rat: conditioned freezing to an acoustic stimulus predictive of footshock. We found that intra-amygdaloid infusions of a dopaminergic antagonist disrupted conditioned freezing [17]. These observations are consistent with the recently published results of Lamont and Kokkinidis [24], which indicate that the amygdaloid dopaminergic system contributes to the expression of fear in the fear potentiated startle paradigm. The present study was designed to extend our preliminary findings by investigating the dose-dependent effects of intra-amygdaloid infusions of either a dopaminergic agonist or antagonist on the acquisition and expression of Pavlovian fear conditioning.
Section snippets
Experiment 1A
The purpose of Experiment 1A was to assess the effects of intra-amygdaloid infusions of the D1-receptor antagonist, SCH 23390, on the acquisition and expression of conditioned fear. Fear conditioned to both acoustic and background contextual cues was assessed by measuring freezing, a well-established measure of conditioned fear in the rat 4, 38. A D1 receptor antagonist was chosen because of the existence of post-synaptic D1 receptors in the amygdala 1, 2, 20, 36.
Histology
Cannulae placements were considered accurately located if both guide cannula tips were microscopically verified to be no more than 0.7 mm dorsal to the surface of the amygdala in the region of the amygdaloid central nucleus and did not produce damage to any amygdaloid nuclei. All placements meeting these criteria were located between 2.12–3.0 mm posterior to bregma. Fig. 1 depicts all the accurate placements from Experiment 1A. A total of 17 of the 48 animals were not included in the
Discussion
The results of Experiment 1A demonstrate that intra-amygdaloid infusions of the selective D1 receptor antagonist, SCH 23390, given prior to training, prior to testing or prior to both attenuated the expression of Pavlovian fear conditioning to acoustic and contextual stimuli in rats during retention testing. The statistically significant effects observed on freezing during the CS presentations were more consistent and robust, however, than the effects observed on freezing during the PRE-CS
Acknowledgements
This research was supported by NIMH NRSA Fellowship MH11627-02 awarded to F.A.G. The authors would like to thank Dr. Stacey L. Young for her valuable assistance designing and conducting these experiments.
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