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Regulation of extinction-related plasticity by opioid receptors in the ventrolateral periaqueductal gray matter.

Parsons RG, Gafford GM, Helmstetter FJ - Front Behav Neurosci (2010)

Bottom Line: The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning.Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training.These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Wisconsin-Milwaukee Milwaukee, WI, USA.

ABSTRACT
Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-d-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

No MeSH data available.


Related in: MedlinePlus

Opioid but not NMDA receptor blockade in the vlPAG disrupts memory for fear extinction. (A,F) A schematic depicting the behavioral procedure. (C,H) Photomicrographs showing gray scale Nissl stained images of representative cannulae placements into vlPAG for both experiments. (B,G) Freezing levels during CS-US (CS-shock) presentations and after CS-US (Post CS-shock) for the fear acquisition session in both experiments. (D) Freezing behavior during extinction training and the first four trials of the test for extinction retention in rats infused with saline (N = 6, black) or naloxone (N = 6, red). (E) Extinction retention reflected as a function of the decrease between extinction training and testing in these same rats. (I) Freezing during extinction training and retention testing in rats infused with CPP (N = 9, blue) or saline (N = 9, black), and (J) the change scores in the same animals. Graphs show the average time spent freezing (±SEM) to the CS extinction training and the first 4 trials of testing. Data were also analyzed by (E,J) computing the average change in freezing levels from extinction to test (*p < .0.05).
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Figure 1: Opioid but not NMDA receptor blockade in the vlPAG disrupts memory for fear extinction. (A,F) A schematic depicting the behavioral procedure. (C,H) Photomicrographs showing gray scale Nissl stained images of representative cannulae placements into vlPAG for both experiments. (B,G) Freezing levels during CS-US (CS-shock) presentations and after CS-US (Post CS-shock) for the fear acquisition session in both experiments. (D) Freezing behavior during extinction training and the first four trials of the test for extinction retention in rats infused with saline (N = 6, black) or naloxone (N = 6, red). (E) Extinction retention reflected as a function of the decrease between extinction training and testing in these same rats. (I) Freezing during extinction training and retention testing in rats infused with CPP (N = 9, blue) or saline (N = 9, black), and (J) the change scores in the same animals. Graphs show the average time spent freezing (±SEM) to the CS extinction training and the first 4 trials of testing. Data were also analyzed by (E,J) computing the average change in freezing levels from extinction to test (*p < .0.05).

Mentions: Figure 1 shows the effect of the opioid receptor antagonist naloxone (NAL) on long-term extinction memory when infused into the vlPAG. No differences were seen before drug infusion during acquisition (Figure 1B), or during the first four trials of extinction training. Data from the extinction training session revealed no significant effect of Drug, but a significant effect of Block (F(1,10) = 19.84, p < 0.01), and no Drug × Block interaction. These results argue that both groups showed normal within-session extinction. During testing, rats infused with NAL in the vlPAG showed a disruption in the retention of extinction (Figure 1D, right side, Figure 1E). This is supported by a Student's t-tests indicating that whereas rats treated with NAL froze similarly to controls during the first four CS presentations of extinction training (t < 1.0), they showed significantly more freezing to the CS during the extinction memory test [t(10) = 2.843, p < 0.05]. Change scores were computed for rats in each group by subtracting freezing during extinction training from freezing during the extinction memory test, resulting in a value reflecting the difference in freezing behavior between sessions (Figure 1E). A t-test on these values show that compared to saline infused rats, NAL treated animals showed little decrease between sessions [t(10) = 3.287, p < 0.01] indicating of a disruption in long-term extinction memory.


Regulation of extinction-related plasticity by opioid receptors in the ventrolateral periaqueductal gray matter.

Parsons RG, Gafford GM, Helmstetter FJ - Front Behav Neurosci (2010)

Opioid but not NMDA receptor blockade in the vlPAG disrupts memory for fear extinction. (A,F) A schematic depicting the behavioral procedure. (C,H) Photomicrographs showing gray scale Nissl stained images of representative cannulae placements into vlPAG for both experiments. (B,G) Freezing levels during CS-US (CS-shock) presentations and after CS-US (Post CS-shock) for the fear acquisition session in both experiments. (D) Freezing behavior during extinction training and the first four trials of the test for extinction retention in rats infused with saline (N = 6, black) or naloxone (N = 6, red). (E) Extinction retention reflected as a function of the decrease between extinction training and testing in these same rats. (I) Freezing during extinction training and retention testing in rats infused with CPP (N = 9, blue) or saline (N = 9, black), and (J) the change scores in the same animals. Graphs show the average time spent freezing (±SEM) to the CS extinction training and the first 4 trials of testing. Data were also analyzed by (E,J) computing the average change in freezing levels from extinction to test (*p < .0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927240&req=5

Figure 1: Opioid but not NMDA receptor blockade in the vlPAG disrupts memory for fear extinction. (A,F) A schematic depicting the behavioral procedure. (C,H) Photomicrographs showing gray scale Nissl stained images of representative cannulae placements into vlPAG for both experiments. (B,G) Freezing levels during CS-US (CS-shock) presentations and after CS-US (Post CS-shock) for the fear acquisition session in both experiments. (D) Freezing behavior during extinction training and the first four trials of the test for extinction retention in rats infused with saline (N = 6, black) or naloxone (N = 6, red). (E) Extinction retention reflected as a function of the decrease between extinction training and testing in these same rats. (I) Freezing during extinction training and retention testing in rats infused with CPP (N = 9, blue) or saline (N = 9, black), and (J) the change scores in the same animals. Graphs show the average time spent freezing (±SEM) to the CS extinction training and the first 4 trials of testing. Data were also analyzed by (E,J) computing the average change in freezing levels from extinction to test (*p < .0.05).
Mentions: Figure 1 shows the effect of the opioid receptor antagonist naloxone (NAL) on long-term extinction memory when infused into the vlPAG. No differences were seen before drug infusion during acquisition (Figure 1B), or during the first four trials of extinction training. Data from the extinction training session revealed no significant effect of Drug, but a significant effect of Block (F(1,10) = 19.84, p < 0.01), and no Drug × Block interaction. These results argue that both groups showed normal within-session extinction. During testing, rats infused with NAL in the vlPAG showed a disruption in the retention of extinction (Figure 1D, right side, Figure 1E). This is supported by a Student's t-tests indicating that whereas rats treated with NAL froze similarly to controls during the first four CS presentations of extinction training (t < 1.0), they showed significantly more freezing to the CS during the extinction memory test [t(10) = 2.843, p < 0.05]. Change scores were computed for rats in each group by subtracting freezing during extinction training from freezing during the extinction memory test, resulting in a value reflecting the difference in freezing behavior between sessions (Figure 1E). A t-test on these values show that compared to saline infused rats, NAL treated animals showed little decrease between sessions [t(10) = 3.287, p < 0.01] indicating of a disruption in long-term extinction memory.

Bottom Line: The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning.Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training.These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Wisconsin-Milwaukee Milwaukee, WI, USA.

ABSTRACT
Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-d-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.

No MeSH data available.


Related in: MedlinePlus