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Results: 7

1.
Figure 3

Figure 3. Kappa opioid receptor activation in vitro blocks LTPGABA. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A), LTPGABA in a dopamine cell from a naïve rat perfused with DMSO. (B), SNAP does not induce LTPGABA in a dopamine neuron perfused with the kappa agonist, U69593 (1 μM) 10 min prior to SNAP application. (C), Averaged experiments; U69593 (n = 6), DMSO (n = 5). Insets, representative IPSCs before (Control) and 30 min after SNAP (SNAP). Scale bars: 20 ms, 100 pA.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
2.
Figure 4

Figure 4. Kappa opioid receptor activation is not required for long-term potentiation at excitatory synapses on DA neurons in the VTA. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A) AMPAR- (red) and NMDAR-mediated (black) EPSCs recorded from a dopamine neuron from a naïve animal (naïve). (B) AMPAR- and NMDAR-mediated EPSCs 24 hours after stress. (C) AMPA/NMDA ratios recorded in dopamine neurons from naïve animals and animals 24 hours after stress. Asterisk, p < 0.05, t-test. (D) AMPAR and NMDAR EPSCs from an animal injected with saline or (E) nor-BNI prior to forced swim stress. (F) Summary of AMPA/NMDA ratios recorded in dopamine neurons from saline and nor-BNI pretreated animals 24 hours after swim stress. Scale bars: 50 pA, 20 ms.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
3.
Figure 7

Figure 7. Proposed model of signaling molecules involved in LTPGABA. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A), an in vivo exposure to stress blocks LTPGABA through activation of kappa opioid receptors (KORs) with subsequent modulation of the NO signaling pathway at a point downstream of NO production. Presynaptic terminals expressing LTPGABA may originate from local interneurons or extrinsic GABAergic afferents. (B), in vivo exposure to morphine alters LTPGABA through activation of μ-opioid receptors (μOR), inhibiting the cGMP pathway at the level of sGC (soluble guanylate cyclase)(Niehaus et al., 2010). (C), Forskolin potentiates GABAergic synapses by activating adenylyl cyclase (AC), which in turn activates the cAMP/PKA pathway. This pathway is unaffected by in vivo manipulations with morphine or stress (Nugent et al., 2009).

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
4.
Figure 2

Figure 2. Blocking KORs rescues the stress-induced block of LTPGABA. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A), Injection protocol for naloxone treated animals. (B) LTPGABA in a dopamine cell from an animal administered saline 15 minutes prior to swim stress; slices were prepared 24 hrs after stress. Insets, representative IPSCs before (Control) and 30 minutes after SNAP application (SNAP). (C) Rescue of SNAP-induced LTPGABA in a slice from an animal treated with naloxone prior to stress. (D) Averaged experiments (saline-treated rats, n = 17; naloxone-treated rats, n = 9). (E) Injection protocol for nor-BNI treated animals; nor-BNI is effective for over a week following injection (Endoh et al., 1992). (F) Absence of LTPGABA in a dopamine cell from an animal administered saline 24 hrs prior to stress and (G) from an animal pretreated with nor-BNI 24 hours prior to stress. (H) Averaged experiments (saline-treated rats, n = 8; nor-BNI-treated rats, n = 8). Scale bars: 20 ms, 100 pA.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
5.
Figure 1

Figure 1. Stress blocks LTPGABA; forskolin can still potentiate GABAergic synapses. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A), Single experiment illustrating SNAP-induced LTPGABA in a dopamine cell from a naïve animal, or (B) from an animal exposed to five min cold water forced swim. SNAP was bath-applied as indicated by the bar. (C), LTPGABA in slices from naïve or stressed animals (IPSC amplitudes, naïve rats: 128.2 ± 7.9% of control values, n = 3, 24 hours after stress, 95.4 ± 2.0%, n = 3; p < 0.05). (D), Single experiment illustrating forskolin-induced LTPGABA in slices from naïve animals or (E), in slices from animals exposed to forced swim stress. Forskolin (10 μM) was bath-applied as indicated by the bar. (F), Averaged data showing that forskolin potentiates IPSCs in dopamine neurons from naive and stressed animals. Insets: IPSCs before (Control) and 30 minutes after drug application (SNAP, 400 μM). Scale bars: 20 ms, 100 pA. Insets for this and all figures are averages of ten IPCSs.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
6.
Figure 6

Figure 6. Blocking kappa opioid receptors in the VTA blocks stress-induced reinstatement of cocaine seeking. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A) Training protocol: 19 d of intravenous cocaine self-administration (2 h per day) were followed by daily extinction sessions until lever pressing decreased to <15% of responding on the last day of cocaine self-administration. Rats required ≤ 8 days to achieve this criterion. Twenty-four hours following the attainment of extinction criterion, animals were given a microinfusion of nor-BNI or vehicle into the VTA. 24 hours later, they were exposed to a cold swim stressor and tested for reinstatement responding 24 hours later. (B) Total active and inactive lever presses during the reinstatement phase are shown from animals administered vehicle (n = 7) or 2.5 μg (n = 7) nor-BNI into the ventral tegmental area prior to stress. Unlike the vehicle controls, animals that received nor-BNI infusions into the VTA did not show significant reinstatement of cocaine responding as compared to their extinction responding.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.
7.
Figure 5

Figure 5. Morphine and stress block LTPGABA through distinct mechanisms. From: Kappa opioid receptors regulate stress-induced cocaine-seeking and synaptic plasticity.

(A) Diagram of injection protocol for B-C. (B) SNAP fails to induce LTPGABA in a dopamine neuron from an animal administered saline prior to morphine. Slices were prepared 24 h after the animal was exposed to morphine. Insets, representative IPSCs before (Control) and 30 min after SNAP application (SNAP). (C) SNAP also fails to induce LTPGABA in a slice from an animal treated with nor-BNI prior to morphine. (D) Injection protocol for E-F. (E) Rescue of SNAP-induced LTPGABA in a dopamine cell from an animal treated with cyprodime prior to morphine. (F) Averaged experiments showing that LTPGABA is blocked in dopamine cells from animals treated with saline (black symbols, n = 15) or with nor-BNI (gray symbols, n=9) before morphine; LTPGABA is rescued in dopamine cells from animals pretreated with cyprodime (open symbols, n = 6). No significant differences were found between groups of saline pretreated animals, so the data were pooled. (G) Injection protocol prior to stress (H-I). (H) Lack of LTPGABA in a slice from an animal treated with cyprodime prior to stress. (I) SNAP does not induce LTPGABA in cyprodime pretreated stressed animals (n=8). Scale bars: 20 ms, 100 pA.

Nicholas M. Graziane, et al. Neuron. 2013 March 6;77(5):942-954.

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