Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction - PubMed (original) (raw)

Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction

Marsida Kallupi et al. Biol Psychiatry. 2013.

Abstract

Background: Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA).

Methods: We identified KOR-related physiological changes in the CeA following escalation of cocaine self-administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1-hour (short access [ShA]) or 6-hour (long access [LgA]) sessions induced plasticity at CeA gamma-aminobutyric acid (GABA)ergic synapses or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (norbinaltorphimine [norBNI]). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors.

Results: Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared with cocaine-naïve rats. Acute cocaine (1 µmol/L) application significantly decreased GABA release in all groups (naïve, ShA, and LgA rats). Application of U50488 (1 µmol/L) significantly decreased GABAergic transmission in the CeA from naïve rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naïve rats but decreased it in LgA rats. Norbinaltorphimine did not alter the acute cocaine-induced inhibition of GABAergic responses. Finally, CeA microinfusion of norBNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm.

Conclusions: Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction.

Keywords: Addiction; GABA; anxiety; central amygdala; cocaine; kappa-opioid receptor.

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Conflict of interest statement

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1

Cocaine self-administration in LgA (6h/d) and ShA (1h/d) rats. LgA rats displayed a significant escalation of intake over repeated cocaine self-administration sessions (***p < 0.001). Data are expressed as mean ± SEM of the number of cocaine infusions/session on the left axis and mg/kg cocaine intake on the right axis.

Figure 2

Basal evoked GABAergic transmission is enhanced in ShA and LgA rats. A: Input-output curves of mean GABAA-IPSP amplitudes. Mean baseline GABAergic transmission is significantly (*p < 0.05) increased in neurons from ShA (n = 24) and LgA (n = 29) animals compared with naive rats (n = 28). B: Histograms plotting the baseline PPF ratio of IPSPs in CeA neurons from naïve, ShA, and LgA rats. In the ShA (n = 22) and LgA (n = 20) groups, baseline PPF ratios were significantly (*p < 0.05) lower versus naïve (n = 23).

Figure 3

Acute application of cocaine decreases baseline evoked and spontaneous GABAergic transmission. A: Top Panel: Representative evoked IPSPs recorded before, during cocaine (1 μM) application, and washout in naïve, ShA, and LgA rats. Bottom Panel: Pooled data of the experiments from A: time course depicting changes in evoked IPSP amplitude upon cocaine application and washout in the three groups. Insert: Histograms representing maximal percent decrease in mean (± SEM) evoked IPSP amplitudes averaged over the middle three stimulus strength intensities tested with cocaine application. *Indicates p < 0.05. B: Top Panel: Representative recordings of evoked PPF of IPSPs in CeA neurons from naïve, ShA, and LgA rats. Bottom Panel: Cocaine significantly (*p < 0.05) increases the PPF ratio of IPSPs in the CeA from naïve and LgA rats. C: Top Panel: Representative mIPSC recordings in CeA neurons from a cocaine-naïve rat during control, application of 1 uM cocaine, and washout. Cocaine decreased mIPSC frequency and (bottom panel) shifted the cumulative frequency histogram to the right, indicating a longer inter-event interval (lower frequencies) during cocaine application. D: Mean ± SEM frequency, amplitude, rise, and decay time of mIPSCs for CeA neurons. Cocaine significantly (*p < 0.05) decreases the mean mIPSC frequency but does not change mean mIPSC amplitude, rise, or decay time.

Figure 4

KOR antagonism does not block the decrease of GABAergic transmission induced by acute cocaine application. A: Top Panel: Representative evoked IPSPs recorded in control, nor-BNI (200 nM), and cocaine (1 μM) plus nor-BNI in the CeA of a cocaine-naïve rat. Bottom Panel: Histograms representing maximal percent decrease in mean (± SEM) evoked IPSP amplitudes averaged over the middle three stimulus strength intensities tested during the experimental protocol. Nor-BNI increased evoked IPSP amplitudes while cocaine reduced them (n = 7). *Indicates p < 0.05 between nor-BNI and control; # Indicates p < 0.05 between cocaine plus nor-BNI and nor-BNI alone. B: Mean ± SEM frequency, amplitude, rise, and decay time of mIPSCs for CeA neurons. Nor-BNI significantly (*p < 0.05) increased the mean mIPSC frequency while cocaine in the presence of nor-BNI significantly (#p < 0.05) decreased it. No changes in mean mIPSC amplitude, rise, or decay time were observed. C: Top Panel: Representative mIPSC recordings in CeA neurons from a cocaine-naïve rat during control, application of 200 nM nor-BNI, and 1 uM cocaine plus nor-BNI. D: Nor-BNI shifted the cumulative frequency histogram to the left, indicating a shorter inter-event interval (higher frequencies) during nor-BNI application. Cocaine decreased mIPSC frequency and shifted the cumulative frequency histogram to the right, indicating a longer inter-event interval (lower frequencies) during cocaine application.

Figure 5

Extended access to cocaine self-administration inverts the effects of a KOR agonist (U50488) on evoked and spontaneous CeA GABAergic transmission. A: Top Panel: Representative evoked IPSPs recorded before and during U50488 (1 uM) superfusion and washout in naïve, ShA, and LgA rats. Bottom Panel: Pooled data of the experiments from A: time course depicting changes in evoked IPSP amplitude upon U50488 application and washout in the three groups. In naive and ShA rats, U50488 significantly decreased evoked IPSPs. In contrast, U50488 increases evoked IPSPs in neurons from LgA rats. Insert: Histograms representing percent decrease in mean (± SEM) evoked IPSP amplitudes averaged over three stimulus strength intensities tested with U50488 application. *Indicates p < 0.05. B: Top Panel: Representative evoked PPF of IPSPs from CeA neurons of naïve, ShA, and LgA rats. Bottom Panel: U50488 significantly (*p < 0.05) increases the PPF ratio in CeA from naïve and ShA, but not LgA rats. C: Representative mIPSC recordings in CeA neurons from naïve and LgA rats. U50488 decreases the mIPSC frequency in the CeA from naïve rats but increased frequencies in LgA rats. D: Upon U50488 application the cumulative frequency histogram for the same neuron of C was shifted to the right, indicating lower frequencies in CeA neurons of naïve rats. U50488 shifted to the left the cumulative frequency histogram, indicating higher frequencies in CeA neurons of LgA rats. E: Mean ± SEM frequency, amplitude, rise, and decay time of mIPSCs for 9 and 7 CeA neurons from naïve and LgA rats, respectively. In naive rats, U50488 significantly (*p < 0.05) decreased the mean mIPSC frequency. In LgA rats, U50488 significantly (*p < 0.05) increased the mean mIPSC frequency. U50488 did not alter the mean mIPSC amplitude, rise, or decay time in the two groups. Also see Supplement: Figure S2.

Figure 6

Long access cocaine administration inverts the effects of a KOR antagonist (nor-BNI) on evoked and spontaneous GABAergic transmission in the CeA. A: Top Panel: Representative evoked IPSPs recorded before and during superfusion of nor-BNI (200 nM) and washout in naïve and LgA rats. Bottom Panel: Pooled data of the experiments from A: time course depicting changes in evoked IPSP amplitude upon nor-BNI application and washout in the two groups. In naive rats, nor-BNI significantly (p < 0.05) increases evoked IPSP amplitudes. In contrast, nor-BNI significantly (p < 0.05) decreases evoked IPSP amplitudes in neurons from LgA rats. Insert: Histograms representing percent decrease in mean (± SEM) evoked IPSP amplitudes during nor-BNI application. *Indicates p < 0.05. B: Top Panel: Representative recordings of evoked 50 msec paired-pulse IPSPs in representative CeA neurons from naïve and LgA rats. Bottom Panel: nor-BNI significantly (*p < 0.05) decreases the 50 msec PPF ratio of IPSPs in CeA neurons from naïve rats, but increases ratios in 8 CeA neurons from LgA rats. C: Representative mIPSC recordings in CeA neurons from naïve and LgA rats. Superfusion of nor-BNI increases the mIPSC frequency in the CeA of naïve rats and decreases frequency in LgA rats. D: Upon nor-BNI application, the cumulative frequency histogram for the same neuron of C was shifted to the left, indicating higher frequencies in neurons of naïve rats (Left Panel). Nor-BNI shifted the cumulative frequency histogram to the right, indicating lower frequencies in neurons of LgA rats (Right Panel). E: Mean ± SEM frequency, amplitude, rise, and decay time of mIPSCs for 9 and 7 CeA neurons from naïve and LgA rats, respectively. In naive rats, nor-BNI significantly (*p < 0.05) increased mean mIPSC frequency, while in LgA rats, nor-BNI significantly (*p < 0.05) decreased mean mIPSC frequency. Nor-BNI did not alter the mean mIPSC amplitude, rise, or decay time in the two groups. Also see Supplement: Figure S2.

Figure 7

Blockade of cocaine sensitization and withdrawal-related behaviors by prior CeA kappa-opioid receptor (KOR) antagonism. A: Repeated cocaine produced progressively greater increases in locomotor activity in comparison to chronic saline (Bonferroni tests, *p < 0.05, ** p <0.001), while intra-CeA nor-BNI markedly abolished these effects of cocaine. Even after the fifth challenge, the single nor-BNI pretreatment still prevented increases in cocaine-induced locomotion (Neuman-Keuls tests, **p < 0.01). B: Forty-eight hours after the last saline or cocaine injection, animals were subjected to the defensive burying test to evaluate the anxiogenic-like effects of a shock-paired stimulus following the treatment regimens. Cocaine/vehicle-treated animals displayed more anxiety-like behavior (indicated by a significantly increased height of burial mound) compared to control animals (# p < 0.05). Intra-CeA nor-BNI administered prior to cocaine exposure attenuated the anxiogenic effects of cocaine withdrawal compared to intra-CeA vehicle (*p < 0.05, Neuman-Keuls test). Cocaine/nor-BNI-treated animals also displayed a significantly attenuated total time burying (i.e., an anxiolytic-like effect) compared to the cocaine/saline-treated group (*p < 0.05, Neuman-Keuls test).

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Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction - PubMed (original) (raw)