Importance of GluA1 subunit-containing AMPA glutamate receptors for morphine state-dependency.
- Authors
- Aitta-aho, Teemu; Möykkynen, Tommi P; Panhelainen, Anne E; Vekovischeva, Olga Yu; Bäckström, Pia; Korpi, Esa R
- Year
- 2012
- Journal
- PloS one
- PMID
- 22675452
- DOI
- 10.1371/journal.pone.0038325
- PMCID
- PMC3365010
In state-dependency, information retrieval is most efficient when the animal is in the same state as it was during the information acquisition. State-dependency has been implicated in a variety of learning and memory processes, but its mechanisms remain to be resolved. Here, mice deficient in AMPA-type glutamate receptor GluA1 subunits were first conditioned to morphine (10 or 20 mg/kg s.c. during eight sessions over four days) using an unbiased procedure, followed by testing for conditioned place preference at morphine states that were the same as or different from the one the mice were conditioned to. In GluA1 wildtype littermate mice the same-state morphine dose produced the greatest expression of place preference, while in the knockout mice no place preference was then detected. Both wildtype and knockout mice expressed moderate morphine-induced place preference when not at the morphine state (saline treatment at the test); in this case, place preference was weaker than that in the same-state test in wildtype mice. No correlation between place preference scores and locomotor activity during testing was found. Additionally, as compared to the controls, the knockout mice showed unchanged sensitization to morphine, morphine drug discrimination and brain regional μ-opioid receptor signal transduction at the G-protein level. However, the knockout mice failed to show increased AMPA/NMDA receptor current ratios in the ventral tegmental area dopamine neurons of midbrain slices after a single injection of morphine (10 mg/kg, s.c., sliced prepared 24 h afterwards), in contrast to the wildtype mice. The results indicate impaired drug-induced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity.
Distance moved during each of the eight conditioning trials for the GluA1−/− (−/−) mice and their littermate wildtype GluA1+/+ mice (+/+).In CS+ trials, animals were injected with saline (saline control animals) (A), morphine 10 mg/kg (B) or morphine 20 mg/kg (C) immediately before transferring them into cages, in which their locomotor activity was recorded for 30 min. Saline was injected in CS− trials. Data represent means ± SEM, n = 24–49. *p<0.05, **p<0.01, ***p<0.001, between the genotypes, t-test. S = Saline; 10 and 20 denote doses of morphine in mg/kg.
Morphine-induced locomotor sensitization in GluA1−/− and GluA1+/+ mice.(A–B), Distance moved in the CS+ (morphine, or saline for saline control animals) trials is shown. The scores indicate 1) significant morphine effects and dose-response (# p<0.05, ## p<0.01, ### p<0.001, compared to the previous dose, Bonferroni test), 2) significant locomotor sensitization to morphine (& p<0.05, && p<0.01, &&& p<0.001, compared to the previous day, Bonferroni test), 3) significant habituation in GluA1—mice (saline control group) (HH p<0.01, compared to the first trial, Bonferroni test). Data represent means ± SEM, n = 24–49. * p<0.05, ** p<0.01, *** p<0.001, between the genotypes, t-test. The scores were derived from the raw data depicted in Fig. 1. (C–D), The difference in distance moved between trials 1 and 2 (CS+ minus CS−) on each conditioning day. The data indicate 1) that the activity of GluA1−/− is strongly reduced, in comparison to GluA1+/+ mice, during the second trial of the first conditioning day after both saline control and morphine injections (* p<0.05, ** p<0.01, *** p<0.001, between the genotypes, t-test), 2) that during the following days, GluA1−/− and GluA1+/+ mice were equally activated by 10 mg/kg morphine and 3) that morphine 20 mg/kg produced incremental locomotor activity in both mouse lines (# p<0.05, ## p<0.01, ### p<0.001, compared to the previous dose, Bonferroni test). Data represent means ± SEM, n = 24–49. The scores were derived from the raw data depicted in Fig. 1.
State-dependency is impaired in GluA1−/− mice in morphine-conditioned place preference.(A) Time spent in the morphine-associated zone during 15 min (900 s). Animals were tested either in Sal-state (priming injection of saline) or in Mor10-state (priming injection of 10 mg/kg morphine). (B) Distance moved during the 15 min preference test. Data represent means ± SEM, n = 8–33. * p<0.05, *** p<0.001, between the genotypes, t-test; $ p<0.05, $$ p<0.01, $$$ p<0.001, between testing states, t-test; # p<0.05, ## p<0.01, between conditioning doses, compared to saline control, Bonferroni test; & p<0.05, between conditioning doses, compared to morphine 10 mg/kg conditioning dose, Bonferroni test. Sal = Saline, Mor = Morphine.
Unaltered detection of opioid stimulus in GluA1−/− mice.Mice were trained to discriminate 5 mg/kg morphine from saline and then tested for various doses of morphine in a 20-min drug discrimination test session. (A) Dose-response curves for discriminative stimulus effects of morphine; data show morphine-appropriate lever responses expressed as percentage of total responses on both levers. (B) Dose-response curves for response rate-lowering effects of morphine during the dose-response tests. Data are shown as means ± SEM, n = 5–6.
Lack of morphine-induced increase in the ventral tegmental area dopamine neuron AMPA/NMDA ratios in GluA1−/− mice.A single morphine (10 mg/kg) or saline injection was administered one day before ex vivo electrophysiological recordings from slices. (A) Representative traces displaying AMPA and NMDA receptor-mediated current components. (B) Quantification of the electrophysiological data, which is represented as means ± SEM, n = 6–11. * p<0.05, between the genotypes; ## p<0.01, compared to the corresponding saline control, Bonferroni test.
Unchanged μ-opioid receptor function in GluA1−/− mice as shown by DAMGO-stimulated GTPγ[35S] autoradiography.(A) Representative autoradiographs from a control GluA1+/+ mouse showing GTPγ[35S] binding in various brain regions. The figure shows basal binding, non-specific (Non-spec.) binding in the presence of 10 µM cold GTPγS and specific 10 µM DAMGO-stimulated binding with and without the opioid receptor antagonist naltrexone (10 µM). (B) Dose-response curves of DAMGO-stimulated GTPγ[35S] binding in the caudate-putamen, nucleus accumbens and ventral tegmental area. The data are means ± SEM, n = 5–7. See Table 1 for EC50 and maximal stimulation values for DAMGO. Amyg, amygdala; CPu, caudate-putamen; Hypot, hypothalamus; IC, inferior colliculus; LC, locus coeruleus; NAc, nucleus accumbens; PAG, periaqueductal gray; SNR, substantia nigra reticulata; Thal, thalamus; VTA, ventral tegmental area.
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| AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence. | Hu X et al. | — | 2018 | → |
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| Involvement of AMPA/Kainate Glutamate Receptor in the Extinction and Reinstatement of Morphine-Induced Conditioned Place Preference: A Behavioral and Molecular Study. | Siahposht-Khachaki A et al. | — | 2017 | → |
| Evidence of CNIH3 involvement in opioid dependence. | Nelson EC et al. | — | 2016 | → |
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| Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice. | Maksimovic M et al. | — | 2014 | → |
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