Search

Extinction and reinstatement of morphine-induced conditioned place preference were studied in glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor GluA1 subunit-deficient mice (global GluA1-KO mice). In line with previous findings, both acquisition and expression of conditioned place preference to morphine (20 mg/kg, subcutaneously) were fully functional in GluA1 KO mice compared with wild-type littermate controls (GluA1-WT), thus enabling the study of extinction. With a 10-session extinction paradigm, the GluA1 KO mice showed complete extinction similar to that of the GluA1-WT mice. Morphine-induced reinstatement (10 mg/kg, subcutaneously) was detected in both mouse lines. GluA1 KO mice moved more during all the phases of the experiment, including the place conditioning trials, extinction sessions, and place preference tests. The results suggest that the GluA1 subunit may be dispensable or prone to compensation at the neural circuitries delineating extinction and reinstatement. The GluA1 KO mice show altered long-term between-session habituation, which extends longer than previously anticipated.

Extrasynaptic δ subunit-containing γ-aminobutyric acid type A receptors (δ-GABA A Rs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ-GABA A Rs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ-GABA A R knockout mice (δ-KO). It is not known whether δ-GABA A Rs are important for the effects of other drugs, such as opioids (that also inhibit GABA neurons) and stimulants (that primarily elevate monoamine levels). Here, we used δ-KO mice and conditioned place preference (CPP) test to study the rewarding effects of morphine (20 mg/kg), methamphetamine (1 mg/kg) and mephedrone (5 mg/kg). Morphine-induced nociception was also assessed using tail-flick and hot-plate tests. We found that the δ-KO mice failed to express morphine-induced CPP, but that they were more sensitive to morphine-induced analgesia in the tail-flick test. In contrast, stimulant-induced CPP in the δ-KO mice was similar to that in the wild-type controls. Thus, the conditioned rewarding effect by opioids, but not that of stimulants, was impaired in the absence of δ-GABA A Rs. Further studies are warranted to assess the potential of δ-GABA A R antagonists as possible targets for reducing morphine reward and potentiating morphine analgesia., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Previously we found that morphine's effects on locomotor activity and brain dopamine metabolism were enhanced in mice after cessation of 7-week oral nicotine treatment. In the present experiments we show that such chronic nicotine exposure cross-sensitizes NMRI mice to the reinforcing effect of morphine in the conditioned place preference paradigm. The nicotine-treated mice developed conditioned place preference after being conditioned twice with morphine 5 mg/kg s.c. whereas in control mice a higher dose (10 mg/kg) of morphine was required. Since the reinforcing effect of morphine is mediated via micro-opioid receptors we used [3H]DAMGO autoradiography to study whether the number (B(max)) or affinity (K(D)) of mu-opioid receptors in the mouse brain are affected following chronic nicotine exposure. However, no changes were found in the number or affinity of micro-opioid receptors in any of the brain areas studied. Neither did we find alterations in the functional activity of mu-opioid receptors studied by [35S]GTPgammaS-binding. In conclusion, chronic oral nicotine treatment augments the reinforcing effects of morphine in mice, and this cross-sensitization does not seem to be mediated by micro-opioid receptors.

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 m-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 druginduced state-dependency in GluA1 knockout mice, correlating with impaired opioid-induced glutamate receptor neuroplasticity. [ABSTRACT FROM AUTHOR]

Initial effects of drugs of abuse seem to converge on the mesolimbic dopamine pathway originating from the ventral tegmental area (VTA). Even after a single dose, many drugs of abuse are able to modulate the glutamatergic transmission activating the VTA dopamine neurons, which may represent a critical early stage in the development of addiction. Ligands acting on the benzodiazepine site of the inhibitory γ-aminobutyric acid type A (GABAA) receptors are known to be rewarding in animal models and have abuse liability in humans, but notably little evidence exists on the involvement of the mesolimbic dopamine system in their effects. Here we report that single in vivo doses of benzodiazepine-site agonists, similar to morphine and ethanol, induce a modulation in the glutamatergic transmission of VTA dopamine neurons. This is seen 24 h later as an increase in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory currents using whole-cell patch-clamp configuration in mouse VTA slices. The effect was due to increased frequency of spontaneous miniature AMPA receptor-mediated currents. It lasted at least 3 days after the injection of diazepam, and was prevented by coadministration of the benzodiazepine-site antagonist flumazenil or the NMDA receptor antagonist dizocilpine. A single injection of the GABAA receptor α1 subunit-preferring benzodiazepine-site ligand zolpidem also produced an increase in the AMPA/NMDA ratio in VTA dopamine neurons. These findings suggest a role for the mesolimbic dopamine system in the initial actions of and on neuronal adaptation to benzodiazepines.Neuropsychopharmacology (2009) 34, 290–298; doi:10.1038/npp.2008.89; published online 18 June 2008 [ABSTRACT FROM AUTHOR]

It has been suggested that opioid peptides play a role in the reinforcing effects of alcohol. The present study was designed to examine the function of the μ-opioid receptor system in rat lines selectively bred for alcohol preference (AA [Alko, Alcohol] rat line) and alcohol avoidance (ANA [Alko, Non-Alcohol] rat line). The functional coupling of μ-opioid receptors to G proteins was determined autoradiographically using Tyr-d-Ala-Gly-N(Me)Phe-Gly-ol-enkephalin-stimulated [35S]GTPγS binding in brain cryostat sections. The binding was significantly increased in the striatal patches and substantia nigra reticulata of the AA rats in comparison with that of the ANA rats. Within the AA rat line, there was a significant positive correlation between 3 mg/kg morphine-induced locomotor activity and activation of G-proteins in the substantia nigra compacta and nucleus accumbens core. These results of the selective breeding experiment suggest that brain region-specific differences in μ-opioid receptor function may correlate with innate differences in alcohol preference. [Copyright &y& Elsevier]