Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of -opioid receptor (MOR) trafficking in one of these adaptations, specifically, changes in GABA transmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3Ј,5Ј-(hydrogenphosphorothioate) triethylammonium] (50 ng/0.5 l), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 l), directly tying enhanced cAMP-driven GABA release to naloxone-precipitated morphine withdrawal in the VTA.

Gamma-aminobutyric acid (GABA) transmission in the ventral tegmental area (VTA) is critical for fine tuning the activity of dopamine neurons in response to opioids. However, the precise mechanism by which GABA input shapes opioid reward is poorly understood. One day after chronic morphine treatment, we observed a reduction of conditioned place preference (CPP) for low doses of the opioid [D-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO) and a switch in the functional effects of mu-opioid receptor modulation of GABA postsynaptic currents in the mouse VTA. Specifically, while in naïve mice DAMGO inhibits GABA post-synaptic currents, after chronic morphine treatment, GABAergic currents are instead potentiated by DAMGO. Importantly, pre-treatment with the 3’–5’-cyclic-adenosine monophosphate (cAMP) signaling inhibitor (R)-Adenosine, cyclic 3',5'-(hydrogenphosphorothioate) triethylammonium (rp-cAMPS), both restored DAMGO reward and reversed the DAMGO mediated potentiation, thereby re-establishing the inhibitory effects of opioids on GABA currents. Thus, a paradoxical bidirectionality in mu-receptor mediated control of GABA transmission following chronic morphine treatment is a critical mechanism that determines the expression of opioid reward in the VTA.

Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic treatments are limited by side effects, including reduced efficacy in alcoholics, addiction, and sedation. We examined whether the neuropeptide S receptor (NPSR) was effective at controlling ethanol consumption and the anxiety and depression produced by forced abstinence from ethanol. We found that the anxiolytic and anti-depressant effects of NPS are enhanced in acute ethanol abstinent mice. In addition, we found that NPS reduced ethanol consumption and is not in and of itself rewarding. We also provide evidence that ethanol consumption increases the ability of NPS to modulate neuronal activity in the basolateral amygdala. Finally, we found that local injection of NPS in the basolateral amygdala promotes anxiolysis after chronic ethanol consumption, thereby providing insight into the molecular mechanism underlying the changes in behavioral response to NPS. In light of the improved anxiolytic efficacy and benign side effects of NPS in ethanol-withdrawn animals, the NPSR may prove a suitable target for reducing relapse in alcoholism.

Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/ NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.