The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (− / − ) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP ( − / − ) rats selfadminister less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP ( − / − ). When NOP ( − / − ) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP ( − / − ) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol selfadministration in Wt rats but not in NOP ( − / − ) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.

Marchigian-Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol along with anxious phenotype. In these animals, two single nucleotide polymorphisms in position −1836 and −2097 from the first start codon of the CRF1-R transcript have been found. Here we examined whether these point mutations account for the heightened anxiety-like behavior and stress responsiveness of msP rats. We re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and point mutations (AA), respectively. CRF1-R gene expression analysis revealed significant dysregulation of the system in the extended amygdala of AA rats. At the behavioral level, using the elevated plus maze, we found that both AA and GG lines had higher basal anxiety compared to Wistar rats. In the defensive burying test, AA rats showed decreased burying behavior compared to the GG and the unselected Wistar lines. Freezing/immobility did not differ among AA and GG but was higher than that of Wistars. The selective CRF1-R antagonist antalarmin (0, 10, 20 mg/kg) reduced burying behavior in Wistar animals. However, antalarmin (10 mg/kg) tended to increase rather than reducing this behavior when tested in the msP lines, an effect that appeared more marked in the GG as compared to the AA line. The present data suggest that rats with msP genetic background are more anxious and show different sensitivity to stress and CRF1-R blockade than Wistars. The point mutations occurring in the CRF1-R gene do not seem to influence basal anxiety while they appear to affect active responses to stress.

The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.

These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.

An isoform of peroxisome proliferator-activated receptors (PPARs), PPAR␥, is the receptor for the thiazolidinedione class of antidiabetic medications including pioglitazone. Neuroanatomical data indicate PPAR␥ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPAR␥ manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPAR␥ deletion (PPAR␥ (Ϫ/Ϫ)) and their littermate wild-type (PPAR␥ (ϩ/ϩ)) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPAR␥ during nicotine withdrawal. Brain site-specific microinjections of the PPAR␥ agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPAR␥ by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPAR␥ (ϩ/ϩ)) mice. This effect was blocked by the PPAR␥ antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPAR␥ increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPAR␥ in nicotine withdrawal and indicates that activation of PPAR␥ may offer an interesting strategy for smoking cessation.

BACKGROUND AND PURPOSEOpioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice. EXPERIMENTAL APPROACHWe monitored analgesia on alternate days using the tail immersion test. , bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance. KEY RESULTS Daily administration of morphine (30 mg·kg− CONCLUSIONS AND IMPLICATIONSOverall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.

Abnormal resting‐state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph‐theoretical analyses, enabling improved resolution and fine‐grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large‐scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region‐specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular–supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment.

A few studies have reported aberrant functional connectivity in alcoholic patients, but the specific neural circuits involved remain unknown. Moreover, it is unclear whether these alterations can be reversed upon treatment. Here, we used functional MRI to study resting state connectivity in rats following chronic intermittent exposure to ethanol. Further, we evaluated the effects of SB-277011-a, a selective dopamine D3 receptor antagonist, known to decrease ethanol consumption. Alcohol-dependent and control rats (N = 13/14 per group), 3 weeks into abstinence, were administered SB-277011-a or vehicle before fMRI sessions. Resting state connectivity networks were extracted by independent component analysis. A dual-regression analysis was performed using independent component maps as spatial regressors, and the effects of alcohol history and treatment on connectivity were assessed. A history of alcohol dependence caused widespread reduction of the internal coherence of components. Weaker correlation was also found between the insula cortex (IC) and cingulate cortices, key constituents of the salience network. Similarly, reduced connectivity was observed between a component comprising the anterior insular cortex, together with the caudate putamen (CPu-AntIns), and the posterior part of the IC. On the other hand, postdependent rats showed strengthened connectivity between salience and reward networks. In particular, higher connectivity was observed between insula and nucleus accumbens, between the ventral tegmental area and the cingulate cortex and between the VTA and CPu-AntIns. Interestingly, aberrant connectivity in postdependent rats was partially restored by acute administration of SB-277011-a, which, conversely, had no significant effects in naïve rats.