Conditioned Place Preference Model Research Articles

Kappa antagonist to prevent drug relapse: Does stage in addiction cycle matter?

Introduction: An upregulation of the kappa opioid receptor (KOR) system during drug preoccupation stage in addiction cycle will cause dysphoria among addicts which can lead to relapse. Therefore, KOR antagonism treatment might hold the key to prevent relapse. In this study, we aim to identify the exact addiction’s stage in which KOR antagonist can be given. Methods: Using a conditioned place preference (CPP) model, adult male Swiss albino mice were divided into two major groups. The first group received treatment at the initial stage of morphine withdrawal (7.5 mg/kg, i.p) while the second group received treatment after complete abstinence was achieved. Each major groups were further divided into two treatment groups (n=8-12), either received a functional KOR antagonist (0.3 mg/kg buprenorphine/ 1 mg/kg naltrexone combination, i.p) or a selective KOR antagonist (10 mg/kg nor-BNI, i.p) prior to morphine priming (2.5 mg/kg, i.p). All data were analyzed using paired sample t-test. Results: The results showed that relapse was successfully attenuated in the groups that received KOR antagonists only after complete abstinence was successfully achieved (not significantly different from their baseline). However, the mice developed unusual sign of behavior sensitization (intermittent freezing, licking) when buprenorphine/naltrexone combination was given at initial stage of withdrawal. Conclusions: Our initial findings suggest that KOR antagonism might be beneficial only after the addicts achieved complete abstinence to prevent future druginduced relapse. Brain study should be conducted to explain the unusual behavior seen when the drug intervention is given at an earlier stage of withdrawal.

Morphine modulates hippocampal neurogenesis and contextual memory extinction via miR-34c/Notch1 pathway in male ICR mice

AbstractBackgroundThe opioid Morphine is known to affect neurogenesis in the hippocampus. Evidence has shown that several microRNAs modulate morphine-induced neurogenesis, and hence morphine-induced contextual memory. This complex network has yet to be elucidated. In this study, we screened for morphine addiction related microRNA and determined its effects on hippocampal neurogenesis and morphine-induced contextual memory using the conditioned place preference (CPP) model.MethodsThe previously established CPP model was utilized in this study. For differential expression of miRNA in the hippocampus, the GeneChip miRNA array was used. Lentivirus technology was used to overexpress or downregulate the miRNA, and changes in expression level was verified with qRT-PCR. Protein expression levels were measured with western blot. Immunofluorescence was used to observe the protein expression during the differentiation of NSCs.ResultsThe results showed that morphine administration upregulated microRNA-34c (miR-34c) and Notch1. Downregulating miR-34c in vivo decreased Notch1 expression and partially rescued the morphine-induced inhibition of the differentiation of neural stem cells (NSCs). This did not affect the morphine-induced proliferation of cells. Furthermore, downregulating miR-34c in vivo prolonged the extinction of morphine-induced contextual memory without affecting acquired CPP response.ConclusionThe miR-34c regulates the hippocampal neurogenesis in addicted mice by up-regulating Notch1 expression, by inhibiting differentiation of neural precursor cells. The miR-34c/Notch1 pathway may be a new potential target for the prevention and treatment of opioid psychotic dependence.

Uncoupling nNOS-PSD-95 in mPFC inhibits morphine priming-induced reinstatement after extinction training

Extremely high relapse rate is the dramatic challenge of drug abuse at present. Environmental cues play an important role in relapse of drug abuse. However, the specific mechanism underlying relapse remains unclear. Using morphine conditioned place preference (CPP) model, we show that association of neuronal nitric oxide synthase (nNOS) with postsynaptic density-95 (PSD-95) plays a significant role in morphine priming-induced reinstatement. The nNOS-PSD-95 coupling and c-Fos expression in the medial prefrontal cortex (mPFC) was significantly increased after extinction of morphine CPP. Dissociation of nNOS-PSD-95 in the mPFC by ZL006 inhibited the reinstatement of morphine CPP induced by a priming dose of morphine. Significantly reduced phosphorylation of cAMP-response element binding protein (CREB) in the mPFC was observed in the mice exposed to morphine after the extinction training. Uncoupling nNOS-PSD-95 reversed the morphine-induced CREB dysfunction. Moreover, effects of ZL006 on the reinstatement of morphine CPP and CREB activation depended on nNOS-PSD-95 target. Together, our findings suggest that nNOS-PSD-95 in the mPFC contributes to reinstatement of morphine CPP, possibly through CREB dysfunction, offering a potential target to prevent relapse of drug abuse.

TAAR1 and Psychostimulant Addiction.

Trace amine-associated receptor 1 is one of the best-characterized receptors of trace amines. Growing evidence shows that TAAR1 negatively regulates the monoaminergic activity, including dopamine transmission in the mesocorticolimbic system. Neurochemical assays demonstrated that selective TAAR1 full and partial agonists were effective to prevent psychostimulants-induced dopamine transmission in vitro and in vivo. In the last decade, many preclinical models of psychostimulant addiction such as drug-induced behavioral sensitization, drug-induced conditioned place preference, drug self-administration, drug discrimination, and relapse models were used to assess the effects of TAAR1 agonists on psychostimulants' behavioral effects. In general, activation of TAAR1 attenuated while knockout of TAAR1 potentiated psychostimulant abuse-related behaviors. Here, we review the advances in TAAR1 and its agonists in modulating psychostimulant addiction. We discuss the similarities and differences between the neurochemical and behavioral effects of TAAR1 full and partial agonists. We also discuss several concerns including the abuse liability, sleep reduction, and species-dependent effects that might affect the successful translation of TAAR1 agonists from preclinical studies to clinical application. In conclusion, although further investigations are in need to address certain concerns and the underlying neural mechanisms, TAAR1 agonists appear to be a promising pharmacotherapy to treat psychostimulant addiction and prevent relapse.

Inhibition of naltrexone on relapse in methamphetamine self-administration and conditioned place preference in rats

Methamphetamine (METH) addiction has been widely spread and caused severe problems both in society and public health in recent years, but there is a shortage of medication available. The naltrexone (NTX) as a non-selective opioid receptor antagonist has been widely applied to treat alcohol addiction and the relapse to opioid addiction after detoxification. In the present study, we investigated the potent pharmacotherapeutic effect of NTX in attenuating relapse to drug-seeking behavior in the METH self-administration and conditioned place preference (CPP) in rats. The results showed that acute intragastrical administration of NTX (40 mg/kg) significantly reduced cue-induced drug-seeking behavior after extinction training. The similar inhibition effect was observed in the CPP model, that the intragastrical administration of NTX (30 mg/kg) significantly disrupted the reactivation induced by intraperitoneal injection of METH (0.5 mg/kg) after the extinction training process. However, respective intragastrical administration of NTX (20 or 40 mg/kg) failed to alter the dose-response curve of METH under fixed ratio 2 program and intraperitoneal injection of METH (1.0 mg/kg)-induced reinstatement in rats self-administration. Overall, our findings suggest that NTX has the pharmacotherapeutic potential in reducing the relapse of METH addiction, which deserves further investigation as a promising medication for the treatment of METH addiction.

α-Conotoxin TxIB: A Uniquely Selective Ligand for α6/α3β2β3 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Conditioned Place Preference in Mice.

α-Conotoxin TxIB is a specific antagonist of α6/α3β2β3(α6β2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6β2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6β2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.

Methanolic extract of Mitragyna speciosa Korth leaf inhibits ethanol seeking behaviour in mice: involvement of antidopaminergic mechanism.

In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300mg/kg, p.o.) and clozapine (1mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75mg/kg, p.o.) and reference drugs; acamprosate (300mg/kg, p.o.) and clozapine (1mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.

The role of the neuropeptide PEN receptor, GPR83, in the reward pathway: Relationship to sex-differences

GPR83, the receptor for the neuropeptide PEN, exhibits high expression in the nucleus accumbens of the human and rodent brain, suggesting that it plays a role in modulating the mesolimbic reward pathway. However, the cell-type specific expression of GPR83, its functional impact in the reward pathway, and in drug reward-learning has not been fully explored. Using GPR83/eGFP mice, we show high GPR83 expression on cholinergic interneurons in the nucleus accumbens and moderate expression on ventral tegmental area dopamine neurons. In GPR83 knockout mice, baseline dopamine release in the nucleus accumbens is enhanced which disrupts the ratio of tonic vs phasic release. Additionally, GPR83 knockout leads to changes in the expression of dopamine-related genes. Using the morphine conditioned place preference model, we identify sex differences in morphine reward-learning, show that GPR83 is upregulated in the nucleus accumbens following morphine conditioned place preference, and show that shRNA-mediated knockdown of GPR83 in the nucleus accumbens leads to attenuation morphine reward. Together, these findings detect GPR83 expression in the reward-pathway, and show its involvement in dopamine release and morphine reward-learning.

Neural Circuits Associated with 5-HT1B Receptor Agonist Inhibition of Methamphetamine Seeking in the Conditioned Place Preference Model.

5-HT1B receptors (5-HT1BRs) modulate psychostimulant reward and incentive motivation in rodents. Here we investigated the effects of the 5-HT1BR agonist CP94253 (10 mg/kg, IP) on the acquisition and expression of methamphetamine (Meth) conditioned place preference (CPP) in C57BL/6 male mice. We subsequently examined the potential brain regions involved in CP94253 effects using FOS as a marker of neural activity. In the acquisition experiment, mice received the agonist 30 min before each of the Meth injections given during conditioning. In the expression experiment, mice that had acquired Meth-CPP were given either saline or CP94253 and were tested for CPP 30 min later. We found that CP94253 attenuated the expression of Meth-CPP, but had no effect on acquisition. Mice expressing Meth-CPP had elevated numbers of FOS+ cells in the ventral tegmental area (VTA) and basolateral amygdala (BlA) and reduced FOS+ cells in the central amygdala (CeA) compared to saline controls. CP94253 given before the expression test, but not acutely in drug-naive mice, enhanced FOS+ cells in the VTA, the nucleus accumbens (NAc) shell and core, and the dorsomedial striatum and reversed the Meth-conditioned changes in FOS in the BlA and CeA. Approximately 50-70% of FOS+ cells in the NAc and VTA were GABAergic regardless of group. By contrast, we did not observe FOS-labeling in dopamine neurons in the VTA. The findings suggest that CP94253 attenuates the motivational effects of the Meth-associated environment and highlight the amygdala, VTA, NAc, and dorsomedial striatum as potential regions involved in this effect.

Cocaine conditioning induces persisting changes in ventral hippocampus synaptic transmission, long-term potentiation, and radial arm maze performance in the mouse

The effects of drugs of abuse, such as cocaine, on learning and memory processes are thought to contribute to drug craving and relapse susceptibility. Using an Escalating (Esc) or Double Escalating (2x Esc) cocaine i.p. dosing schedule with the conditioned place preference (CPP) model we investigated the persisting effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of the ventral hippocampus (vH), and spatial working memory in a radial arm maze (RAM) task. Interestingly, vH LTP was increased 4 weeks after the last injection day in animals that received only saline vehicle injections. A single pre-treatment with the kappa-opioid receptor antagonist, norbinaltorphimine (norBNI), blocks this stress-like effect of the conditioning protocol on vH LTP without altering the behavioral responses of the animals to cocaine. In animals that received the 2x Esc/norBNI cocaine conditioning, vH LTP was significantly decreased compared to those that received saline vehicle 4 weeks after the last dose. These 2x Esc/norBNI treated animals also exhibited a significant leftward shift in the stimulus-response curve of the baseline field excitatory postsynaptic potential (fEPSP) measurements. A separate group of 2x Esc/norBNI displayed an impaired ability to learn a spatial working memory RAM task compared to saline-conditioned mice following a similar 4 week abstinence period. Together, these results demonstrate that cocaine-induced alterations in synaptic transmission and LTP in the vH are associated with persisting drug-induced impairments in learning and memory performance.

Glucagon-like peptide-1 receptors within the nucleus of the solitary tract regulate alcohol-mediated behaviors in rodents

The ability of glucagon-like peptide-1 (GLP-1) to reduce food intake involves activation of GLP-1 receptors (GLP-1R) in the nucleus of the solitary tract (NTS). It has also been demonstrated that systemic administration of GLP-1R agonists attenuates alcohol-mediated behaviors via, to date, unknown mechanisms. Therefore, we evaluated the effects of NTS-GLP-1R activation by exendin-4 (Ex4) on alcohol-induced locomotor stimulation, accumbal dopamine release and memory of alcohol reward in the conditioned place preference (CPP) model in mice. Moreover, the ability of Ex4 infusion into the NTS on alcohol intake was explored in rats. Ex4 into the NTS inhibits the acute effects of alcohol as measured by alcohol-induced locomotor stimulation, accumbal dopamine release and the memory consolidation of alcohol reward in the CPP paradigm. In addition, NTS-Ex4 dose-dependently decreases alcohol intake in rats consuming alcohol for 12 weeks. Pharmacological suppression of GLP-1R in the NTS prevents the ability of systemic Ex4 to block the alcohol-induced locomotor stimulation in mice. These data add a functional role of GLP-1R within the NTS, involving alcohol-related behaviors. In addition, they may provide insight into the GLP-1R containing brain areas that modulate the ability of GLP-1R agonists to reduce alcohol reinforcement. Collectively, this further supports GLP-1R as potential treatment targets for alcohol use disorder.

Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents

Glucagon-like peptide 1 (GLP-1), an incretin hormone that reduces food intake, was recently established as a novel regulator of alcohol-mediated behaviors. Clinically available analogues pass freely into the brain, but the mechanisms underlying GLP-1-modulated alcohol reward remains largely unclear. GLP-1 receptors (GLP-1R) are expressed throughout the nuclei of importance for acute and chronic effects of alcohol, such as the laterodorsal tegmental area (LDTg), the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We therefore evaluated the effects of bilateral infusion of the GLP-1R agonist exendin-4 (Ex4) into NAc shell, anterior (aVTA), posterior (pVTA) or LDTg on the acute alcohol-induced locomotor stimulation and memory of alcohol reward in the conditioned place preference (CPP) model in mice, as well as on alcohol intake in rats consuming high amounts of alcohol for 12 weeks. Ex4 into the NAc shell blocks alcohol-induced locomotor stimulation and memory of alcohol reward as well as decreases alcohol intake. The GLP-1R expression in NAc is elevated in high compared to low alcohol-consuming rats. On the contrary, GLP-1R activation in the aVTA does not modulate alcohol-induced behaviors. Ex4 into the pVTA prevents alcohol-induced locomotor simulation, but does neither modulate CPP-dependent alcohol memory nor alcohol intake. Intra-LDTg-Ex4 attenuates alcohol-induced locomotor stimulation and reduces alcohol intake, but does not affect memory of alcohol reward. Collectively, these data provide additional knowledge of the functional role of GLP-1R in reward-related areas for alcohol-mediated behaviors and further support GLP-1R as a potential treatment target for alcohol use disorder.

Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of reduced expression on cocaine self-administration. There have been no reports of PTPRD targeting by any small molecule. There are no data about behavioral effects of any PTPRD ligand. We now report (i) robust effects of heterozygous PTPRD KO on cocaine self-administration (These data substantially extend prior conditioned place-preference data and add to the rationale for PTPRD as a target for addiction therapeutics.); (ii) identification of 7-butoxy illudalic acid analog (7-BIA) as a small molecule that targets PTPRD and inhibits its phosphatase with some specificity; (iii) lack of toxicity when 7-BIA is administered to mice acutely or with repeated dosing; (iv) reduced cocaine-conditioned place preference when 7-BIA is administered before conditioning sessions; and (v) reductions in well-established cocaine self-administration when 7-BIA is administered before a session (in WT, not PTPRD heterozygous KOs). These results add to support for PTPRD as a target for medications to combat cocaine use disorders. 7-BIA provides a lead compound for addiction therapeutics.

Effects and Mechanisms of Jinniu Capsule on Methamphetamine-Induced Conditioned Place Preference in Rats

Abstract The aim of this study was to determine the effects of Jinniu Capsule on methamphetamine (METH)-induced conditioned place preference (CPP) in rats and identify the underlying mechanisms. An intraperitoneal injection of 3 mg/kg METH was used for CPP training in rats. The effects of Jinniu Capsule following a single dose on rat CPP and repeat dosing on METH withdrawal were evaluated. Western Blot analysis was used to measure protein expression of the PI3K-AKT-mTOR signaling pathway to determine the mechanisms of Jinniu Capsule. A single dose of Jinniu Capsule did not influence METH-induced CPP in rats. However, repeat dosing for 7 days significantly promoted METH withdrawal. Furthermore, METH withdrawal activated the PI3K-AKT-mTOR signaling pathway phosphorylation cascade, and Jinniu Capsule partly blocked this cascade. Jinniu Capsule demonstrated potential in promoting METH withdrawal in a rat CPP model, which may be related to its influence on the PI3K-AKT-mTOR signaling pathway.

The distinct role of kappa opioid receptor in attenuating relapse to morphine/methamphetamine (polydrug) dependence in mice

A Combination of 0.3mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment shows a promising result due to its ability to attenuate reinstatement (relapse) in morphine/methamphetamine (polydrug)-dependent mice in a conditioned place preference (CPP) model. This prompted us to identify which opioid receptor that contributes to its anti-relapse activity. Using the same CPP model, 10 mg/kg nor- BNI (a selective kappa opioid receptor [KOR] antagonist) was used to evaluate the involvement of KOR in mediating relapse to polydrug dependence. By applying the immunohistochemistry (IHC) technique, the investigation was extended to the mice brain using KOR antibody (EPR18881), focusing on the brain regions that are abundant in KOR density. The results showed that nor-BNI alone failed to attenuate relapse to polydrug dependence. However, the IHC results proved that the number of KOR significantly increased in the striatum during reinstatement compared to post-conditioning (p <0.05). The KOR was significantly suppressed in the treatment group which strengthens the findings from previous studies proving that the KOR plays an important role in mediating relapse to polydrug dependence.

Effects of Clavulanic Acid on the Acquisition and Reinstatement Following Morphine-induced Conditioned Place Preference in Mice.

Introduction:β-Lactam antibiotics like Clavulanic Acid (CA) enhances cellular glutamate uptake through activation of Glutamate Transporter subtype 1 (GLT-1) and decreases the level of glutamate in the nervous system. Based on studies, blocking the glutamate activity inhibits morphine-induced Conditioned Place Preference (CPP) in animals. Therefore, the effects of CA on the acquisition of morphine craving were evaluated using the CPP model in the current study.Methods:CA (1, 50 and 150 mg/kg, ip) was co-administered with morphine (40 mg/kg) for 4 days in the conditioning phase. On day 8, the effects of CA on morphine preference was assessed. In another experiment, the effect of CA on reinstatement of morphine preference by a single morphine injection (10 mg/kg) was evaluated after an extinction period.Results:In the first method, the morphine-induced place preference was markedly reduced following administration of CA (50 and 150 mg/kg). In the second experiment, a single administration of CA (50 and 150 mg/kg) markedly inhibited the reinstatement of morphine preference on day 16. The results indicated that CA (50, 150 mg/kg) can block both morphine-induced CPP and the reinstatement of place preference following priming dose of morphine. Also memantine (as a positive control) (10 mg/kg) significantly inhibited both acquisition and reinstatement of morphine CPP.Conclusion:Considering the important role of glutamate neurotransmission in morphine dependence, the effects of CA may be partly due to decrease in glutamate level in synaptic space and blockade of N-Methyl-D-aspartate Acid (NMDA) receptors. Although, we need further studies to determine exact cellular mechanism.

Role of μ-δ heterodimer in down-regulation of expression of excitatory amino acid transporter 3 in hippocampi caused by reinstatement of morphine-induced conditioned place preference in rats

Objective To evaluate the role of μ-δ heterodimer in down-regulation of the expression of excitatory amino acid transporter 3 (EAAT3) in hippocampi caused by reinstatement of morphine-induced conditioned place preference (CPP) in rats. Methods Thirty-two healthy clean-grade male Sprague-Dawley rats, weighing 200-240 g, were assigned into 4 groups (n=8 each) using a random number table method: control group (group C), extinction group (group E), reinstatement group (group R) and reinstatement plus interference plasmid group (group RI). The model of morphine-induced CPP was established, and extinction of CPP was gradually induced by stopping administration.A small dose of morphine 5 mg/kg was intraperitoneally injected again to induce CPP reinstatement, and dwell time around the medicine box was recorded.μ-δ heterodimer interference plasmid 5 μl was injected into the lateral cerebral ventricle after successful establishment of CPP model in group RI.The content of glutamate (Glu) in hippocampi was measured using high-performance liquid chromatography.The EAAT3 expression in hippocampal CA1 and CA3 regions was detected using Western blot. Results Compared with group C, no significant change was found in the dwell time around the medicine box or content of Glu in hippocampi (P>0.05), and the expression of EAAT3 in hippocampal CA1 and CA3 regions was significantly up-regulated in group E, and the dwell time around the medicine box was significantly prolonged, the content of Glu in hippocampi was increased (P 0.05). Compared with group E, the dwell time around the medicine box was significantly prolonged, the content of Glu in hippocampi was increased, and the expression of EAAT3 in hippocampal CA1 and CA3 regions was down-regulated in group R (P<0.05). Compared with group R, the dwell time around the medicine box was significantly shortened, the content of Glu in hippocampi was decreased, and the expression of EAAT3 in hippocampal CA1 and CA3 regions was up-regulated in group RI (P<0.05). Conclusion μ-δ heterodimer is involved in down-regulation of EAAT3 expression in the hippocampus caused by reinstatement of morphine-induced CPP in rats. Key words: Receptors, opioid; Morphine Dependence; Excitatory amino acid transporter 3; Hippocampus; Heterodimer

Activation of amylin receptors attenuates alcohol-mediated behaviours in rodents.

Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut–brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol‐related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol‐induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward‐dependent memory consolidation. In addition, sCT pre‐treatment attenuated alcohol intake in low alcohol‐consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

Morphine antinociception on thermal sensitivity and place conditioning in male and female rats treated with intraplantar complete freund’s adjuvant

The experience of pain is characterized by the presence of a noxious sensory stimulus combined with negative affect, which is often treated clinically through administration of drugs such as morphine or other opioids. This study investigated the effects of morphine one and seven days after intraplantar administration of complete freund’s adjuvant (CFA) in male and female rats. Hargreaves test for thermal nociception and conditioned place preference (CPP) were performed following subcutaneous administration of saline or morphine (1.0, 4.0, 8.0, 12.0 mg/kg). Hargreaves test results revealed that male rats were more sensitive to morphine antinociceptive actions as compared to female rats one day after CFA treatment; however, this sex difference was not detected seven days after CFA treatment. One day after CFA treatment, morphine doses of 8.0 and 12.0 mg/kg produced a CPP in male rats, while female rats exhibited CPP with only the 12.0 mg/kg dose. Seven days after CFA treatment, both male and female rats exhibited a CPP with morphine doses of 4.0 mg/kg and higher. These results reveal sexually dimorphic properties of morphine in the paw withdrawal latencies and conditioned place preference models, representing reflexive and non-reflexive behavioral assays employed to examine inflammatory nociception. Our findings also suggest that antinociceptive effects of morphine are dynamic across early and later periods of CFA-induced inflammatory pain.

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

The field of neuroimmunology has expanded in recent years providing new insights and therapies into pathologies like stroke, autism, and depression. However, few works explore the relationship between inflammatory stimuli and motivation. Thus, the aim of this study was to determine how non-painful inflammatory stimuli affect reward. To test reward-response, we used the morphine and the nicotine induced conditioned place-preference and place-aversion model in rats with non-painful inflammation. The following inflammatory models were used: non-painful infectious inflammation: 24 hrs prior to conditioning sessions, an injection with Calmette-Guerin bacillus (CGB) 1 × 107 cfu, ip, was administered. Non-painful non-infectious inflammation: 24 hrs prior to conditioning sessions, rats’ sciatic nerve was blocked and cut, followed by the injection of carrageenan (750 μl) in the paw. We then measured the cytokine concentration to determine the inflammatory profile of each of our models. Finally, we administered ibuprofen to determine if it could prevent the effect of inflammation over conditioned place-preference. We show that carrageenan significantly reduced the morphine-induced reward. Non-painful inflammatory stimulus, CGB and denervation + carrageenan, inhibit the conditioned place-preference to morphine and nicotine, CGB also block conditioned place-aversion to nicotine; carrageenan has no effect on CPA. The administration of ibuprofen reinstates conditioned place-preference to morphine and nicotine in the carrageenan model, but has no effect in the CGB model; finally ibuprofen has no effect on CPA. Our data suggest that non-painful-inflammatory stimuli inhibit the reward system, independent of cytokine concentration. Furthermore, the administration of a PGE 2 inhibitor can importantly modulate this phenomenon.