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Opioid addiction is a chronic and relapsing mental health disorder. However, only some individuals exposed to opioids, either recreationally or during the course of pain management, will develop addiction. The reasons why some individuals develop addiction and some are spared are not fully understood. Studies indicate that it is likely a combination of genetic predispositions and environmental conditions. Given the role of environmental factors in human addiction, this review examines the role of social environments and social interactions in the development of opioid addictive-like behaviors in rodent studies. To date, three major behavioral approaches have been used in these studies, namely social isolation, environmental enrichment, and social housing with a variety of cage-mates that differ in their drug administration conditions. This review highlights the importance of an individual’s social network in influencing the outcomes of drug abuse and the need to further elucidate the molecular mechanisms underlying these effects. Better understanding is likely to contribute to the development of novel and more effective treatments for addiction disorders. [ABSTRACT FROM AUTHOR]

Activity of hemantane, an amino adamantane derivative, exhibiting the properties of lowaffinity non-competitive NMDA receptor antagonist, was evaluated in experimental in vivo models of alcoholism. Hemantane had no effects on the formation and manifestation of behavioral sensitization to ethanol in DBA/2 mice. Under conditions of free choice between 10% ethanol and water, hemantane (20 mg/kg/day for 14 days, intraperitoneally) significantly reduced the daily ethanol intake in random-bred male rats with formed alcohol motivation (>4 g/kg of ethanol). During modelling of withdrawal syndrome, hemantane administered intraperitoneally in doses of 5-20 mg/kg dose-dependently attenuated alcohol-deprivation effect after acute withdrawal with no effects on protracted abstinence. It was found that hemantane suppressed alcohol drinking behavior in long-term ethanol experienced rats and attenuated alcohol-seeking behavior after acute withdrawal. [ABSTRACT FROM AUTHOR]

Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether “cross-sensitization” occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2 g/kg) for 15 days. The biochemical effects of low- or high-dose ethanol were examined in terms of N -methyl- d -aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5 g/kg) but not the high dose (2 g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence. [ABSTRACT FROM AUTHOR]

Background and Aim The cholinergic system can affect drug reward. The present study aimed to examine the roles of muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in morphine-induced behavioral sensitization. Methods To analyze the roles of mAChR and nAChR in behavioral sensitization induced by morphine (5 mg/kg), seven experiments were designed. Experiments 1 and 2 examined the effects of 3, 1, and 0.3 mg/kg scopolamine and 0.2, 0.1, and 0.05 mg/kg scopolamine, respectively, on the locomotor activity when administered alone. Experiments 3 and 4 explored the effect of scopolamine on morphine-induced behavioral sensitization. Experiment 5 studied the effect of mecamylamine on morphine-induced behavioral sensitization. Experiments 6 and 7 investigated the effects of scopolamine + huperzine A and mecamylamine + huperzine A, respectively, on morphine-induced behavioral sensitization. Results The results revealed that 3 mg/kg scopolamine, which significantly enhanced locomotor activity when administered alone, inhibited the acquisition of morphine-induced sensitization. However, mecamylamine (0.5, 1, 2 mg/kg) did not have these effects. The co-administration of scopolamine (0.05 mg/kg) + huperzine A (0.4 mg/kg) or mecamylamine (1 mg/kg) + huperzine A (0.4 mg/kg) did not affect the acquisition of morphine-induced behavioral sensitization. Scopolamine (0.05 mg/kg) which did not affect the locomotor activity when administered alone, but not mecamylamine (1 mg/kg), reversed the acute attenuation effect of huperzine A (0.4 mg/kg) on morphine-induced locomotor activity at the acquisition stage and reversed the inhibition of huperzine A on the expression of morphine-induced sensitization. Conclusion The mAChR might play a more important role in morphine-induced locomotor activity and the expression of morphine-induced behavioral sensitization. The mechanisms of mAChR and nAChR were relatively separate in morphine-induced sensitization. [ABSTRACT FROM AUTHOR]

Male flies under the influence of ethanol display disinhibited courtship, which is augmented with repeated ethanol exposures. We have previously shown that dopamine is important for this type of ethanol-induced behavioral sensitization but the underlying mechanism is unknown. Here we report that DopEcR, an insect G-protein coupled receptor that binds to dopamine and steroid hormone ecdysone, is a major receptor mediating courtship sensitization. Upon daily ethanol administration, dumb and damb mutant males defective in D1 (dDA1/DopR1) and D5 (DAMB/DopR2) dopamine receptors, respectively, showed normal courtship sensitization; however, the DopEcR-deficient der males exhibited greatly diminished sensitization. der mutant males nevertheless developed normal tolerance to the sedative effect of ethanol, indicating a selective function of DopEcR in chronic ethanol-associated behavioral plasticity. DopEcR plays a physiological role in behavioral sensitization since courtship sensitization in der males was reinstated when DopEcR expression was induced during adulthood but not during development. When examined for the DopEcR's functional site, the der mutant's sensitization phenotype was fully rescued by restored DopEcR expression in the mushroom body (MB) αβ and γ neurons. Consistently, we observed DopEcR immunoreactivity in the MB calyx and lobes in the wild-type Canton-S brain, which was barely detectable in the der brain. Behavioral sensitization to the locomotorstimulant effect has been serving as a model for ethanol abuse and addiction. This is the first report elucidating the mechanism underlying behavioral sensitization to another stimulant effect of ethanol. [ABSTRACT FROM AUTHOR]

Rationale: It is necessary to understand better how chronic food restriction (CFR) and psychostimulant drugs interact in motivated behavior unrelated to food or energy homeostasis. Objectives: We examined whether CFR augments methylphenidate (MPH)-potentiated responding reinforced by visual sensation (VS) and whether repeated MPH injections or prolonged CFR further augments such responses. Methods: Before starting the following experiments, rats on a CFR diet received a limited daily ration in such a way that their body weights decreased to 85-90% of their original weights over 2 weeks. In experiment 1, rats on CFR and ad libitum diet received four injections of varying MPH doses (0, 2.5, 5, and 10 mg/kg). In experiment 2, CFR and ad libitum groups received repeated injections of MPH (2.5 mg/kg). In experiment 3, half of CFR rats received repeated injections of MPH (2.5 mg/kg), and the other half received saline, and following a 7-day abstinence, they all received the 2.5-mg/kg dose of MPH. Results: CFR rats increased VS-reinforced responding more than ad libitum rats when they received MPH. Repeated injections of MPH with prolonged CFR further increased VS-reinforced responding. We found a double dissociation where prolonged CFR (3 vs. 6 weeks) made VS-reinforced responding, but not locomotor activity, more responsive to MPH, whereas repeated MPH injections made locomotor activity, but not VS-reinforced responding, more responsive to MPH. Conclusions: CFR markedly potentiates effects of MPH on VS-reinforced responding. The present study demonstrates that the longer CFR continues, the greater psychostimulant drugs augment behavioral interaction with salient stimuli. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies have shown that repeated exposure to drugs of abuse is associated with changes in clock genes expression and that mice strains with various mutations in clock genes show alterations in drug-induced behaviors. Objective: The objective of this study is to characterize the role of the clock gene mPer1 in the development of morphine-induced behaviors and a possible link to histone deacetylase (HDAC) activity. Methods: In Per1 null mutant mice and wild-type (WT) littermates, we examined whether there were any differences in the development of morphine antinociception, tolerance to antinociception, withdrawal, sensitization to locomotion, and conditioned place preference (CPP). Results: Per1 mutant mice did not show any difference in morphine antinociception, tolerance development, nor in physical withdrawal signs precipitated by naloxone administration compared to WT. However, morphine-induced locomotor sensitization and CPP were significantly impaired in Per1 mutant mice. Because a very similar dissociation between tolerance and dependence vs. sensitization and CPP was recently observed after the co-administration of morphine and the HDAC inhibitor sodium butyrate (NaBut), we studied a possible link between mPer1 and HDAC activity. As opposed to WT controls, Per1 mutant mice showed significantly enhanced striatal global HDAC activity within the striatum when exposed to a locomotor-sensitizing morphine administration regimen. Furthermore, the administration of the HDAC inhibitor NaBut restored the ability of morphine to promote locomotor sensitization and reward in Per1 mutant mice. Conclusions: Our results reveal that although the mPer1 gene does not alter morphine-induced antinociception nor withdrawal, it plays a prominent role in the development of morphine-induced behavioral sensitization and reward via inhibitory modulation of striatal HDAC activity. These data suggest that PER1 inhibits deacetylation to promote drug-induced neuroplastic changes. [ABSTRACT FROM AUTHOR]

The behavioral manifestations of psychostimulant-induced sensitization vary markedly between young and adult rats, suggesting that the neural mechanisms mediating this phenomenon differ across ontogeny. In this project we examined the importance of D1 and D2 receptors for the induction and expression of cocaine-induced behavioral sensitization during the preweanling period. In the behavioral experiments, rats were injected with reversible D1 and/or D2 antagonists (SCH23390 and/or raclopride) or an irreversible receptor antagonist (EEDQ) either before cocaine administration on the pretreatment day (induction) or before cocaine challenge on the test day (expression). In the EEDQ experiments, receptor specificity was assessed by using selective dopamine antagonists to protect D1 and/or D2 receptors from inactivation. Receptor binding assays showed that EEDQ caused substantial reductions in dorsal striatal D1 and D2 binding sites, while SCH23390 and raclopride fully protected D1 and D2 receptors from EEDQ-induced alkylation. Behavioral results showed that neither D1 nor D2 receptor stimulation was necessary for the induction of cocaine sensitization in preweanling rats. EEDQ disrupted the sensitization process, suggesting that another receptor type sensitive to EEDQ alkylation was necessary for the induction process. Expression of the sensitized response was prevented by an acute injection of a D1 receptor antagonist. The pattern of DA antagonist-induced effects described for preweanling rats is, with few exceptions, similar to what is observed when the same drugs are administered to adult rats. Thus, it appears that maturational changes in D1 and D2 receptor systems are not responsible for ontogenetic differences in the behavioral manifestation of cocaine sensitization. [ABSTRACT FROM AUTHOR]

Objectives Environmental enrichment (EE) produces differential effects on psychostimulant-related behaviors. Therefore, we investigated whether the timing of EE exposure - during rearing and before cocaine exposure versus in adulthood and after cocaine exposure might be a determining factor. Methods In Experiment 1, rats reared with EE or not (non-EE) were conditioned with cocaine (5, 10 or 20 mg/kg) in one compartment of a CPP apparatus and saline in the other, and later tested for cocaine CPP. In Experiment 2, locomotor activity in response to repeated injections of saline or cocaine was measured in rats raised with EE or non-EE. In Experiment 3 we measured the effects of EE or non-EE during rearing on food-based conditioned approach learning. In Experiment 4, rats were exposed to cocaine CPP conditioning then underwent 60 days of EE or non-EE treatment after which they were tested for cocaine CPP. Results Our results show that rearing in EE did not reduce cocaine CPP or cocaine-induced locomotor activity (Experiments 1 and 2) but significantly facilitated conditioned approach learning (Experiment 3). On the other hand, EE treatment introduced after cocaine conditioning significantly reduced the expression of cocaine CPP (Experiment 4). Conclusions These findings suggest that EE does not protect against cocaine's rewarding and stimulant effects but can reduce already established cocaine effects, suggesting that EE might be an effective treatment for cocaine addiction-related behaviors. [ABSTRACT FROM AUTHOR]

CB1 receptor antagonists have been shown to prevent acute and long-term behavioral effects of cocaine. Here we evaluate the effectiveness of the CB1 receptor antagonist rimonabant to modify sensitized responses to cocaine. Mice were treated with saline or cocaine injections in a 15-day intermittent sensitization treatment and subsequently treated with either vehicle, 1 or 10 mg/kg rimonabant in the drug-associated environment for 8 consecutive days. Animals were then challenged with saline and cocaine in the open-field apparatus on subsequent days to evaluate the expression of conditioned and sensitized effects to cocaine. c-Fos protein expression was evaluated in the nucleus accumbens (NAcc), ventral tegmental area (VTA), basolateral amygdala (BLA), medial prefrontal cortex (mPFC) and caudate-putamen (CPu) after the last (cocaine) challenge. Previous treatment with 10 mg/kg rimonabant blocked the expression of conditioned hyperlocomotion and behavioral sensitization to cocaine, but not acute cocaine-induced hyperlocomotion. These behavioral effects were accompanied by significant changes in c-Fos expression in the brain reward system. Chronic cocaine sensitization blunted a subsequent acute cocaine-induced increase in c-Fos protein in the NAcc, effect that was reversed by previous treatment with rimonabant. Treatment with 10 mg/kg rimonabant also attenuated the significant increase in c-Fos expression in the CPu, mPFC and BLA induced by previous chronic sensitization with cocaine. Our findings add to the evidence that drugs targeting CB1 receptors are good candidates for the treatment of cocaine abuse and provide further insights into the mechanisms underlying endocannabinoid signaling within the brain reward system in the context of cocaine abuse. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis. [ABSTRACT FROM AUTHOR]

In previous study, we demonstrated that ethanol preexposure may increase ethanol consumption in both adolescent and adult mice, in a two-bottle choice model. We now questioned if ethanol exposure during adolescence results in changes of consumption pattern using a three-bottle choice procedure, considering drinking-inthe- dark and alcohol deprivation effect as strategies for ethanol consumption escalation. We also analyzed aldehyde dehydrogenase (ALDH) activity as a measurement of ethanol metabolism. Adolescent and adult Swiss mice were treated with saline (SAL) or 2.0 g/kg ethanol (EtOH) during 15 days (groups: Adolescent-SAL, Adolescent-EtOH, Adult-SAL and Adult-EtOH). Five days after the last injection, mice were exposed to the threebottle choice protocol using sucrose fading procedure (4% + sucrose vs. 8%-15% ethanol + sucrose vs. water + sucrose) for 2 h during the dark phase. Sucrose was faded out from 8% to 0%. The protocol was composed of a 6-week acquisition period, followed by four withdrawals and reexposures. Both adolescent and adult mice exhibited ethanol behavioral sensitization, although the magnitude of sensitization in adolescents was lower than in adults. Adolescent-EtOH displayed an escalation of 4% ethanol consumption during acquisition that was not observed in Adult-EtOH. Moreover, Adult-EtOH consumed less 4% ethanol throughout all the experiment and less 15% ethanol in the last reexposure period than Adolescent-EtOH. ALDH activity varied with age, in which older mice showed higher ALDH than younger ones. Ethanol pretreatment or the pattern of consumption did not have influence on ALDH activity. Our data suggest that ethanol pretreatment during adolescence but not adulthood may influence the pattern of ethanol consumption toward an escalation in ethanol consumption at low dose, without exerting an impact on ALDH activity. [ABSTRACT FROM AUTHOR]

Background: Early exposure to enriched environments has been shown to decrease the locomotor effects induced by repeated injections of cocaine and modify basal and cocaine-induced total protein levels of the transcription factor ΔFosB in the whole striatum of mice. In this study, we aimed at characterizing whether the profile of ΔFosB accumulation induced by enriched environments and cocaine would be similar or different in terms of brain areas and cell type. Methods: We used mice expressing the eGFP protein in D1 receptor positive (D1R(+)) neurons to determine whether ΔFosB induced by enriched environment or cocaine injections (5 × 15 mg/kg) would occur in selective subpopulations of neurons in several subregions of the striatum and prefrontal cortex. Results: We found that: (1) exposure to enriched environment reduces cocaine-induced locomotor activation, confirming our previous findings; (2) exposure to enriched environment by itself increases the accumulation of ΔFosB mostly in D1R(-) cells in the shell part of the nucleus accumbens and dorsal striatum, whereas in the nucleus accumbens core, ΔFosB accumulates in both D1R(+) and D1R(-) neurons; (3) in standard environment mice, cocaine induces accumulation of ΔFosB selectively in D1R(+) cells in the nucleus accumbens, dorsal striatum, and infralimbic cortex; and (4) the effects of enriched environments and cocaine on accumulation of ΔFosB were reciprocally blocked by their combination. Conclusions: Altogether, these results suggest that the enriched environment-induced reduction in behavioral effects of cocaine might result from 2 distinct effects on ΔFosB in striatal medium-sized spiny neurons belonging to the direct and indirect pathways. [ABSTRACT FROM AUTHOR]

Rationale We have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. Objective Evaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. Methods Animals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5 mg/kg ziprasidone or 0.1 mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. Results While treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. Conclusions Both neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects. [ABSTRACT FROM AUTHOR]

Crack cocaine has a high potential to induce cocaine addiction and its smoke contains cocaine’s pyrolysis product anhydroecgonine methyl ester (AEME), a partial agonist at M 1 - and M 3 -muscarinic acetylcholine receptor and an antagonist at the remaining subtypes. No reports have assessed AEME’s role in addiction. Adult male Wistar rats were intraperitoneally administered with saline, 3 mg/kg AEME, 15 mg/kg cocaine, or a cocaine-AEME combination on every other day during a period of 9 days. After a 7-days withdrawal period, a challenge injection of the respective drugs was performed on the 17th day. The locomotor activity was evaluated on days 1, 3, 5, 7, 9 and 17, as well as dopamine levels (9th day) and dopaminergic receptors proteins (D 1 R and D 2 R on the 17th day) in the caudate-putamen (CPu) and nucleus accumbens (NAc). AEME was not able to induce the expression of behavioral sensitization, but it substantially potentiates cocaine-effects, with cocaine-AEME combination presenting higher expression than cocaine alone. An increase in the dopamine levels in the CPu in all non-saline groups was observed, with the highest levels in the cocaine-AEME group. There was a decrease in D 1 R protein level in this brain region only for cocaine and cocaine-AEME groups. In the NAc, an increase in the dopamine levels was only observed for cocaine and cocaine-AEME groups, with no changes in both D 1 R and D 2 R protein levels. These behavioral and neurochemical data indicate that AEME alone does not elicit behavioral sensitization but it significantly potentiates cocaine effects when co-administered, resulting in dopamine increase in CPu and NAc, brain regions where dopamine release is mediated by cholinergic activity. [ABSTRACT FROM AUTHOR]

Addiction is a multifactorial disease that comprises physiological mechanisms of learning and memory. Addict subjects have intense plasticity in cortical and limbic circuits during intoxication, abstinence or even in drug seeking behavior. Locomotor sensitization is a classic animal model of drug addiction that mimics the changes that occur in the transition from drug use to drug addiction. Several studies have demonstrated the importance of contextual associative processes in this task. However, whether the mechanisms of sensitization are maintained and precise over the time remain an open question. Thus, the aim of this study was to investigate the importance of context in the maintenance and precision of locomotor sensitization across time. For this, male c57bl/6 mice were submitted to different contexts during the acquisition phase of amphetamine-induced locomotor sensitization. We found that after 3 days of withdrawal, the expression of locomotor sensitization was context dependent, as characterized by an increased locomotion in the acquisition context (A), but not in the novel context (B). Surprisingly, when the expression of locomotor sensitization was tested after 28 days of withdrawal, mice that acquired sensitization in the context A exhibited increased locomotion in both contexts (A and B), suggesting that memories associated with amphetamine drugs generalize following long periods of abstinence. The same generalization did not occur in mice sensitized in a well-known context (home cage). These results demonstrate, for the first time, the influence of memory generalization in amphetamine-induced locomotor sensitization. The evidence that memory generalization also occurs in sensitization provides new advances in the comprehension of the mechanisms underlying memory role in addiction process. Elucidating the mechanisms of amphetamine sensitization may shed some light on understanding the transition from drug use to addiction. [ABSTRACT FROM AUTHOR]

The disinhibition of dopamine neurons in the VTA by morphine is considered an important contributor to the reward potency of morphine. In this report, three experiments were conducted in which a low dose of apomorphine (0.05 mg/kg) was used as a pretreatment to reduce dopamine activity. Locomotor hyperactivity was used as the behavioral response to morphine (10.0 mg/kg). In the first experiment, five treatments with morphine induced the development of locomotor and conditioned hyperactivity that were prevented by apomorphine given 10 min prior to morphine. Apomorphine before either vehicle or morphine induced equivalent reductions in locomotion. In the second experiment, the apomorphine pretreatment was initiated after induction of a conditioned hyperactivity and apomorphine prevented the expression of the conditioning. To assess the effects of apomorphine on VTA and the nucleus accumbens, ERK measurements were carried out after the induction of locomotor and conditioned hyperactivity. Increased ERK activation was found and these effects were prevented by the apomorphine in both experiments. A third experiment was conducted to assess the effects of acute morphine on ERK before locomotor stimulation was induced by morphine. Acute morphine did not increase locomotion, but a robust ERK response was produced indicating that the morphine-induced ERK activation was not secondary to locomotor stimulation. ERK activation was again prevented by the apomorphine pretreatment. We suggest that contiguity between the ongoing behavioral activity and the morphine activation of the dopamine reward system incentivizes and potentiates the ongoing behavior generating equivalent behavioral sensitization and conditioned effects. • Acute MOR did not increase locomotion but repeated MOR induced hyperactivity. • Conditioned MOR hyperactivity was equivalent to MOR induced hyperactivity. • APO pretreatment prevented the development and expression of MOR conditioning. • Acute MOR and conditioned MOR increased ERK activation in the VTA and NAc. • All MOR induced increases in ERK activity were prevented by the APO pretreatment. [ABSTRACT FROM AUTHOR]

Background: Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterized as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromer-preferring agonist promoted antinociception comparable with morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory., Methods: Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice, including behavioral sensitization, conditioned place preference and withdrawal., Results: We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behavior. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference., Conclusions: Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

While clinical and pre-clinical evidence suggests that adolescence is a risk period for the development of addiction, the underlying neural mechanisms are largely unknown. Stress during adolescence has a huge influence on drug addiction. However, little is known about the mechanisms related to the interaction among stress, adolescence and addiction. Studies point to ΔFosB as a possible target for this phenomenon. In the present study, adolescent and adult rats (postnatal day 28 and 60, respectively) were restrained for 2 hours once a day for 7 days. Three days after their last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens was dissected to measure ΔFosB protein levels. We found that repeated restraint stress increased amphetamine-induced locomotion in both adult and adolescent rats. Furthermore, in adult rats, stress-induced locomotor sensitization was associated with increased expression of ΔFosB in the nucleus accumbens. Our data suggest that ΔFosB may be involved in some of the neuronal plasticity changes associated with stress induced-cross sensitization with amphetamine in adult rats.