Reward-related Behaviors Research Articles

Reward motivation and cognitive flexibility in tau null-mutation mice

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau−/−) and wild-type mice using progressive ratio and reversal learning tasks. Tau−/− mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau−/− mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.

Topographic transcriptomics of the nucleus accumbens shell: Identification and validation of fatty acid binding protein 5 as target for cocaine addiction

Substance use disorders for cocaine are major public health concerns with few effective treatment options. Therefore, identification of novel pharmacotherapeutic targets is critical for future therapeutic development. Evolution has ensured that genes are expressed largely only where they are needed. Therefore, examining the gene expression landscape of the nucleus accumbens shell (NAcSh), a brain region important for reward related behaviors, may lead to the identification of novel targets for cocaine use disorder. In this study, we conducted a novel two-step topographic transcriptomic analysis using five seed transcripts with enhanced expression in the NAcSh to identify transcripts with similarly enhanced expression utilizing the correlation feature to search the more than 20,000 in situ hybridization experiments of the Allen Mouse Brain Atlas. Transcripts that correlated with at least three seed transcripts were analyzed with Ingenuity Pathway Analysis (IPA). We identified 7-fold more NAcSh-enhanced transcripts than our previous analysis using single voxels in the NAcSh as the seed. Analysis of the resulting transcripts with IPA identified many previously identified signaling pathways such as retinoic acid signaling as well as novel pathways. Manipulation of the retinoic acid pathway specifically in the NAcSh of male rats via viral vector-mediated RNA interference targeting fatty acid binding protein 5 (FABP5) decreased cocaine self-administration and modulates excitability of medium spiny neurons in the NAcSh. These results not only validate the prospective strategy of conducting a topographic transcriptomic analysis, but also further validate retinoic acid signaling as a promising pathway for pharmacotherapeutic development against cocaine use disorder.

Effects of vapourized THC and voluntary alcohol drinking during adolescence on cognition, reward, and anxiety-like behaviours in rats

Cannabis and alcohol co-use is prevalent in adolescence, but the long-term behavioural effects of this co-use remain largely unexplored. The aim of this study is to investigate the effects of adolescent alcohol and Δ9-tetrahydracannabinol (THC) vapour co-exposure on cognitive- and reward-related behaviours. Male Sprague-Dawley rats received vapourized THC (10 mg vapourized THC/four adolescent rats) or vehicle every other day (from post-natal day (PND) 28–42) and had continuous voluntary access to ethanol (10% volume/volume) in adolescence. Alcohol intake was measured during the exposure period to assess the acute effects of THC on alcohol consumption. In adulthood (PND 56+), rats underwent behavioural testing. Adolescent rats showed higher alcohol preference, assessed using the two-bottle choice test, on days on which they were not exposed to THC vapour. In adulthood, rats that drank alcohol as adolescents exhibited short-term memory deficits and showed decreased alcohol preference; on the other hand, rats exposed to THC vapour showed learning impairments in the delay-discounting task. Vapourized THC, alcohol or their combination had no effect on anxiety-like behaviours in adulthood. Our results show that although adolescent THC exposure acutely affects alcohol drinking, adolescent alcohol and cannabis co-use may not produce long-term additive effects.

Prenatal Opioid Exposure Enhances Responsiveness to Future Drug Reward and Alters Sensitivity to Pain: A Review of Preclinical Models and Contributing Mechanisms

The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure (POE); however, the long-term effects of POE on offspring behavior and neurodevelopment remain relatively unknown. The advantages and disadvantages of the various preclinical POE models developed over the last several decades are discussed in the context of clinical and translational relevance. Although considerable and important variability exists among preclinical models of POE, the examination of these preclinical models has revealed that opioid exposure during the prenatal period contributes to maladaptive behavioral development as offspring mature including an altered responsiveness to rewarding drugs and increased pain response. The present review summarizes key findings demonstrating the impact of POE on offspring drug self-administration (SA), drug consumption, the reinforcing properties of drugs, drug tolerance, and other reward-related behaviors such as hypersensitivity to pain. Potential underlying molecular mechanisms which may contribute to this enhanced addictive phenotype in POE offspring are further discussed with special attention given to key brain regions associated with reward including the striatum, prefrontal cortex (PFC), ventral tegmental area (VTA), hippocampus, and amygdala. Improvements in preclinical models and further areas of study are also identified which may advance the translational value of findings and help address the growing problem of POE in clinical populations.

Targeted Stimulation of an Orbitofrontal Network Disrupts Decisions Based on Inferred, Not Experienced Outcomes.

When direct experience is unavailable, animals and humans can imagine or infer the future to guide decisions. Behavior based on direct experience versus inference may recruit partially distinct brain circuits. In rodents, the orbitofrontal cortex (OFC) contains neural signatures of inferred outcomes, and OFC is necessary for behavior that requires inference but not for responding driven by direct experience. In humans, OFC activity is also correlated with inferred outcomes, but it is unclear whether OFC activity is required for inference-based behavior. To test this, we used noninvasive network-based continuous theta burst stimulation (cTBS) in human subjects (male and female) to target lateral OFC networks in the context of a sensory preconditioning task that was designed to isolate inference-based behavior from responding that can be based on direct experience alone. We show that, relative to sham, cTBS targeting this network impairs reward-related behavior in conditions in which outcome expectations have to be mentally inferred. In contrast, OFC-targeted stimulation does not impair behavior that can be based on previously experienced stimulus–outcome associations. These findings suggest that activity in the targeted OFC network supports decision-making when outcomes have to be mentally simulated, providing converging cross-species evidence for a critical role of OFC in model-based but not model-free control of behavior.SIGNIFICANCE STATEMENT It is widely accepted that the orbitofrontal cortex (OFC) is important for decision-making. However, it is less clear how exactly this region contributes to behavior. Here we test the hypothesis that the human OFC is only required for decision-making when future outcomes have to be mentally simulated, but not when direct experience with stimulus–outcome associations is available. We show that targeting OFC network activity in humans using network-based continuous theta burst stimulation selectively impairs behavior that requires inference but does not affect responding that can be based solely on direct experience. These results are in line with previous findings in animals and suggest a critical role for human OFC in model-based but not model-free behavior.

Acute and chronic bupropion treatment does not prevent morphine-induced conditioned place preference in mice

A substantial barrier to the treatment of Opioid Use Disorder (OUD) is the elevated relapse rates in affected patients, and a significant contributor to these events of relapse is exposure to cues and contexts that are intensely associated with prior drug abuse. The neurotransmitter dopamine plays a key role in reward-related behaviors, and previous studies have illustrated that dopamine hypofunction in periods of abstinence serves to prompt drug craving and seeking. We hypothesized that restoration of dopaminergic signaling could attenuate drug-seeking behaviors. Therefore, we investigated whether use of an FDA-approved drug, bupropion, an inhibitor of the dopamine transporter (DAT), or a dopamine uptake inhibitor with high affinity for DAT, JHW 007, was able to decrease preference for a drug-paired context. In these experiments, mice underwent 5 days of non-contingent morphine (10 mg/kg) exposure in a conditioned place preference (CPP) paradigm. We found that systemic injection of bupropion (20 mg/kg, i. p.) or intracranial injection of JHW 007 into the nucleus accumbens shell did not prevent the expression of morphine CPP. We then investigated whether chronic bupropion treatment (via implanted osmotic pumps) would influence morphine CPP. We observed that chronic bupropion treatment for 21 days following morphine conditioning did not attenuate the prolonged preference for morphine-paired contexts. Overall, with our dose and paradigm, neither acute nor chronic bupropion diminishes morphine CPP. Continued studies should address FDA-approved medications and their potential for recovery in OUD patients.

Drug-Induced Conditioned Place Preference and Its Practical Use in Substance Use Disorder Research.

The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

Upregulation of nAChRs and Changes in Excitability on VTA Dopamine and GABA Neurons Correlates to Changes in Nicotine-Reward-Related Behavior

Previous reports indicate that nicotine reward is mediated through α4β2*, α6β2*, and α4α6β2* nicotinic acetylcholine receptors (nAChRs; * indicates that additional nAChR subunits may be present). Little is known about α4α6β2* nAChR involvement in reward and reinforcement because of a lack of methods that allow the direct investigation of this particular nAChR subtype. Here, we use male and female mice that contain α4-mCherry and α6-GFP nAChR subunits to show that concentrations of nicotine sufficient to evoke reward-related behavior robustly upregulate α4* and α4α6* nAChRs on midbrain dopamine (DA) and GABA neurons. Furthermore, the extent of α4α6* nAChR upregulation on ventral tegmental area (VTA) DA neurons aligns with the magnitude of nicotine reward-related behavior. We also show that the upregulation of nAChRs is accompanied by a functional change in firing frequency of both DA and GABA neurons in the VTA that is directly linked to nicotine reward-related behavior.

High Alcohol-Preferring Mice Show Reaction to Loss of Ethanol Reward Following Repeated Binge Drinking.

Beyond yielding high blood ethanol (EtOH) concentrations (BECs), binge-drinking models allow examination of drinking patterns which may be associated with EtOH's rewarding effects, including front-loading and consummatory successive negative contrast (cSNC), a decrease in intake when only water is available to subjects expecting EtOH. The goals of the current study were to broaden our understanding of these reward-related behaviors during binge EtOH access in high alcohol-preferring (HAP) replicate lines (HAP2 and HAP3) of mice selectively bred to prefer alcohol. We hypothesized that both lines would show evidence of front-loading during binge EtOH access and that we would find a cSNC effect in groups where EtOH was replaced with water, as these results have been shown previously in HAP1 mice. HAP replicate 2 and replicate 3 female and male mice were given 2hours of EtOH or water access in the home cage for 15 consecutive days using "drinking in the dark" (DID) procedures. Mice received the same fluid (either 20% unsweetened EtOH or water) for the first 14days. However, on the 15th day, half of the mice from these 2 groups were provided with the opposite assigned fluid (EtOH groups received water and vice versa). Intake was measured in 1-minute bins using specialized sipper tubes, which allowed within-session analyses of binge-drinking patterns. EtOH front-loading was observed in both replicates. HAP3 mice displayed front-loading on the first day of EtOH access, whereas front-loading developed following alcohol experience in HAP2 mice, which may suggest differences in initial sensitivity to EtOH reward. Consummatory SNC, which manifests as lower water intake in mice expecting EtOH as compared to mice expecting water, was observed in both replicates. These findings increase confidence that defined changes in home cage consummatory behavior are driven by the incentive value of EtOH. The presence of cSNC across HAP replicates indicates that this reaction to loss of reward is genetically mediated, which suggests that there is a biological mechanism that might be targeted.

Flavors Enhance Nicotine Vapor Self-administration in Male Mice.

IntroductionAlthough the use of combustible cigarettes has decreased in many urban regions of America, the use of electronic nicotine delivery systems (ENDS) has dramatically increased. ENDS, or electronic cigarettes (e-cigarettes), differ from combustible cigarettes given that there are no restrictions on flavorant additives in e-liquids. With 95% of ENDS users vaping flavored e-liquids, it is critical to understand how flavors alter vaping-related behaviors. We have previously shown that menthol and green apple flavors enhance nicotine reward-related behavior in a mouse model and in the present study have investigated how menthol and green apple flavors alter e-Vape self-administration behavior in male mice.MethodsAdult C57/BL6J male mice were used in vapor-inhalation self-administration assays. Mice were assigned vaping e-liquids (6 mg/mL nicotine with or without menthol or green apple flavor) to escalate on a fixed-ratio 1 (FR1) schedule in daily 3-hour sessions to examine initiation-related behaviors. Following escalation, mice were transitioned to a FR3 and progressive ratio schedules in 3-hour sessions to examine reinforcement-related behaviors.ResultsHere we observed that male mice exhibited increased rates of self-administration escalation on a FR1 schedule when assigned to flavored e-liquids. Upon transition to FR3, mice continued to exhibit enhanced levels of reinforcement with flavored e-liquids. We also observed that mice self-administer zero-nicotine green apple flavored e-liquids.ConclusionsThese data provide additional evidence that ENDS flavors enhance vaping-related initiation and reinforcement-related behavior and promote the need to continue investigating the role ENDS flavors play in vaping-related behaviors.ImplicationsThere has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our study here shows that flavors significantly enhance the acquisition and reinforcement of vaping-related behavior. This suggests that flavors in electronic nicotine delivery systems significantly increase the risk of addiction-related behaviors among users of vaping products.

μ-Opioid Receptors on Distinct Neuronal Populations Mediate Different Aspects of Opioid Reward-Related Behaviors.

μ-Opioid receptors (MORs) are densely expressed in different brain regions known to mediate reward. One such region is the striatum where MORs are densely expressed, yet the role of these MOR populations in modulating reward is relatively unknown. We have begun to address this question by using a series of genetically engineered mice based on the Cre recombinase/loxP system to selectively delete MORs from specific neurons enriched in the striatum: dopamine 1 (D1) receptors, D2 receptors, adenosine 2a (A2a) receptors, and choline acetyltransferase (ChAT). We first determined the effects of each deletion on opioid-induced locomotion, a striatal and dopamine-dependent behavior. We show that MOR deletion from D1 neurons reduced opioid (morphine and oxycodone)-induced hyperlocomotion, whereas deleting MORs from A2a neurons resulted in enhanced opioid-induced locomotion, and deleting MORs from D2 or ChAT neurons had no effect. We also present the effect of each deletion on opioid intravenous self-administration. We first assessed the acquisition of this behavior using remifentanil as the reinforcing opioid and found no effect of genotype. Mice were then transitioned to oxycodone as the reinforcer and maintained here for 9 d. Again, no genotype effect was found. However, when mice underwent 3 d of extinction training, during which the drug was not delivered, but all cues remained as during the maintenance phase, drug-seeking behavior was enhanced when MORs were deleted from A2a or ChAT neurons. These findings show that these selective MOR populations play specific roles in reward-associated behaviors.

High fat diet consumption restricted to adolescence has minimal effects on adult executive function that vary by sex

ABSTRACT Early life environment can have a lasting effect on brain development and behavior. Diet is a potent environmental factor that can positively or negatively affect neurodevelopment, and unfortunately, the likelihood of a poor diet is high during adolescence. Adverse effects of adolescent high fat diet have been observed on reward-related behaviors, reversal learning, and hippocampal-dependent learning tasks in rodents when tested in adulthood. The prefrontal cortex (PFC) continues to develop throughout adolescence and is thus vulnerable to environmental insults such as poor diet. Therefore, we sought to examine the effects of a high fat diet (HFD) consumed only during adolescence on later life adult PFC-dependent executive function. Male and female mice were fed a HFD (60% energy from fat) during either early or late adolescence then switched to standard chow and tested in a battery of touchscreen-based operant tests of executive function in adulthood. Contrary to our prediction of an adverse effect of HFD, there was no effect of adolescent HFD in males, and females showed faster learning and decreased inattention in adulthood. We conclude that the effects of adolescent-limited HFD on adult executive function are mild, positive, and vary by sex.

Glutamatergic input from the insula to the ventral bed nucleus of the stria terminalis controls reward-related behavior.

Individuals suffering from substance use disorder often experience relapse events that are attributed to drug craving. Insular cortex (IC) function is implicated in processing drug-predictive cues and is thought to be a critical substrate for drug craving, but the downstream neural circuit effectors of the IC that mediate reward processing are poorly described. Here, we uncover the functional connectivity of an IC projection to the ventral bed nucleus of the stria terminalis (vBNST), a portion of the extended amygdala that has been previously shown to modulate dopaminergic activity within the ventral tegmental area (VTA), and investigate the role of this pathway in reward-related behaviors. We utilized ex vivo slice electrophysiology and in vivo optogenetics to examine the functional connectivity of the IC-vBNST projection and bidirectionally control IC-vBNST terminals in various reward-related behavioral paradigms. We hypothesized that the IC recruits mesolimbic dopamine signaling by activating VTA-projecting, vBNST neurons. Using slice electrophysiology, we found that the IC sends a glutamatergic projection onto vBNST-VTA neurons. Photoactivation of IC-vBNST terminals was sufficient to reinforce behavior in a dopamine-dependent manner. Moreover, silencing the IC-vBNST projection was aversive and resulted in anxiety-like behavior without affecting food consumption. This work provides a potential mechanism by which the IC processes exteroceptive triggers that are predictive of reward.

Diet containing stearic acid increases food reward-related behaviors in mice compared with oleic acid

Obesity is currently a worldwide phenomenon. The consumption of calorie-rich foods is responsible for most obesity cases, but not all humans exposed to high-calorie diets develop obesity. According to recent studies, exposure to fat-rich diets may be the actual cause of obesity. Dietary long-chain fatty acids affect brain function and are linked to food intake and motivation-related behaviors. Recently, many studies have shown that different types of fatty acids play different roles in animals. In our study, the effects of stearic acid (a saturated fatty acid) and oleic acid (a monounsaturated fatty acid) in diets on hedonic feeding behaviors were investigated, and changes of feeding-related protein levels in the brain were detected to explore the possible mechanism underlying the effects of these fatty acids. As a result, mice fed a diet containing stearic acid, compared to a diet containing oleic acid, exhibited increased food intake, hedonic eating, and an operant response to sucrose and locomotor activity. Furthermore, stearic acid corresponded to a higher level of leptin in serum than oleic acid. In addition, the stearic acid treated group had lower protein levels of p-JAK2 and p-STAT3 in the VTA and a higher dopamine concentration in the NAc than the oleic acid-treated group. Meanwhile, the protein level of TH in the NAc was higher and the protein level of the DA transporter in the VTA was lower in the stearic acid-fed group than in the oleic acid-fed group. In conclusion, these findings indicated that a diet containing stearic acid can increase hedonic feeding behavior and affect mesolimbic dopamine system signals in mice. Moreover, the lowering of serum leptin and leptin signaling in the VTA may contribute to this effect.

Chemical stimulation of the lateral hypothalamus induced seeking behaviors in rats: Involvement of orexin receptors in the ventral tegmental area

Orexinergic projections originated from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) play essential role in reward-related behaviors. Our previous studies show that intra-LH injection of carbachol, as a cholinergic agonist, induces conditioned place preference (CPP) in rats. This study aimed to determine whether chemical stimulation of the LH alone can induce reinstatement or not, and whether intra-VTA orexin receptors are involved in the reinstatement of intra-LH carbachol-induced CPP in the rats. The animals were unilaterally treated by carbachol (250 nM) in the LH during 3-day conditioning phase. Then, they underwent an extinction phase without receiving carbachol, and on the reinstatement day, animals received a different priming dose of carbachol in the separate groups. Extinguished animals unilaterally received intra-VTA administration of SB334867 or TCS OX2 29 as orexin-1 or orexin-2 receptor antagonists to evaluate the role of orexin receptors before effective priming dose of carbachol on the reinstatement day. Findings showed that intra-LH microinjection of a priming dose of carbachol (25 and 50 nM) induced the reinstatement of LH chemical stimulation-induced CPP. Moreover, it was indicated that, intra-VTA administration of either SB334867 or TCS OX2 29 (10 and 30 nM) before to intra-LH injection of the priming dose of carbachol (50 nM) dose-dependently inhibited the reinstatement of intra-LH carbachol-induced CPP. Also, the orexin-2 receptor antagonist was a little more effective than orexin-1 receptor antagonist for inhibiting the reinstatement of LH chemical stimulation-induced CPP. The consequences propose that both orexin receptors in the VTA play roles in the reinstatement of intra-LH carbachol-induced CPP.

A role for neurogenesis in probabilistic reward learning.

Rewards are often unreliable and optimal choice requires behavioral flexibility and learning about the probabilistic nature of uncertain rewards. Probabilistic learning occurs over multiple trials, often without conscious knowledge, and is traditionally associated with striatal function. While the hippocampus is classically recognized for its role in memory for individual experiences, recent work indicates that it is also involved in probabilistic forms of learning but little is known about the features that support such learning. We hypothesized that adult neurogenesis may be involved, because adult-born neurons contribute to both learning and reward-related behaviors. To test this, we used an appetitive probabilistic reversal learning task where a correct lever is rewarded with 80% probability and an incorrect lever is rewarded with 20% probability. Behavioral flexibility was assessed by switching correct-incorrect lever identities after 8 consecutive correct choices. Transgenic male rats that lacked adult neurogenesis displayed an initial deficit in discriminating the correct and incorrect levers, but they were not impaired at reversing behavior when the reward contingencies switched. When reward was withheld after a correct lever choice, neurogenesis-deficient rats were more likely to choose the incorrect lever on the subsequent trial. Also, rats with intact neurogenesis were more sensitive to reward at the incorrect lever. Differences were not observed in control transgenic rats that had intact neurogenesis. These results identify a novel role for neurogenesis in learning about uncertain, probabilistic rewards. Altered sensitivity to reward and negative feedback furthermore implicates neurogenesis in cognitive phenotypes associated with mood disorders such as depression. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The role of dopamine in reward-related behavior: shining new light on an old debate.

The role dopamine plays in reward-related behaviors has been debated for decades. Heymann et al. (Heymann G, Jo YS, Reichard KL, McFarland N, Chavkin C, Palmiter RD, Soden ME, Zweifel LS. Neuron 105: 909-920, 2020) identify subpopulations of dopamine-producing neurons that separately mediate reward association and motivation. Their results help demonstrate that dopamine signaling may partake in both reinforcement learning and incentive salience functions, instantiated by neuropeptide-defined subpopulations of the ventral tegmental area with different projection targets.

Reward Contributions to Serotonergic Functions.

The brain serotonin systems participate in numerous aspects of reward processing, although it remains elusive how exactly serotonin signals regulate neural computation and reward-related behavior. The application of optogenetics and imaging techniques during the last decade has provided many insights. Here, we review recent progress on the organization and physiology of the dorsal raphe serotonin neurons and the relationships between their activity and behavioral functions in the context of reward processing. We also discuss several interesting theories on serotonin's function and how these theories may be reconciled by the possibility that serotonin, acting in synergy with coreleased glutamate, tracks and calculates the so-called beneficialness of the current state to guide an animal's behavior in dynamic environments.

Differential Roles of Intra-accumbal Orexin Receptors in Acquisition and Expression of Methamphetamine-Induced Conditioned Place Preference in the Rats.

A large amount of document has revealed that the orexin system in the reward circuity, including the nucleus accumbens (NAc), contributes to the modification of drug reinforcement. It has proven that the orexin receptors (OXRs) are expressed on dopamine terminals in the NAc; therefore, it can modulate reward-related behaviors. In the present study, the conditioned place preference (CPP) paradigm was used to evaluate the role of OXRs in the NAc in the acquisition and expression of methamphetamine (METH)-induced CPP. Based on previous studies, animals received METH (1mg/kg; sc) on a 5-day schedule to induce CPP. The rats bilaterally received SB334867, OX1R antagonist, or TCS OX2 29, OX2R antagonist, (1, 10, and 30nM/0.5µl DMSO 12%) over five days of conditioning by METH to display the role of OXRs in reward acquisition. Moreover, the rats bilaterally received SB334867 or TCS OX2 29 in the NAc before the post-conditioning test to consider the impact of OXR antagonists on the expression of METH-induced CPP. The data revealed that the administration of SB334867 or TCS OX2 29 in the NAc led to a decrease in the acquisition of METH-induced CPP. Additionally, intra-accumbal injection of OX1R antagonist inhibited the expression of METH-induced CPP, while the OX2R antagonist failed to change this expression. Finally, the intra-NAc microinjection of both OXR antagonists was more effective in inhibiting acquisition than blocking the expression phase of METH. Data from the current study confirms that OXRs in the NAc regulate the reward-related effects of METH.

A novel method to study reward-context associations and drug-seeking behaviors

Animal models have significantly contributed to the understanding of reward-related behaviors, such as in Substance Use Disorder research. One of the most heavily utilized paradigms to date is conditioned place preference (CPP). However, CPP is limited by non-contingent exposure.Our new method advances this classic method by utilizing its benefits and simultaneously diminishing its limitations. We used a traditional 3-compartment CPP apparatus, where each chamber differs by both visual and tactile contexts. We restructured the apparatus allowing for insertion of bottles so that mice could orally self-administer sucrose or morphine-containing solutions in a specific context.Our results show that mice who self-administer sucrose or morphine show a place preference for the sucrose- or morphine-paired chamber. This place preference lasts for 21 d in sucrose-treated, but not morphine-treated mice. Additionally, we found that that mice will drink more water in the morphine-paired context during extinction tests.This model combines the distinct contextual cues associated with conditioned place preference and combines them with voluntary self-administration, thus enabling researchers to measure behavior using a model that incorporates spatial memory involved in affective states, while also providing a quantifiable readout of context/environment-specific drug seeking.In conclusion, we combined CPP and voluntary intake to establish a novel technique to assess not only preference for a context associated with rewarding stimuli (natural or drug), but also seeking, retention, and locomotor activity. This model can be further utilized to examine other drugs of abuse, extinction training, other learning models, or to allow for the assessment of neurobiological manipulations.