Conditioned Place Preference Task Research Articles

The role of lateral habenula NMDA receptors in tramadol-induced conditioning.

The role of the lateral habenula (LHb) as a hub for receiving and relaying signals from the limbic system to serotonergic, dopaminergic, and norepinephrinergic regions in the brainstem makes this area a critical region in the control of reward and addiction. Behavioral evidence reveals the vital role of the LHb in negative symptoms during withdrawal. In this investigation, we study the role of the LHb N-Methyl D-Aspartate receptor (NMDAR) in the modulation of tramadol reward. Male adult Wistar rats were used in this study. The effect of intra-LHb micro-injection of NMDAR agonist (NMDA, 0.1, 0.5, 2 µg/rat) and antagonist (D-AP5, 0.1, 0.5, 1 µg/rat) was evaluated in conditioned place preference (CPP) paradigm. The obtained results showed that intra-LHb administration of NMDA induced place aversion dose-dependently, while blockade of NMDAR in the LHb using D-AP5 micro-injection led to an increased preference score in the CPP task. Co-administration of NMDA (0.5 µg/rat) with tramadol (4 mg/kg) reduced preference score, while co-administration of D-AP5 (0.5 µg/rat) with a non-effective dose of tramadol (1 mg/kg) potentiate the rewarding effect of tramadol. LHb receives inputs from the limbic system and projects to the monoaminergic nuclei in the brainstem. It has been declared that NMDAR is expressed in LHb, and as obtained data revealed, these receptors could modulate the rewarding effect of tramadol. Therefore, NMDA receptors in the LHb might be a new target for modulating tramadol abuse.

Changes in social, sexual, and hedonic behaviors in rats in response to stress and restoration by a negative allosteric modulator of α5-subunit containing GABA receptor

Major depressive disorder (MDD) is a debilitating and costly human condition. Treatment for MDD relies heavily on the use of antidepressants that are slow to produce mood-related changes and are not effective in all patients, such as selective serotonin reuptake inhibitors (SSRIs). Several novel compounds, including negative allosteric modulators of GABA-A receptors containing the α5-subunit (GABA-NAMs), are under investigation for potential fast acting therapeutic use in MDD. Preclinical evidence that these compounds produce a rapid antidepressant-like response comes primarily from simple tests of escape behavior and preference for rewarding stimuli after chronic stress. To increase the ethological relevance of these compounds, we tested the hypothesis that the GABA-NAM, L-655,708, would produce an antidepressant-like response in more complex stress-sensitive social and sex behaviors, which are of relevance to the symptoms of human depression. In male rats subjected to chronic restraint stress, injection of L-655,708 increased reward in a sexual conditioned place preference task, increased male sexual activity with a receptive female, and re-established male social dominance hierarchies within 24 h. We also report increased sucrose preference in the social defeat stress (SDS) model of depression following GABA-NAM administration, demonstrating that its antidepressant-like actions are independent of the type of chronic stress administered. This work extends the impact of GABA-NAMs beyond traditional tests of anhedonia and further supports the development of alpha5 subunit-selective GABA-NAMs as a potential fast-acting therapeutic approach for treating human MDD.

β-caryophyllene, a cannabinoid receptor 2 agonist, decreases the motivational salience and conditioning place preference for palatable food in female mice.

β-caryophyllene (BCP) is a cannabinoid receptor CB2 agonist plant-derived terpenoid found in different essential oil plants, including rosemary, black pepper, copaiba and cannabis. It has GRAS (generally recognized as safe) status and is approved by the FDA (Food and Drug Administration) for food use. BCP displays agonist activity on the CB2 receptor and is a potential therapeutic target in several neuropsychiatric disorders, including anxiety and drug addiction. Unlike CB1 receptors, activation of the CB2 receptors is devoid of psychotomimetic and addictive properties. In this regard, this study aimed to evaluate the effects of BCP on incentive salience ("wanting") performance and motivational properties elicited by sweetened palatable foods in female Swiss mice. After 9days of training for incentive salience performance for a sweet reward (hazelnut cream with chocolate), food-restricted mice received a systemic injection of BCP (50 and 100 mg/kg) before testing over 3days. Moreover, independent groups of female mice were tested on sweet reward-induced conditioned place preference (CPP) for 22 consecutive days. To evaluate BCP effects on the expression of seeking behaviour for sweetened food, mice received a single intraperitoneal injection of BCP (50 mg/kg) 30min before testing on the CPP task. BCP significantly decreased the incentive performance for a sweet reward compared with the control group in a CB2 receptor-dependent manner. Also, BCP suppressed the expression of sweet reward-CPP. Altogether, these preclinical data demonstrate the potential role of BCP in treating disorders associated with food addiction-like behaviour.

Evaluation of drug seeking behavior on nicotine conditioned place preference in zebrafish

Seeking of drugs is commonly evaluated in a specific environment for assessing drug preference. However, cognitive strategies involved in drug seeking are mostly unknown. To assess the strength of environmental cues that can be associated with nicotine in the zebrafish brain reward circuitry, we have designed herein a modified conditioned place preference (CPP) paradigm. This task was devised to identify salient environmental cues relevant for strong nicotine–environment association and drug seeking induction. During test sessions, background colors of the CPP tank chambers were shifted and preference for colors associated to nicotine was assessed. We have compared several tank designs and different compartment colors. Our findings indicated that zebrafish seeking behavior was strongly dependent on compartment color shades. Combination of red and yellow environments, which were preferred and avoided compartments, respectively, was the most effective design presenting the highest CPP-score. Interestingly, animals that stayed for longer periods in the environment conditioned to nicotine during a first testing interval were also able to follow the background color shade conditioned to nicotine to the other compartment immediately after background colors were relocated between compartments. During a second testing period, zebrafish also stayed for longer periods in the colored compartment paired to nicotine during conditioning. These findings suggest that under salient environmental conditions, zebrafish voluntarily followed a shifting visual cue previously associated with nicotine delivery. Furthermore, our findings indicate that zebrafish exhibit spatial associative learning and memory, which generates a repertoire of conspicuous locomotor behaviors induced by nicotine preference in the CPP task.

Post-training intra-basolateral complex of the amygdala infusions of clenbuterol enhance memory for conditioned place preference and increase ARC protein expression in dorsal hippocampal synaptic fractions

The basolateral complex of the amygdala (BLA) is critically involved in modulation of memory by stress hormones. Noradrenergic activation of the BLA enhances memory consolidation and plays a necessary role in the enhancing or impairing effects of stress hormones on memory. The BLA is not only involved in the consolidation of aversive memories but can regulate appetitive memory formation as well. Extensive evidence suggests that the BLA is a modulatory structure that influences consolidation of arousing memories through modulation of plasticity and expression of plasticity-related genes, such as the activity regulated cytoskeletal-associated (Arc/Arg 3.1) protein, in efferent brain regions. ARC is an immediate early gene whose mRNA is localized to the dendrites and is necessary for hippocampus-dependent long-term potentiation and long-term memory formation. Post-training intra-BLA infusions of the β-adrenoceptor agonist, clenbuterol, enhances memory for an aversive task and increases dorsal hippocampus ARC protein expression following training on that task. To examine whether this function of BLA noradrenergic signaling extends to the consolidation of appetitive memories, the present studies test the effect of post-training intra-BLA infusions of clenbuterol on memory for the appetitive conditioned place preference (CPP) task and for effects on ARC protein expression in hippocampal synapses. Additionally, the necessity of increased hippocampal ARC protein expression was also examined for long-term memory formation of the CPP task. Immediate post-training intra-BLA infusions of clenbuterol (4 ng/0.2 µL) significantly enhanced memory for the CPP task. This same memory enhancing treatment significantly increased ARC protein expression in dorsal, but not ventral, hippocampal synaptic fractions. Furthermore, immediate post-training intra-dorsal hippocampal infusions of Arc antisense oligodeoxynucleotides (ODNs), which reduce ARC protein expression, prevented long-term memory formation for the CPP task. These results suggest that noradrenergic activity in the BLA influences long-term memory for aversive and appetitive events in a similar manner and the role of the BLA is conserved across classes of memory. It also suggests that the influence of the BLA on hippocampal ARC protein expression and the role of hippocampal ARC protein expression are conserved across classes of emotionally arousing memories.

Learning a non-neutral conditioned stimulus: place preference in the crab Neohelice granulata.

In the wild, being able to recognize and remember specific locations related to food sources and the associated attributes of landmarks is a cognitive trait important for survival. In the present work, we show that the crab Neohelice granulata can be trained to associate a specific environment with an appetitive reward in a conditioned place preference task. After a single training trial, when the crabs were presented with a food pellet in the target quadrant of the training arena, they were able to form a long-term memory related to the event. This memory was evident at least 24 h after training and was protein synthesis dependent. Importantly, the target area of the arena proved to be a non-neutral environment, given that animals initially avoided the target quadrant. In the present work, we introduce for the first time an associative one-trial memory paradigm including a conditioned stimulus with a clear valence performed in a crustacean.

Comparison and interaction of morphine and CB1 agonist conditioned place preference in the rat model of early life stress.

Early life stress (ELS) disrupts brain development and subsequently affects physical and psychological health. ELS has been associated with an increased risk of relapse and inadequate treatment response in addicted patients. The current study was designed to find the effect of ELS on the rewarding effect of morphine and cannabinoid and their interaction. Pregnant female Wistar rats were used in this study. On postnatal day 2 (PND2), pups were separated from their mothers for 3hr daily. This procedure was repeated every day at the same time until PND 14. The control group was kept in the standard nesting way with their mothers. The adult male offspring of maternal separated (MS) and standard nested (SN) rats were used. Using conditioned place preference task (CPP), the rewarding effect of morphine (0.75, 1.25, 2.5, and 5mg/kg) was evaluated in both MS and SN groups. Besides, the rewarding effect of cannabinoids was investigated using the administration of CB1 receptor agonist (ACPA, 0.25, 0.5, 1µg/rat) and inverse agonist (AM-251, 30, 60, and 90ng/rat) in the nucleus accumbens (NAc). To evaluate the interaction between NAc cannabinoidergic system and morphine, the noneffective dose of ACPA and AM-251 were administered with a noneffective dose of morphine (0.75mg/kg) on both MS and SN animals. Obtained results indicated that MS groups had a leftward shift in the rewarding effect of morphine and conditioned with low doses of morphine. However, they had a rightward shift in the rewarding effect of cannabinoids. In addition, coadministration of noneffective doses of morphine and ACPA potentiate conditioning in both MS and SN groups. Previous evidence shows that ELS induced changes in the brain, especially in the reward circuits. Here, we demonstrated that MS animals are more sensitive to the rewarding effect of morphine compared with SN animals. In addition, ELS disrupts the cannabinoid system and affect the rewarding effect of cannabinoids.

Astrocyte modulation of extinction impairments in ethanol-dependent female mice

Rates of alcohol use disorders are increasing in women, and there is growing evidence that both the cognitive and biological consequences of alcohol dependence are distinct in women as compared to men. Despite this, the neurobehavioral outcomes of chronic alcohol exposure are poorly characterized in women and female animals. In this study, we find that ethanol dependence impaired extinction of reward seeking in a food conditioned place preference task in female mice. At the same time point, ethanol-dependent females exhibited astrocytic dysregulation as indicated by a brain region-specific reduction in glial fibrillary acidic protein (GFAP) expression. Using a chemogenetic strategy, we demonstrate that modulating astrocyte function via chemogenetic activation of Gq-signaling in nucleus accumbens astrocytes transiently rescued extinction in ethanol-dependent females without impacting basal reward seeking. These findings identify astrocyte function as a potential target for the restoration of behavioral flexibility following chronic alcohol exposure in females.

ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors.

Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular dopamine (DA) levels. Here, we report that extracellular steady-state levels of DA are reduced in the medial prefrontal cortex (mPFC; −65%), hippocampus (−53%) and nucleus accumbens (NAc; −35%), but are elevated in the dorsal striatum (+25%) of ErbB4 knock-out mice (ErbB4 KOs) relative to wild-type controls. This pattern of DA imbalance recapitulates the reported prefrontal cortical reduction and striatal increase of DA levels in schizophrenia patients. Next, we report on a battery of behavioral tasks used to evaluate locomotor, cognitive and motivational behaviors in ErbB4 KOs relative to controls. We found that ErbB4 KOs are hyperactive in a novel open field but not in their familiar home cage, are more sensitive to amphetamine, perform poorly in the T-maze and novel object recognition (NOR) tasks, exhibit reduced spatial learning and memory on the Barnes maze, and perform markedly worse in conditioned place preference (CPP) tasks when associating cued-reward palatable food with location. However, we found that the poor performance of ErbB4 KOs in CPP are likely due to deficits in spatial memory, instead of reward seeking, as ErbB4 KOs are more motivated to work for palatable food rewards. Our findings indicate that ErbB4 signaling affects tonic DA levels and modulates a wide array of behavioral deficits relevant to psychiatric disorders, including schizophrenia.

Examining Cocaine Conditioning Place Preference in Mice.

A key component of combating substance use disorders is understanding the neural mechanisms that support drug reward. Tasks such as self-administration assess the reinforcing properties of a drug using a learned behavior but require numerous training sessions and surgery. In comparison, the conditioned place preference (CPP) task assesses reward with little training, without costly surgeries, and confounds that accompany the use of anesthesia or pain-relieving drugs. The CPP task contains three phases: pretest, conditioning, and posttest. During the pretest, mice are allowed to explore a three-compartment apparatus. The two outer compartments contain unique olfactory, tactile, and visual cues whereas the middle compartment is used as an entrance and exit for the mice on test days. During conditioning, mice receive cocaine before being confined to one of the outer compartments. The following day, mice are given saline then confined to the other outer compartment. These pairings are then repeated once. At posttest, mice are permitted to freely explore all compartments in a drug-free state while the time spent in each compartment is recorded. A CPP score is calculated for both the pretest and posttest by comparing the time spent in the cocaine-paired and saline-paired compartments. Enhancements in the CPP score from the pretest to the posttest serve as a measure of the rewarding property of the cocaine. This task offers several notable advantages: 1) the simultaneous recording of locomotor activity and reward, which may utilize different neural mechanisms, 2) the three-compartment CPP setup removes the bias that can be observed in a two-compartment design, and 3) use of multimodal cues support the acquisition of a robust preference in a variety of mouse strains.

Pharmacological mechanisms of alcohol analgesic-like properties in mouse models of acute and chronic pain

Alcohol use and chronic pain are highly comorbid. Acute alcohol use typically produces an analgesic effect. However, chronic use can worsen the progression of chronic pain. In rodent models, acute models of pain have primarily been used to investigate the relationship between alcohol and pain analgesia. Here, we use two models of chronic pain, chronic inflammatory and peripheral neuropathic pain, to investigate acute alcohol's antinociceptive and analgesic properties. We hypothesize that acute ethanol is acting through opioid receptors to create an analgesic-like effect in both reflexive and affective dimensions of pain.Using male and female C57BL/6J mice, oral ethanol administration (0–1.25 g/kg) showed a dose-dependent reversal of mechanical hypersensitivity in both Complete Freund's Adjuvant (CFA) and chronic constriction injury (CCI) models of chronic inflammatory and neuropathic pain. No sex differences were observed. Using the conditioned place preference (CPP) task to assess the subjective responses to ethanol's anti-nociceptive properties, CCI-injured animals showed a preference for the ethanol-paired side, suggesting a reduction in an aversive and pain-like state produced by nerve injury. These effects are likely mediated through the kappa and possibly the mu opioid systems, since ethanol-induced anti-nociception following CCI was fully reversed by pretreatment with the kappa selective antagonist, nor-BNI, or high doses of naltrexone. These data show that ethanol possesses analgesic-like properties in chronic inflammatory and neuropathic pain models in mice and provide new insight into ethanol as it relates to chronic pain.

The presence of a social stimulus reduces cocaine-seeking in a place preference conditioning paradigm.

One challenge in the treatment of substance use disorders is to re-engage the interest toward non-drug-related activities. Among these activities, social interaction has had a prominent role due to its positive influence on treatment outcome. Our aim was to study whether the presence of a social stimulus during the cocaine-induced conditioned place preference test was able to reduce the time spent in the drug-paired compartment. For that purpose, mice were trained for four days on a conditioned place preference task with one compartment paired with cocaine and the opposite with saline. On the test day, we introduced an unfamiliar juvenile male mouse into the saline-conditioned compartment (inside a pencil cup) to analyse the animal preference towards the two rewarding stimuli (cocaine vs mouse). Additionally, to discard the possible effect of novelty, as well as the housing condition (social isolation) on social preference, we decided to include a novel object during the test session, as well as perform the same conditioned place preference protocol with a group of animals in social housing conditions. The social stimulus was able to reduce the preference for cocaine and enhance the active interaction with the juvenile mouse (sniffing) compared to the empty pencil cup paired with the drug. The introduction of a novel object during the test session did not reduce the preference for the cocaine-paired compartment, and interestingly, the preference for the social stimulus was independent of the housing condition. c-Fos immunohistochemistry revealed a different pattern of activation based on cocaine-paired conditioning or the presence of social stimulus. These results suggest that social interaction could constitute a valuable component in the treatment of substance use disorders by reducing the salience of the drug.

Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats.

Vagus nerve stimulation (VNS) enhances extinction of conditioned fear in rats. Previous findings support the hypothesis that VNS effects on extinction are due to enhanced consolidation of extinction memories through promotion of plasticity in extinction-related brain pathways however, alternative explanations are plausible. According to one hypothesis, VNS may produce a hedonic effect and enhance extinction through counter-conditioning. According to another hypothesis, VNS reduces anxiety during exposure and this weakens the association of conditioned stimuli with aversive conditioned responses. The present set of experiments (1) used conditioned place preference (CPP) to identify potential rewarding effects associated with VNS and (2) examined the peripheral effects of VNS on anxiety and extinction enhancement. Male Sprague–Dawley rats were surgically implanted with cuff electrodes around the vagus nerve and subjected to a CPP task in which VNS and sham stimulation were each paired with one of two distinct contexts over the course of 5 d. Following this procedure, rats did not show a place preference, suggesting that VNS is not rewarding or aversive. The role of the peripheral parasympathetic system in the anxiolytic effect of VNS on the elevated plus maze was examined by blocking peripheral muscarinic receptors with intraperitoneal administration of methyl scopolamine prior to VNS. Methyl scopolamine blocked the VNS-induced reduction in anxiety but did not interfere with VNS enhancement of extinction of conditioned fear, indicating that the anxiety-reducing effect of VNS is not necessary for the extinction enhancement.

Crucial Role of Dopamine D2 Receptor Signaling in Nicotine-Induced Conditioned Place Preference.

Nicotine in tobacco causes psychological dependence through its rewarding effect in the central nervous system (CNS). Although nicotine dependence is explained by dopamine receptor (DR) signaling together with nicotinic acetylcholine receptors (nAChRs), the synaptic molecular mechanism underlying the interaction between dopamine receptor and nAChRs remains unclear. Since reward signaling is mediated by dopamine receptors, we hypothesized that the dopamine D2 receptor (D2R), in part, mediates the synaptic modulation of nicotine-induced conditioned place preference (CPP) in addition to dopamine D1 receptor. To investigate the involvement of D2R, wild-type (WT) and dopamine D2 receptor knockout (D2RKO) mice were assessed using the CPP task after induction of nicotine-induced CPP. As expected, D2RKO mice failed to induce CPP behaviors after repeated nicotine administration (0.5mg/kg). When kinase signaling was assessed in the nucleus accumbens and hippocampal CA1 region after repeated nicotine administration, both Ca2+/calmodulin-dependent protein kinase (CaMKII) and extracellular signal-regulated kinase (ERK) were upregulated in WT mice but not in D2RKO mice. Likewise, nicotine-induced CPP was associated with elevation of pro- brain-derived neurotropic factor (BDNF) and BDNF protein levels in WT mice, but not in D2RKO mice. Taken together, in addition to dopamine D1 receptor signaling, dopamine D2 receptor signaling is critical for induction of nicotine-induced CPP in mice.

Impaired innate and conditioned social behavior in adult C57Bl6/J mice prenatally exposed to chlorpyrifos

BackgroundSigns of pervasive developmental disorder and social deficits were reported in toddlers and children whose mothers were exposed to organophosphate pesticides during pregnancy. Deficits in social preference were reported in adult male mice exposed to chlorpyrifos on gestational days 12–15. This study aimed (a) to test the hypothesis that adult female and male mice that were exposed prenatally to subtoxic doses of chlorpyrifos would be impaired in social behavior and (b) to determine if prenatal chlorpyrifos altered the expression of transcripts for oxytocin in the hypothalamus. Pregnant mice were treated by gavage with corn oil vehicle or 2.5 mg/kg or 5 mg/kg of CPF on gestational days 12–15. Social preference, social and non-social conditioned place preference tasks were tested in adults. Expression of oxytocin transcripts in hypothalamus was measured by qPCR.ResultsChlorpyrifos (5 mg/kg on GD 12–15) reduced the innate preference for a conspecific in a dose and sex dependent manner. Adult males exposed prenatally to 5 mg/kg CPF showed a reduction in social preference. Socially conditioned place preference was impaired in offspring of dams treated with either dose of CPF. Non-social appetitive place conditioning was impaired in offspring of dams exposed to 2.5 mg/kg, but not to 5 mg/kg chlorpyrifos. Prenatal chlorpyrifos treatment did not alter the expression of the oxytocin mRNA in the hypothalamus, although expression was significantly lower in females.ConclusionsPrenatal chlorpyrifos induced innate and learned social deficits and non-specific conditioning deficits in adult mice in a sex-dependent manner. Males showed specific social deficits following the higher dose whereas both males and females showed a more generalized conditioning deficit following the intermediate dose.

Behavioral validation of a wireless low-power neurostimulation technology in a conditioned place preference task

Objective. Neurostimulation technologies are important for studying neural circuits and the connections that underlie neurological and psychiatric disorders. However, current methods come with limitations such as the restraint on movement imposed by the wires delivering stimulation. The objective of this study was to assess whether the e-Particle (EP), a novel wireless neurostimulator, could sufficiently stimulate the brain to modify behavior without these limitations. Approach. Rats were implanted with the EP and a commercially available stimulating electrode. Animals received rewarding brain stimulation, and performance in a conditioned place preference (CPP) task was measured. To ensure stimulation-induced neuronal activation, immediate early gene c-fos expression was also measured. Main results. The EP was validated in a commonly used CPP task by demonstrating that (1) wireless stimulation via the EP induced preference behavior that was comparable to that induced by standard wired electrodes and (2) neuronal activation was observed in projection targets of the stimulation site. Significance. The EP may help achieve a better understanding of existing brain stimulation methods while overcoming their limitations. Validation of the EP in a behavioral model suggests that the benefits of this technology may extend to other areas of animal research and potentially to human clinical applications.

Adolescent THC exposure does not sensitize conditioned place preferences to subthreshold d-amphetamine in male and female rats.

The acute effects of marijuana consumption on brain physiology and behaviour are well documented, but the long-term effects of its chronic use are less well known. Chronic marijuana use during adolescence is of increased interest, given that the majority of individuals first use marijuana during this developmental stage , and adolescent marijuana use is thought to increase the susceptibility to abusing other drugs when exposed later in life. It is possible that marijuana use during critical periods in adolescence could lead to increased sensitivity to other drugs of abuse later on. To test this, we chronically administered ∆ 9-tetrahydrocannabinol (THC) to male and female Long-Evans (LER) and Wistar (WR) rats directly after puberty onset. Rats matured to postnatal day 90 before being exposed to a conditioned place preference task (CPP). A subthreshold dose of d-amphetamine, found not to induce place preference in drug naïve rats, was used as the unconditioned stimulus. The effect of d-amphetamine on neural activity was inferred by quantifying cfos expression in the nucleus accumbens and dorsal hippocampus following CPP training. Chronic exposure to THC post-puberty had no potentiating effect on a subthreshold dose of d-amphetamine to induce CPP. No differences in cfos expression were observed. These results show that chronic exposure to THC during puberty did not increase sensitivity to a sub-threshold dose of d-amphetamine in adult LER and WR rats. This supports the concept that THC may not sensitize the response to all drugs of abuse.

Adolescent THC exposure does not sensitize conditioned place preferences to subthreshold d-amphetamine in male and female rats

The acute effects of marijuana consumption on brain physiology and behaviour are well documented, but the long-term effects of its chronic use are less well known. Chronic marijuana use during adolescence is of increased interest, given that the majority of individuals first use marijuana during this developmental stage , and adolescent marijuana use is thought to increase the susceptibility to abusing other drugs when exposed later in life. It is possible that marijuana use during critical periods in adolescence could lead to increased sensitivity to other drugs of abuse later on. To test this, we chronically administered ∆ 9-tetrahydrocannabinol (THC) to male and female Long-Evans (LER) and Wistar (WR) rats directly after puberty onset. Rats matured to postnatal day 90 before being exposed to a conditioned place preference task (CPP). A subthreshold dose of d-amphetamine, found not to induce place preference in drug naïve rats, was used as the unconditioned stimulus. The effect of d-amphetamine on neural activity was inferred by quantifying cfos expression in the nucleus accumbens and dorsal hippocampus following CPP training. Chronic exposure to THC post-puberty had no potentiating effect on a subthreshold dose of d-amphetamine to induce CPP. No differences in cfos expression were observed. These results show that chronic exposure to THC during puberty did not increase sensitivity to a sub-threshold dose of d-amphetamine in adult LER and WR rats. This supports the concept that THC may not sensitize the response to all drugs of abuse.

Forebrain medial septum sustains experimental neuropathic pain

The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception. The effect of intraseptal muscimol on PH was comparable to that seen with microinjection of the local anesthetic, lidocaine, into rostral ventromedial medulla which is implicated in facilitating experimental chronic nociception. Cellular analysis in the CCI model showed that the MS region sustains nociceptive gain with CCI by facilitating basal nociceptive processing and the amplification of stimulus-evoked neural processing. Indeed, consistent with the idea that excitatory transmission through MS facilitates chronic experimental pain, intraseptal microinjection of antagonists acting at AMPA and NMDA glutamate receptors attenuated CCI-induced PH. We propose that the MS is a central monitor of bodily nociception which sustains molecular plasticity triggered by persistent noxious insult.

Intolerance of uncertainty and conditioned place preference in opioid addiction.

Several personality factors have been implicated in vulnerability to addiction by impacting learning and decision making. One such factor is intolerance of uncertainty (IU), the tendency to perceive uncertain situations negatively and avoid them. Conditioned place preference (CPP), which compares preference for contexts paired with reward, has been used to examine the motivation for both drug and non-drug rewards. However, preference for locations associated with non-drug reward, as well as the potential influence of IU, has not been thoroughly studied in individuals with addiction. In the current study, we examined CPP using a computer-based task in a sample of addicted individuals undergoing opioid maintenance treatment and never-addicted controls. Patients were confirmed to have higher IU than controls. In the CPP task, the two groups did not differ in overall time spent in the previously-rewarded context. However, controls were more likely than patients to immediately return to this context. Contrary to our predictions, IU was not a significant predictor of preference for the previously-rewarded context, although higher IU in controls was associated with a higher number of rewards obtained in the task. No such relationship was found in patients.