Place Preference Task Research Articles

Differential functions of the dorsal and intermediate regions of the hippocampus for optimal goal-directed navigation in VR space

Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich virtual reality environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.

Differential functions of the dorsal and intermediate regions of the hippocampus for optimal goal-directed navigation in VR space.

Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich virtual reality environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.

Generation and Characterization of a Novel Prkcd-Cre Rat Model.

Activity of central amygdala (CeA) PKCδ expressing neurons has been linked to appetite regulation, anxiety-like behaviors, pain sensitivity, and addiction-related behaviors. Studies of the role that CeA PKCδ+ neurons play in these behaviors have largely been carried out in mice, and genetic tools that would allow selective manipulation of PKCδ+ cells in rats have been lacking. Here, we used a CRISPR/Cas9 strategy to generate a transgenic Prkcd-cre knock-in rat and characterized this model using anatomical, electrophysiological, and behavioral approaches in both sexes. In the CeA, Cre was selectively expressed in PKCδ+ cells. Anterograde projections of PKCδ+ neurons to cortical regions, subcortical regions, several hypothalamic nuclei, the amygdala complex, and midbrain dopaminergic regions were largely consistent with published mouse data. In a behavioral screen, we found no differences between Cre+ rats and Cre- wild-type littermates. Optogenetic stimulation of CeA PKCδ+ neurons in a palatable food intake assay resulted in an increased latency to first feeding and decreased total food intake, once again replicating published mouse findings. Lastly, using a real-time place preference task, we found that stimulation of PKCδ+ neurons promoted aversion, without affecting locomotor activity. Collectively, these findings establish the novel Prkcd-Cre rat line as a valuable tool that complements available mouse lines for investigating the functional role of PKCδ+ neurons.

Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

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.

Molecular insights from the crab Neohelice memory model.

Memory acquisition, formation and maintenance depend on synaptic post-translational machinery and regulation of gene expression triggered by several transduction pathways. In turns, these processes lead to stabilization of synaptic modifications in neurons in the activated circuits. In order to study the molecular mechanisms involved in acquisition and memory, we have taken advantage of the context-signal associative learning and, more recently, the place preference task, of the crab Neohelice granulata. In this model organism, we studied several molecular processes, including activation of extracellular signal-regulated kinase (ERK) and the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) transcription factor, involvement of synaptic proteins such as NMDA receptors and neuroepigenetic regulation of gene expression. All these studies allowed description of key plasticity mechanisms involved in memory, including consolidation, reconsolidation and extinction. This article is aimed at review the most salient findings obtained over decades of research in this memory model.

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.

Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association.

Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain's reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders. We sought to determine how cell type-specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1fl/fl mice and striatal output pathway cre lines (Drd1a -cre; D1, Adora2a -cre; A2a) to generate cell type-specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays. Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task. This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.

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.

Infralimbic Cortex Biases Preference Decision Making for Offspring over Competing Cocaine-Associated Stimuli in New Mother Rats.

In the context of drug abuse, converging evidence suggests that cocaine use in new mothers is significantly reduced by the competing motivation related to child rearing. Given the demonstrated importance of the medial prefrontal cortex (mPFC) in decision-making processes, we investigated the contribution of distinct regions of the mPFC [anterior cingulate (Cg1), prelimbic (PrL), infralimbic (IL)] to decision making in new mother rats performing a concurrent pup/cocaine choice conditioned place preference (CPP) task. When given a choice, inactivation of IL cortex significantly biased decision making of mother rats toward cocaine-associated cues, highly contrasting the distribution of preferences by control groups. In contrast, inactivation of PrL cortex had the opposite effect, significantly increasing offspring bias in the decision making, such that none of the mothers chose the cocaine-associated alternative. Cg1 inactivation was without effect. Functional inactivation of these same mPFC subregions had no effect in a non-conflict CPP task in which context-induced cocaine or pup seeking were examined separately. Notably, inactivation of the IL cortex also interfered with maternal behavior. Taken together, we have identified a specific role of the IL cortex in the prioritization of offspring over drug competing alternatives, thus promoting resistance to drug use in new mothers.

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.

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.

Extinction to amphetamine-associated context in female rats is dependent upon conditioned orienting.

Females are considered more susceptible to the reinforcing effects of drugs and subsequently at increased risk for drug abuse and relapse after treatment. Estrogen is known to facilitate drug effects in females. However, other factors which contribute to the incidence of drug abuse are important to identify in order to recognize early risk factors and develop effective prevention and treatment schemes. Cue-directed behavior (aka sign tracking) has been implicated as a behavioral phenotype which identifies populations susceptible to drug abuse, partly due to its association with impulsivity and heightened dopamine function. In this study, we investigate the viability of conditioned orienting (a form of cue-directed behavior) as a potential phenotype which predicts drug proclivity in female rats. In addition, we examine any influence endogenous female hormones across the estrous cycle may have on conditioned orienting and drug proclivity. Utilizing an amphetamine-conditioned place preference task, results suggest that the orienting phenotype is an effective predictor of drug proclivity in females. Rats exhibiting enhanced orienting behavior show more robust preference for an amphetamine-associated context and are more resistant to extinction of this preference than nonorienting counterparts. Furthermore, both conditioned orienting behavior and conditioned place preference are minimally influenced by the estrous cycle.

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.