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Published in final edited form as: Biol Psychiatry. 2020 Jun 29;88(10):777–787. doi: 10.1016/j.biopsych.2020.06.020

Dysregulation of decision-making related to mGlu5, but not midbrain D3, receptor availability following cocaine self-administration in rats

Stephanie M Groman 1,*, Ansel T Hillmer 1,3,4, Liu Heather 3, Krista Fowles 4, Daniel Holden 4, Evan D Morris 3,4,5, Daeyeol Lee 6, Jane R Taylor 1,2,*
PMCID: PMC8935943  NIHMSID: NIHMS1608201  PMID: 32826065

Abstract

Background:

Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships between drug-induced alterations, cocaine taking and maladaptive decision-making processes, however, are difficult to establish in humans.

Methods:

We assessed decision making in adult, male rats using a probabilistic reversal learning (PRL) task and used positron emission tomography with the [11C]-(+)-PHNO and [18F]FPEB radioligands to quantify regional dopamine D2/3 receptors and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 d of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted.

Results:

We found that self-administration of cocaine, but not saline, disrupted behavior in the PRL task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D2/3 and, importantly, midbrain D3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating.

Conclusions:

These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

Keywords: decision-making, reinforcement learning, addiction, dopamine D3 receptor, metabotropic glutamate 5 receptor, cocaine

Introduction

The maladaptive decision making that has been observed in cocaine dependent individuals (1, 2) may be, in part, the consequence of drug-induced disruptions in the neurobiological mechanisms that guide choice behavior. Although the identity of these mechanisms remains unknown, studies using positron emission tomography (PET) in substance-dependent populations have observed disruptions in dopaminergic and glutamatergic receptors (3–10) within brain regions that are known to be critically involved in decision-making processes (11, 12). Drug-induced dysfunction in select dopaminergic and glutamatergic pathways may be the mechanism, therefore, by which inflexible choice behavior emerges in addicted individuals, leading to the manifestation of compulsive behaviors.

Previous studies have observed low levels of dopamine D2/3 and metabotropic glutamate 5 (mGlu5) receptor availability in cortico-striatal regions of stimulant-dependent humans (6, 7, 13) and some of these findings have been observed in non-human primates and rats chronically exposed to psychostimulants (14–16). Recent studies, however, have reported that midbrain D3 receptor availability is higher in stimulant-dependent individuals (8, 10, 17, 18), which has been linked to measures of behavioral impulsiveness and risky decision making in cocaine-dependent individuals (17). We have recently reported that individual differences in midbrain D3 receptor availability prior to any drug exposure actually can predict cocaine self-administration in rats (19), but whether exposure to drugs of abuse, alone, elevates midbrain D3 receptor availability is not known.

Our recent work has suggested that the decision-making processes that confer vulnerability for drug use differ from those that are disrupted by chronic exposure to drugs of abuse (20–22) and, importantly, these factors may be linked to distinct neurobiological mechanisms (12). For example, we have found that disruptions in positive outcome updating – that are linked to greater midbrain D3 receptor availability (23) – are predictive of greater cocaine and methamphetamine self-administration (20, 22), whereas negative-outcome updating is impaired following exposure to methamphetamine (21, 22). Moreover, these specific processes of outcome-updating for decision-making are associated with distinct brain circuits (12): negative-outcome updating is governed by cortical neurons projecting to the striatum that are likely glutamatergic. We hypothesized, therefore, that negative-outcome updating would be functionally linked to cortical mGlu5 receptor dysfunction following cocaine self-administration.

To test this hypothesis, we assessed decision making in adult, male rats using a probabilistic reversal-learning (PRL) task and quantified in vivo dopamine D2/3 and mGlu5 receptor availability with positron emission tomography (PET) before and after rats self-administered cocaine or saline in 6 h daily sessions for 21 days. Tests of motivation, reinstatement and incubation of craving were conducted. Previous studies have demonstrated that cue-induced craving increases during periods of withdrawal (24) which may be related to specific neural adaptations that occur during this time. We hypothesized that self-administration of cocaine would disrupt decision making in the PRL and regional mGlu5 receptor availability.

Methods and materials

Subjects

Adult, male Long Evans rats (N=60) were obtained from Charles River (Raleigh, NC) at approximately 6 weeks of age. Data examining the predictive relationship between decision-making phenotypes and drug use in a subset of these rats (N=50) has been previously published (20).

Probabilistic reversal learning (PRL) task

Decision making was assessed on a ‘three-armed bandit’ PRL task using stochastic reward schedules (Figure 1). Rats initiated trials by entering the magazine which led to the illumination of three noseport apertures located on the opposite panel. One of the apertures was associated with a higher probability of delivering reward than the other two apertures, which was pseudo-randomly assigned at the start of each session for individual rats. Rats could make a single choice on each trial by making a noseport entry into one of the three illuminated ports. After completing 120 trials (referred to as the Acquisition phase), the probability of reward delivery changed and rats completed 120 additional trials under this new reward probability schedule (referred to as the Reversal phase).

Figure 1:

Figure 1:

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The probabilistic reversal learning (PRL) task. (A) A diagram outlining the events of a single trial in the PRL task. (B) One of the reinforcement schedules used in the PRL task. (C) The average choice behavior of rats (N=60) in the PRL. Rats were able to acquire (green line) and reverse (blue line) their choices in the PRL using a 10 trial moving average. The black line is the probability that rats chose the noseport associated with an intermediate probability of reinforcement. (D) The probability of choosing the highest reinforced option was significantly lower following the reversal. (E) Diagram of the procedures that followed the initial PRL assessments. ***p<0.001.

Decision making in the PRL was assessed using two different schedules of reinforcement that varied in probability for 10 days prior to the baseline PET scans. Performance of rats across the two schedules was strongly correlated (Supplemental Figure 1), so dependent measures were collapsed across the two schedules of reinforcement. Five days after completing the last self-administration session, decision making was reassessed for ~10 days in the PRL using both schedules of reinforcement.

Reinforcement-learning model

The choice behavior of rats in the PRL was analyzed with a differential forgetting reinforcement-learning model as previously described (20). This reinforcement-learning model contains four free parameters: a decay rate for the action values of chosen options (γC), a decay rate for the action values of unchosen options (γU), a parameter for the appetitive strength of rewarded outcomes (Δ+, i.e., positive-outcome updating), and a parameter for the aversive strength of unrewarded outcomes (Δ0, i.e., negative-outcome updating). Additional details are provided in the Supplement.

PET Imaging and Processing

Rats underwent PET scans to quantify D2/3 and mGlu5 receptor availability using [11C]-(+)-PHNO and [18F]FPEB, respectively, during one serial PET scanning session collected ~1 week before (N=51) starting and in a subset of rats (N=26; 18 – cocaine; 8 – saline) ~2 weeks after completing the cocaine or saline self-administration paradigm. PET scanning occurred at similar times on each scanning day (~10:00am for [11C]-(+)-PHNO and ~1:00pm for [18F]FPEB). These radiotracers have been shown to have high test-retest reliability in human subjects and rodents (25–27). The procedures for acquiring and processing these dynamic PET data have been previously described (20) and additional details are provided in the Supplement. Reconstructed, three-dimensional [11C]-(+)-PHNO and [18F]FPEB PET images were co-registered to a rat MR template and activity concentration extracted from six regions of interest (ROI): the medial prefrontal cortex (mPFC; included both the vmPFC and dmPFC), orbitofrontal cortex (OFC), ventral striatum (VS), dorsal striatum (DS), midbrain (including the ventral tegmental area and substantia nigra) and the entire cerebellum (Supplemental Figure 2). These regions were selected based on previous work that observed differences in [11C]-(+)-PHNO or [18F]FPEB binding in substance-dependent individuals (4, 10, 17, 28). Time-activity curves from each ROI were fitted with the multilinear reference tissue model (MRTM) using activity from the cerebellum as the reference region (29–31) to provide estimates of BPND, R1 and k2’. The primary outcome measure for both radiotracers was BPND, which is directly proportional to the number of receptor sites available for radioligand binding (32).

Self-administration and addiction-relevant behaviors

Rats were implanted with intrajugular catheters as previously described (22) and were trained to self-administer cocaine (0.5 mg/kg/infusion) or saline in 6 h daily sessions for 21 days (Figure 2A; Supplement). Additional tests of drug-taking and -seeking behaviors were examined using standard procedures described in the Supplement and presented in Figure 1E.

Figure 2:

Figure 2:

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Assessing cocaine self-administration and addiction-relevant behaviors. (A) Rats were trained to self-administer cocaine (N=38) or saline (N=11) in 6 h daily sessions for 21 days. The number of infusions earned each day increased in the cocaine self-administration group and decreased in the saline self-administration group. Individual data is presented in the thin red (cocaine) and gray (saline) lines and the mean in the thick line. (B) The number of responses directed at the active lever under a progressive ratio schedule of reinforcement was significantly higher in the cocaine self-administration group (red bars) compared to the saline self-administration group (black bars). (C) The number of active lever responses during the 6 h extinction test was significantly higher in the cocaine (red line) self-administration group compared to the saline (black lines) self-administration group. (D) The number of active lever responses (solid lines) during the 1h cue induced reinstatement test was higher in the cocaine self- administration group (red lines) compared to the saline (black lines) self-administration group. (E) The number of active (solid lines), but not inactive (dashed lines), lever responses in the cocaine self-administration group increased after 30 days of forced abstinence from cocaine. Thicker lines are the average responses. *** p<0.001.

Statistical analyses

Statistical analyses were conducted using SPSS (version 26; IBM Corp., Armonk, NY) and are described in detail in the Supplement.

Results

Cocaine-induced decision-making deficits are due to disruptions in negative-outcome updating

The ability to make flexible, adaptive choices was assessed in adult, male rats (N=60) on a ‘three-armed bandit’ PRL task (Figure 1A) using stochastic reward schedules (Figure 1B). Rats were able to track these reinforcement probabilities (Figure 1C) and, as expected, chose the most frequently reinforced option significantly less following a change in reward probabilities (e.g., Reversal phase) compared to their performance in the acquisition phase (Figure 1D; χ2=70.62; p<0.001). Performance in the reversal phase was still significantly above chance (t(59)=7.53; p<0.001) indicating that rats were able to adjust their choices following the change in contingencies. A diagram of the experimental design and the number of rats included in each of the procedures is presented in Figure 1E.

Single session PET scans were then acquired to quantify D2/3 and mGlu5 receptor availability using [11C]-(+)-PHNO and [18F]FPEB, respectively, in a subset of subjects (N=51). Rats (N=60) were then implanted with intrajugular catheters and trained to self-administer cocaine (0.5 mg/kg/infusion; N=48) or saline (N=12) in 6 h daily sessions for 21 days (Figure 2A). Twelve rats were excluded from the analyses due to issues with catheter patency or concerns with health resulting in N=38 for the cocaine group and N=11 for the saline group. The number of infusions rats earned across the 21 days significantly increased in the cocaine group (χ2=187.98; p<0.001), whereas the number of infusions earned decreased in the saline group (χ2=1032.72; p<0.001), as shown in Figure 2A. As expected, the number responses under the progressive ratio schedule of reinforcement, during the extinction test, and the cue-induced reinstatement test was significantly greater in the cocaine group compared to the saline group (Figure 2B-D, χ2=187.98; p<0.001). Following 30 days of forced abstinence from cocaine (and after the PRL and PET imaging assessments, see below and Figure 1E), cue-induced reinstatement was reassessed to quantify the incubation effect that had been previously observed (24). As expected, the number of responses directed at the lever previously associated with cocaine significantly increased compared to the first cue-induced reinstatement test (Figure 2E, χ2=160.04; p<0.001).

Decision making performance was reassessed in the PRL task five days after the last self-administration session (see Figure 1E). The number of correct choices rats made in the acquisition phase was not differentially altered following cocaine or saline self-administration (group x time: χ2=0.93; p=0.34), but the number of correct choices rats made in the reversal phase was (group x time: χ2=7.34; p=0.007; Figure 3A,B). Compared to performance prior to self-administration, the number of correct choices rats made in the reversal phase was reduced following cocaine self-administration (χ2=22.44; p<0.001; Figure 3B), but was not altered following saline self-administration (χ2=0.47; p=0.49; Figure 3A; Supplemental Figure 3).

Figure 3:

Figure 3:

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Cocaine self-administration disrupts performance in the PRL task. The probability of choosing the highest reinforced option in the PRL before (open line and open bars) and after (shaded line and closed bars) self-administration of (A) saline or (B) cocaine. The left graphs in each panel are averages using a 10-trial moving average. (C) The probability of repeating a choice as a function of whether the previous choice was rewarded and correct or unrewarded and incorrect before (open bars) and after (closed bars) saline self-administration. (D) Parameter estimates obtained from the differential forgetting, reinforcement-learning model before (open bars) and after (closed bars) saline self-administration. (E) The probability of repeating a choice as a function of whether the previous choice was rewarded and correct or unrewarded and incorrect before (open bars) and after (closed bars) cocaine self-administration. (D) Parameter estimates obtained from the differential forgetting, reinforcement-learning model before (open bars) and after (closed bars) cocaine self-administration. Gray lines are individual subjects. ** p<0.01; *** p<0.001. SA = self-administration.

To delineate the reinforcement-learning mechanisms underlying these deficits, the probability that rats would persist with a rewarded and correct response and the probability that rats would switch after an unrewarded and incorrect response were compared (12). An analysis of the significant three-way interaction (group x time x type: χ2=5.93; p=0.02) indicated that the probability of persisting with a rewarded and correct response was not differentially altered following self-administration (group x time: χ2=2.50; p=0.11), but the probability of switching after an unrewarded and incorrect response was (group x time: χ2=3.59; p=0.05; Figure 3C,E). The probability of switching after an unrewarded and incorrect response decreased in both groups following the self-administration procedures (saline: time, χ2=8.40; p=0.004; cocaine: time, χ2=32.76; p<0.001), but this effect was greater in rats that had self-administered cocaine (Figure 3C,E).

To determine whether these deficits in negative-outcome updating extended into the recent history of choices and outcomes, the choice data during the reversal phase before and after the self-administration procedures was fit with a differential forgetting reinforcement-learning model (12, 33, 34). Post-hoc analyses of the group x time x parameter interaction (χ2=7.69; p=0.05) revealed a significant increase in the Δ0 parameter following cocaine self-administration (time: χ2=8.36; p=0.004), which was not observed following saline self-administration (time: χ2=0.04; p=0.83; Figure 3D,F). None of the other parameters in the reinforcement-learning analyses were differentially affected by cocaine (χ2<0.59; p>0.44). These results, collectively, indicate that the reduction in reversal performance in the PRL following cocaine self-administration is due specifically to disruptions in negative-outcome updating (i.e., insensitivity) that manifests as an increase in the likelihood of rats repeating an unrewarded choice.

Cocaine self-administration increases mGlu5, but not D3, receptor availability

PET scans were acquired before and after the self-administration procedure (see Figure 1E for timeline) in a subset of rats (saline: N=8; cocaine: N=18) to determine the impact of cocaine self-administration on D2/3 and mGlu5 receptor availability using [11C]-(+)-PHNO and [18F]FPEB, respectively. [11C]-(+)-PHNO BPND was not differentially altered following cocaine or saline self-administration (group x time x brain region: χ2=7.73; p=0.10; group x time: χ2=0.61; p=0.43; Figure 4A,B). Moreover, midbrain [11C]-(+)-PHNO BPND, where binding is exclusively due to D3 receptors (35), was not altered following cocaine self-administration (group x time: χ2=0.07; p=0.79). [18F]FPEB BPND, however, was found to be differentially altered (group x time x brain region: χ2=18.25; p=0.001). Post-hoc analyses indicated that [18F]FPEB BPND in the mPFC increased following cocaine self-administration (time: χ2=9.66; p=0.002; Figure 4D), but not after saline self-administration (time: χ2=1.18; p=0.28; Figure 4C).

Figure 4:

Figure 4:

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Cocaine self-administration disrupts mGlu5 BPND. (A,B Top) [11C]-(+)-PHNO BPND in the midbrain, ventral striatum (VS) and dorsal striatum (DS) before (open bars) and after (closed bars) self-administration of (A) saline or (B) cocaine. (A,B Bottom) [11C]-(+)-PHNO BPND maps before (top) and after (below) self-administration of saline (left) or cocaine (right) overlaid on a rat magnetic resonance template. (C,D Top) [18F]FPEB BPND in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), midbrain, ventral striatum (VS), and dorsal striatum (DS) before (open bars) and after (closed bars) self-administration of (C) saline or (D) cocaine. (C,D Bottom) [18F]FPEB BPND maps before (top) and after (below) self-administration of saline (left) or cocaine (right) overlaid on a rat magnetic resonance template. Gray lines are individual subjects. ** p<0.01.

Disruptions in mPFC mGlu5 BPND are related to drug-induced decision-making deficits

Our results indicate that self-administration of cocaine disrupts negative-outcome updating (e.g., Δ0 parameter) and increased mPFC mGlu5 BPND. We then examined whether the degree of disruption in mPFC mGlu5 BPND and negative-outcome updating was related to the quantity of cocaine rats self-administered. There was a significant positive relationship between the cocaine-induced change in the Δ0 parameter (post – pre) and the total amount of cocaine earned (Spearman’s ρ=0.57; p=0.01; Figure 5A), as well as a positive relationship between the cocaine-induced change in mPFC mGlu5 BPND and the total amount of cocaine earned (Spearman’s ρ=0.64; p=0.004; Figure 5B). Specifically, rats that took more cocaine across the 21 days of self-administration had a greater increase in both the Δ0 parameter and the mPFC mGlu5 BPND following self-administration. We hypothesized that cocaine-induced disruptions in mGlu5 BPND also would be related to the disruption in the Δ0 parameter and observed a trend-level positive correlation between the cocaine-induced change in mPFC mGlu5 BPND and the Δ0 parameter (Spearman’s ρ=0.43; p=0.07; Figure 5C).

Figure 5:

Figure 5:

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Cocaine-induced increases in mPFC [18F]FPEB BPND is associated with disruptions in negative-outcome updating. (A) The relationship between the change (after – before self-administration) in the Δ0 parameter and the total number of cocaine infusions earned during the 21 d self-administration procedure. (B) The relationship between the change (after – before self-administration) in mPFC [18F]FPEB BPND and the total number of cocaine infusions earned during the 21 d self-administration procedure. (C) The relationship between the change (after – before self-administration) in mPFC [18F]FPEB BPND and the change (after – before self-administration) in the Δ0 parameter. (D) The relationship between the change (after – before self-administration) in mPFC [18F]FPEB BPND and number of active responses made during the first cue-induced reinstatement test performed 3 days after the last cocaine self-administration session. (E) The relationship between the change (after – before self-administration) in mPFC [18F]FPEB BPND and number of active responses made during the second cue-induced reinstatement test performed 30 days after the last cocaine self-administration session. (F) The relationship between post-cocaine mPFC [18F]FPEB BPND and days of forced abstinence from cocaine.

There is evidence in animals that mGlu5 receptor antagonists reduce reinstatement (36–39). We hypothesized, therefore, that the cocaine-induced change in mGlu5 BPND would predict responses in the cue-induced reinstatement test. The relationship between change in mPFC mGlu5 BPND (post – pre) and responses during the first reinstatement test was not statistically significant (Spearman’s ρ=0.19; p=0.45; Figure 5D), but there was a positive, although non-significant, relationship with the responses during the second reinstatement test performed after a 30 day incubation period (Spearman’s ρ=0.42; p=0.09; Figure 5E). These data suggest that cocaine-induced changes in mPFC mGlu5 receptor signaling may mediate risk for future relapse-like behaviors and could serve as a putative biomarker of relapse risk in humans. We also examined the relationship between cocaine-induced disruptions in the Δ0 parameter and measures of motivation, extinction, and relapse, but none of these relationships were significant (Spearman’s ρ<0.31; p’s>0.21).

Exploratory analyses

Cortical mGlu5 BPND is negatively related to days of cocaine abstinence (28) suggesting that cocaine-induced disruptions in mGlu5 receptor signaling may recover during periods of abstinence from cocaine. To determine if a similar relationship was observed in rats, we compared mPFC mGlu5 BPND measurements collected after cocaine self-administration with the number of cocaine-free days in individual rats (average duration: 15.1 ± 0.48 days). We found a negative relationship between mPFC mGlu5 BPND and abstinence duration (Spearman’s ρ=−0.54; p=0.02; Figure 5F): mPFC mGlu5 BPND was lower in rats that had more cocaine-free days at the time of the PET scans compared to rats that had fewer cocaine-free days.

Discussion

Using longitudinal, dual tracer PET imaging and translationally analogous computational approaches, we report that cocaine-induced decision-making dysfunction in rats is due specifically to disruptions in negative-outcome updating that may be functionally linked to increases in mPFC mGlu5 BPND. We also provide evidence that midbrain D3 BPND, which has been observed to be higher in cocaine-dependent individuals (10, 17), is not altered following cocaine self-administration. Together, these results suggest that cocaine-induced decision-making abnormalities in negative-outcome updating may, in part, be the result of cocaine-induced disruptions in mGlu5 receptor signaling.

Cocaine-induced decision-making deficits are specific to disruptions in negative-outcome updating

We report that the ability to make adaptive choices in the PRL task was disrupted following cocaine self-administration. This effect was specific to the reversal phase of the PRL task, as cocaine self-administration did not disrupt the ability of rats to acquire a discrimination. These findings are consistent with studies in substance-dependent humans (1, 2, 40) and in animals exposed to drugs of abuse (21, 41–43). Our computational approach revealed that the cocaine-induced decision-making impairment was the result of disruptions in negative-outcome updating: following cocaine self-administration rats were more likely to persist with an unrewarded option. Our data add to a growing body of evidence indicating that negative-feedback mechanisms are disrupted in addiction (21, 42, 44, 45) and provide the first evidence that the magnitude of disruption in negative-feedback updating is related to the history of cocaine self-administration.

Conversely, we have recently reported that individual differences in action-value updating following positive feedback predict future cocaine self-administration: rats with poorer positive-outcome updating prior to any drug taking escalated their cocaine intake at a rate significantly greater than rats that displayed better positive-outcome updating (20). Moreover, we found that choice deficits in positive-outcome updating were associated with greater midbrain D3 BPND, but not mPFC mGlu5 BPND, and that midbrain D3 BPND predicted the escalation of cocaine-taking behaviors. Our current findings suggest that cocaine-induced disruptions in negative-outcome updating were specifically associated with drug-induced increases in mPFC mGlu5 BPND and, notably, not to changes in midbrain D3 BPND. These data, collectively, indicate that the select patterns of decision-making strategies which confer risk for cocaine self-administration differ from those that are disrupted by drug self-administration itself.

Importantly, the degree of cocaine-induced disruption in negative-outcome updating was not related to measures of motivation, extinction, or reinstatement, but was related to cocaine self-administration, which suggests that disruptions in negative-outcome updating do not contribute to several addiction-relevant behaviors. These measures, however, only quantify a subset of the pathological, compulsive patterns of behavior observed in addicted individuals (46) that may be linked to other reinforcement-learning mechanisms (47). Another core feature of addiction is the persistence of drug use regardless of the negative consequences. We hypothesize that cocaine-induced changes in negative-outcome updating may contribute to other compulsive-like, drug-taking behaviors and our ongoing studies are testing this hypothesis.

Cocaine self-administration increases mPFC mGlu5 BPND

Previous studies in cocaine-dependent humans have reported that absolute mGlu5 BPND is lower throughout the brains of cocaine-dependent individuals compared to controls (4, 28), and also are reduced in the cingulate cortex and hippocampus of rats following limited cocaine self-administration (16). These findings, however, are difficult to align with previous studies showing that pharmacological antagonism of mGlu5 receptors decreases drug self-administration and relapse-like behaviors in animals (36, 37, 48–54). Indeed, the increase in mPFC mGlu5 BPND following cocaine self-administration observed here is consistent with the hypothesis that cocaine self-administration results in a hyper-glutamatergic state within the PFC (55). Microdialysis studies in behaving rodents have reported that mPFC glutamate levels during tests of cocaine reinstatement are elevated following a 30 day, but not a 3 day, incubation period (55).

Because our rats were anesthetized for the duration of the PET scans this could have altered glutamate levels and impacted our measures of mGlu5 receptor availability. Striatal glutamate levels are reduced by ~45% in anesthetized rats compared to awake rats (56) so it is possible that differences in mGlu5 BPND observed in humans compared to those reported here in rats could be accounted for by anesthesia-induced reductions in endogenous glutamate levels that unmasked available radioligand binding sites and resulted in the increase in mGlu5 BPND observed here.

Although we cannot reject this possibility, we believe it cannot fully account for the current findings as all PET scans were collected under anesthesia and the increase in mPFC mGlu5 BPND was only observed in rats with a history of cocaine self-administration. The current study used the [18F]-FPEB radioligand to quantify mGlu5 BPND whereas previous human studies have used [11C]-ABP688. There is some evidence that the reliability of mGlu5 BPND estimates with the [11C]-ABP688 radioligand is low to moderate (57) but higher with [18F]-FPEB (27), and that diurnal variation may also impact estimates of mGlu5 BPND (58, 59). To reduce this potential confound, [18F]-FPEB PET scans were conducted at approximately the same time during the light cycle (12:00 – 13:00 h) when glutamate levels are lowest (60) and mGlu5 BPND is highest (59).

The elevation in mPFC mGlu5 BPND observed here may be an effect of the experimental procedures used in the current study. Following cocaine self-administration, rats underwent multiple behavioral tests, including tests of motivation, extinction and reinstatement, as well as subsequent tests on the PRL task. These behavioral tests may have inadvertently altered the cocaine-mediated alterations in mGlu5 BPND. Previous studies have suggested that mGlu5 density in the nucleus accumbens of cocaine-experienced rats is increased following extensive extinction training (61) and that mGlu5 receptors are required for the extinction of cocaine-mediated conditioned place preference (62). It is possible, therefore, that the elevation in mPFC mGlu5 BPND observed in the current study are not specific to cocaine self-administration, but rather reflect the confluence of cocaine self-administration and extinction learning (and/or the other behavioral tests performed here).

We report that mPFC mGlu5 BPND is increased in rats following cocaine self-administration and that the magnitude of increase in mPFC mGlu5 BPND was positively related to total cocaine intake suggesting that cumulative cocaine exposure is an important factor in drug-induced mPFC mGlu5 receptor dysfunction. Indeed, a previous study using a long-access self-administration procedure similar to that used here reported that mGlu5 receptor density is elevated in the dmPFC, but decreased in the vmPFC, of rats after brief and extended periods of withdrawal (63). In contrast, rats with limited cocaine self-administration have reductions in striatal and hippocampal mGlu5 BPND (16). There may be, therefore, regionally specific changes in mGlu5 receptor density that depend upon cumulative cocaine exposure, which are difficult to observe in human studies that use self-reported measures of daily and lifetime drug use.

We found that mPFC mGlu5 BPND was increased following 2 weeks of forced abstinence from cocaine and that post-cocaine mGlu5 BPND was negatively correlated with the duration of forced abstinence, a relationship similar to that observed in cocaine-dependent individuals (28). Cocaine-induced mGlu5 receptor dysregulation may, therefore, change over the duration of withdrawal and vary across brain regions. For example, ex vivo studies have reported that mGlu5 receptor density in the vmPFC is not altered following three days of withdrawal from cocaine, but is significantly reduced following 30 days; in contrast, mGlu5 and mGlu1 receptor density in the dmPFC was elevated at both withdrawal timepoints (63). Our binding potential maps (Figure 4D) suggest that the greatest increase in mGlu5 BPND was located between the vmPFC and dmPFC boundaries defined by Ben-Shahar et al. (63). Because of the low resolution of PET, however, it is difficult to know the precise mPFC subregion leading to the observed increase in mGlu5 BPND.

We also report that there was a non-significant, positive relationship between the degree of increase in mPFC mGlu5 BPND and rates of responding in the reinstatement test following 30 days of abstinence, a relationship which was not observed with the absolute post-cocaine mGlu5 BPND measures. This preliminary, non-significant relationship could suggest that risk of relapse is linked to the degree of mGlu5 dysregulation, rather than absolute mGlu5 BPND, demonstrating the need for longitudinal studies of mGlu5 receptors in addiction. Future studies that employ repeated measure designs using PET could directly test the interaction between patterns of drug use, withdrawal duration, and cycles of relapse to cocaine on cortical mGlu5 activity, which we believe will inform studies in cocaine-dependent individuals.

Cocaine self-administration does not alter midbrain D3 BPND

[11C]PHNO BPND in the midbrain – where binding is exclusively due to D3 receptors (29, 35) – is higher in psychostimulant-dependent individuals compared to controls (8, 10, 17). Heightened D3 BPND has been hypothesized to be an effect of drug use, but our results do not support this hypothesis. Moreover, we did not observe drug-induced changes in [11C]PHNO BPND in D2-rich areas, such as the dorsal striatum. This is in contrast to studies that have shown that striatal D2/3 BPND, using antagonist radioligands (e.g., [11C]raclopride), is low in humans drug users (6, 7, 13) and animals following cocaine self-administration (64). [11C]PHNO is an agonist radioligand that is more sensitive to endogenous dopamine levels compared to D2/3 antagonist radioligands, so it is possible that cocaine-induced reductions in dopamine (65, 66) resulted in more available receptor sites, masking the drug-induced reduction in D2 receptors. Post-mortem analyses of D2 and D3 receptor density in tissue from the rats used in the current study is ongoing and may provide insights into this discrepancy (67, 68).

In summary, this study demonstrates that cocaine self-administration increases mPFC mGlu5 receptors and disrupts the integration of negative outcomes into choice action values, which manifests as inflexible, perseverative-like choice behavior. The integration of human-based neuroimaging techniques with computational approaches in rats provides mechanistic insights into the pathological mechanisms of addiction.

Supplementary Material

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Chemical Compound or Drug Cocaine hydrochloride NIDA Drug Supply
Chemical Compound or Drug [11C]-(+)-PHNO Yale PET Center Gallezot et al., 2012
Chemical Compound or Drug [18F]FPEB Yale PET Center Hamill et al., 2015
Organism/Strain Long Evans male rats Charles River Laboratory RRID:RGD_2308852
Software; Algorithm Matlab (2019a) Mathworks RRID:SCR_001622
Software; Algorithm Med PC Med Associates RRID:SCR_014721
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Acknowledgements and Disclosures

We thank and acknowledge the exceptional technical assistance provided by Cynthia Santaniello, Courtney Chabina, Amanda Harsche, Jessica Pursi, and Dayshalis Ofray. We also thank the Yale PET Center and Dr. Irina Esterlis for radioligand support, as well as the Drug Supply Program at the National Institute on Drug Abuse for providing cocaine HCl. This research was supported by Public Health Service grants from the National Institute on Drug Abuse (Grant Numbers: DA041480 and DA043443 [to JRT]), the National Institute on Alcohol Abuse and Alcoholism (Grant Number: K01AA024788 [to ATH]), a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation (to SMG) and funding provided by the State of Connecticut.

SMG and JRT were responsible for the conceptualization. SMG, KF, and DH were responsible for investigation. ATH and HL were responsible for software. SMG was responsible for analysis and writing the original draft. SMG, ATH, HL, KF, DH, EDM, DL, and JRT were responsible for writing, reviewing and editing. All authors approved the final version of the manuscript.

Footnotes

The authors report no biomedical financial interests or potential conflicts of interest.

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References

  • 1.Fillmore MT, Rush CR (2006): Polydrug abusers display impaired discrimination-reversal learning in a model of behavioural control. J Psychopharmacol, 2005/09/22. 20: 24–32. [DOI] [PubMed] [Google Scholar]
  • 2.Ersche KD, Roiser JP, Robbins TW, Sahakian BJ (2008): Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans. Psychopharmacol, 2008/01/25. 197: 421–431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Martinez D, Greene K, Broft A, Kumar D, Liu F, Narendran R, et al. (2009): Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion. Am J Psychiatry, 2009/09/03. 166: 1170–1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Martinez D, Slifstein M, Nabulsi N, Grassetti A, Urban NBL, Perez A, et al. (2014): Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [(11)C]ABP688 and magnetic resonance spectroscopy. Biol Psychiatry. 75: 165–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Milella MS, Marengo L, Larcher K, Fotros A, Dagher A, Rosa-Neto P, et al. (2014): Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [(11)C]ABP688 study. Neuroimage. 98: 195–202. [DOI] [PubMed] [Google Scholar]
  • 6.Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, et al. (1993): Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse, 1993/06/01. 14: 169–177. [DOI] [PubMed] [Google Scholar]
  • 7.Lee B, London ED, Poldrack RA, Farahi J, Nacca A, Monterosso JR, et al. (2009): Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity. J Neurosci, 2009/11/27. 29: 14734–14740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong J, et al. (2012): Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study. J Neurosci. 32: 1353–1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Payer DE, Behzadi A, Kish SJ, Houle S, Wilson AA, Rusjan PM, et al. (2014): Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO. Neuropsychopharmacology. 39: 311–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Matuskey D, Gallezot J-D, Pittman B, Williams W, Wanyiri J, Gaiser E, et al. (2014): Dopamine D₃ receptor alterations in cocaine-dependent humans imaged with [11C](+)PHNO. Drug Alcohol Depend. 139: 100–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Costa VD, Dal Monte O, Lucas DR, Murray EA, Averbeck BB (2016): Amygdala and Ventral Striatum Make Distinct Contributions to Reinforcement Learning. Neuron. 92: 505–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Groman SM, Keistler C, Keip AJ, Hammarlund E, DiLeone RJ, Pittenger C, et al. (2019): Orbitofrontal Circuits Control Multiple Reinforcement-Learning Processes. Neuron. 103: 734–746.e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler M, et al. (2001): Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry, 2001/12/01. 158: 2015–2021. [DOI] [PubMed] [Google Scholar]
  • 14.Groman SM, Lee B, Seu E, James AS, Feiler K, Mandelkern MA, et al. (2012): Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure. J Neurosci. 32: 5843–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR, et al. (2002): Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology, 2002/06/14. 27: 35–46. [DOI] [PubMed] [Google Scholar]
  • 16.de Laat B, Weerasekera A, Leurquin-Sterk G, Bormans G, Himmelreich U, Casteels C, Van Laere K (2018): Glutamatergic Biomarkers for Cocaine Addiction: A Longitudinal Study Using MR Spectroscopy and mGluR5 PET in Self-Administering Rats. J Nucl Med. 59: 952–959. [DOI] [PubMed] [Google Scholar]
  • 17.Payer DE, Behzadi A, Kish SJ, Houle S, Wilson AA, Rusjan PM, et al. (2014): Heightened D(3) dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [(11)C]-(+)-PHNO. Neuropsychopharmacology. 39: 311–318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Worhunsky PD, Matuskey D, Gallezot J-D, Gaiser EC, Nabulsi N, Angarita GA, et al. (2017): Regional and source-based patterns of [ 11 C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D 2 and D 3 receptor availability in cocaine-use disorder. Neuroimage. 148: 343–351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Groman SM, Hillmer AT, Liu H, Fowles K, Holden D, Morris ED, et al. (2020): Midbrain D3 receptor availability predicts escalation in cocaine self-administration. Biol Psychiatry. . doi: 10.1016/j.biopsych.2020.02.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Groman SM, Hillmer A, Liu H, Fowles K, Holden D, Morris ED, et al. (n.d.): Midbrain D3 receptor availability predicts escalation in cocaine self-administration. Biol Psychiatry. . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Groman SM, Rich KM, Smith NJ, Lee D, Taylor JR (2018): Chronic Exposure to Methamphetamine Disrupts Reinforcement-Based Decision Making in Rats. Neuropsychopharmacology. 43: 770–780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Groman SM, Massi B, Mathias SR, Lee D, Taylor JR (2019): Model-Free and Model-Based Influences in Addiction-Related Behaviors. Biol Psychiatry. 85: 936–945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Groman SM, Smith NJ, Petrullli JR, Massi B, Chen L, Ropchan J, et al. (2016): Dopamine D 3 Receptor Availability Is Associated with Inflexible Decision Making. J Neurosci. 36: 6732–6741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Grimm JW, Hope BT, Wise RA, Shaham Y (2001): Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature. 412: 141–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Park E, Sullivan JM, Planeta B, Gallezot JD, Lim K, Lin SF, et al. (2015): Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F]FPEB with bolus plus constant infusion in humans. Eur J Nucl Med Mol Imaging. 42: 1530–1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lee DE, Gallezot J-D, Zheng M-Q, Lim K, Ding Y-S, Huang Y, et al. (2013): Test-Retest Reproducibility of [11C]-(+)-PHNO PET Using the Bolus Plus Constant Infusion Paradigm. Mol Imaging. 12: 77. [PMC free article] [PubMed] [Google Scholar]
  • 27.de Laat B, Leurquin-Sterk G, Celen S, Bormans G, Koole M, Van Laere K, Casteels C (2015): Preclinical Evaluation and Quantification of 18F-FPEB as a Radioligand for PET Imaging of the Metabotropic Glutamate Receptor 5. J Nucl Med. 56: 1954–9. [DOI] [PubMed] [Google Scholar]
  • 28.Milella MS, Marengo L, Larcher K, Fotros A, Dagher A, Rosa-Neto P, et al. (2014): Limbic system mGluR5 availability in cocaine dependent subjects: A high-resolution PET [11C]ABP688 study. Neuroimage. 98: 195–202. [DOI] [PubMed] [Google Scholar]
  • 29.Searle G, Beaver JD, Comley RA, Bani M, Tziortzi A, Slifstein M, et al. (2010): Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol Psychiatry. 68: 392–9. [DOI] [PubMed] [Google Scholar]
  • 30.Wong DF, Waterhouse R, Kuwabara H, Kim J, Brašíc JR, Chamroonrat W, et al. (2013): 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: A first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med. 54: 388–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Patel S, Hamill TG, Connolly B, Jagoda E, Li W, Gibson RE (2007): Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]F-PEB. Nucl Med Biol. 34: 1009–1017. [DOI] [PubMed] [Google Scholar]
  • 32.Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H, et al. (2003): Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab, 2003/09/16. 23: 1096–1112. [DOI] [PubMed] [Google Scholar]
  • 33.Barraclough DJ, Conroy ML, Lee D (2004): Prefrontal cortex and decision making in a mixed-strategy game. Nat Neurosci, 2004/03/09. 7: 404–410. [DOI] [PubMed] [Google Scholar]
  • 34.Ito M, Doya K (2009): Validation of decision-making models and analysis of decision variables in the rat basal ganglia. J Neurosci, 2009/08/07. 29: 9861–9874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Rabiner EA, Slifstein M, Nobrega J, Plisson C, Huiban M, Raymond R, et al. (2009): In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: Studies in non-human primates and transgenic mice. Synapse. 63: 782–93. [DOI] [PubMed] [Google Scholar]
  • 36.Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC (2009): Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res. 202: 238–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Gass JT, Osborne MPH, Watson NL, Brown JL, Olive MF (2009): mGluR5 Antagonism Attenuates Methamphetamine Reinforcement and Prevents Reinstatement of Methamphetamine-Seeking Behavior in Rats. Neuropsychopharmacology. 34: 820–833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Olive MF (2009): Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev. 2: 83–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Carroll FI (2008): Antagonists at Metabotropic Glutamate Receptor Subtype 5. Ann N Y Acad Sci. 1141: 221–232. [DOI] [PubMed] [Google Scholar]
  • 40.Ghahremani DG, Tabibnia G, Monterosso J, Hellemann G, Poldrack RA, London ED (2011): Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals. Neuropsychopharmacology, 2011/02/04. 36: 950–959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Jentsch JD, Olausson P, De La Garza R 2nd, Taylor JR (2002): Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys. Neuropsychopharmacology, 2002/01/16. 26: 183–190. [DOI] [PubMed] [Google Scholar]
  • 42.Zhukovsky P, Puaud M, Jupp B, Sala-Bayo J, Alsiö J, Xia J, et al. (2019): Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis. Neuropsychopharmacology. 44: 2163–2173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Schoenbaum G, Saddoris MP, Ramus SJ, Shaham Y, Setlow B (2004): Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions. Eur J Neurosci, 2004/04/14. 19: 1997–2002. [DOI] [PubMed] [Google Scholar]
  • 44.Parvaz MA, Konova AB, Proudfit GH, Dunning JP, Malaker P, Moeller SJ, et al. (2015): Impaired Neural Response to Negative Prediction Errors in Cocaine Addiction. J Neurosci. 35: 1872–1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Ersche KD, Gillan CM, Jones PS, Williams GB, Ward LHE, Luijten M, et al. (2016): Carrots and sticks fail to change behavior in cocaine addiction. Science (80- ). 352: 1468–1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Vanderschuren LJMJ, Ahmed SH (2013): Animal studies of addictive behavior. Cold Spring Harb Perspect Med. 3: a011932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Ebitz RB, Sleezer BJ, Jedema HP, Bradberry CW, Hayden BY (2019): Tonic exploration governs both flexibility and lapses. (Gershman SJ, editor) PLOS Comput Biol. 15: e1007475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Paterson NE, Semenova S, Gasparini F, Markou A (2003): The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology (Berl). 167: 257–64. [DOI] [PubMed] [Google Scholar]
  • 49.Li X, Peng X-Q, Jordan CJ, Li J, Bi G-H, He Y, et al. (2018): mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism. Sci Rep. 8: 3686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Lee J-Y, Choe ES, Yang CH, Choi KH, Cheong JH, Jang C-G, et al. (2016): The mGluR5 antagonist MPEP suppresses the expression and reinstatement, but not the acquisition, of the ethanol-conditioned place preference in mice. Pharmacol Biochem Behav. 140: 33–38. [DOI] [PubMed] [Google Scholar]
  • 51.Keck TM, Zou M-F, Bi G-H, Zhang H-Y, Wang X-F, Yang H-J, et al. (2014): A novel mGluR5 antagonist, MFZ 10–7, inhibits cocaine-taking and cocaine-seeking behavior in rats. Addict Biol. 19: 195–209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Wang X, Moussawi K, Knackstedt L, Shen H, Kalivas PW (2013): Role of mGluR5 neurotransmission in reinstated cocaine-seeking. Addict Biol. 18: 40–49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Lee B, Platt DM, Rowlett JK, Adewale AS, Spealman RD (2005): Attenuation of Behavioral Effects of Cocaine by the Metabotropic Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in Squirrel Monkeys: Comparison with Dizocilpine. J Pharmacol Exp Ther. 312: 1232–1240. [DOI] [PubMed] [Google Scholar]
  • 54.Hao Y, Martin-Fardon R, Weiss F (2010): Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: Factor in the transition to dependence. Biol Psychiatry. 68: 240–248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Shin CB, Serchia MM, Shahin JR, Ruppert-Majer MA, Kippin TE, Szumlinski KK (2016): Incubation of cocaine-craving relates to glutamate over-flow within ventromedial prefrontal cortex. Neuropharmacology. 102: 103–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Shiraishi M, Kamiyama Y, Hüttemeier PC, Benveniste H (1997): Extracellular glutamate and dopamine measured by microdialysis in the rat striatum during blockade of synaptic transmission in anesthetized and awake rats. Brain Res. 759: 221–227. [DOI] [PubMed] [Google Scholar]
  • 57.Smart K, Cox SML, Nagano-Saito A, Rosa-Neto P, Leyton M, Benkelfat C (2018): Test–retest variability of [ 11 C]ABP688 estimates of metabotropic glutamate receptor subtype 5 availability in humans. Synapse. 72. doi: 10.1002/syn.22041. [DOI] [PubMed] [Google Scholar]
  • 58.DeLorenzo C, Gallezot J-D, Gardus J, Yang J, Planeta B, Nabulsi N, et al. (2017): In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [ 11 C]ABP688 and [ 18 F]FPEB. J Cereb Blood Flow Metab. 37: 2716–2727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Elmenhorst D, Mertens K, Kroll T, Oskamp A, Ermert J, Elmenhorst E-M, et al. (2016): Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain. J Sleep Res. 25: 754–761. [DOI] [PubMed] [Google Scholar]
  • 60.Castañeda TR, Marquez De Prado B, Prieto D, Mora F (2004): Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: Modulation by light. J Pineal Res. 36: 177–185. [DOI] [PubMed] [Google Scholar]
  • 61.Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW (2010): Behavioral/Systems/Cognitive Extinction Training after Cocaine Self-administration Induces Glutamatergic Plasticity to Inhibit Cocaine Seeking. . doi: 10.1523/JNEUROSCI.1244-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Bird MK, Lohmann P, West B, Brown RM, Kirchhoff J, Raymond CR, Lawrence AJ (2014): The mGlu5 receptor regulates extinction of cocaine-driven behaviours. Drug Alcohol Depend. 137: 83–89. [DOI] [PubMed] [Google Scholar]
  • 63.Ben-Shahar O, Sacramento AD, Miller BW, Webb SM, Wroten MG, Silva HE, et al. (2013): Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration. J Neurosci. 33: 495–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Nader MA, Morgan D, Gage HD, Nader SH, Calhoun TL, Buchheimer N, et al. (2006): PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat Neurosci, 2006/07/11. 9: 1050–1056. [DOI] [PubMed] [Google Scholar]
  • 65.Kirkland Henry P, Davis M, Howell LL (2009): Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys. Psychopharmacol, 2009/04/15. 205: 237–247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Calipari ES, Ferris MJ, Jones SR (2014): Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J Neurochem. 128: 224–232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Porrino LJ, Daunais JB, Smith HR, Nader MA (2004): The expanding effects of cocaine: studies in a nonhuman primate model of cocaine self-administration. Neurosci Biobehav Rev, 2004/03/17. 27: 813–820. [DOI] [PubMed] [Google Scholar]
  • 68.Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998): Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse, 1998/08/15. 30: 88–96. [DOI] [PubMed] [Google Scholar]

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