Inversion recovery and saturation recovery pulmonary vein MR angiography using an image based navigator fluoro trigger and variable-density 3D cartesian sampling with spiral-like order.

Contrast enhanced pulmonary vein magnetic resonance angiography (PV CE-MRA) has value in atrial ablation pre-procedural planning. We aimed to provide high fidelity, ECG gated PV CE-MRA accelerated by variable density Cartesian sampling (VD-CASPR) with image navigator (iNAV) respiratory motion correction acquired in under 4 min. We describe its use in part during the global iodinated contrast shortage. VD-CASPR/iNAV framework was applied to ECG-gated inversion and saturation recovery gradient recalled echo PV CE-MRA in 65 patients (66 exams) using .15 mmol/kg Gadobutrol. Image quality was assessed by three physicians, and anatomical segmentation quality by two technologists. Left atrial SNR and left atrial/myocardial CNR were measured. 12 patients had CTA within 6 months of MRA. Two readers assessed PV ostial measurements versus CTA for intermodality/interobserver agreement. Inter-rater/intermodality reliability, reproducibility of ostial measurements, SNR/CNR, image, and anatomical segmentation quality was compared. The mean acquisition time was 3.58 ± 0.60 min. Of 35 PV pre-ablation datasets (34 patients), mean anatomical segmentation quality score was 3.66 ± 0.54 and 3.63 ± 0.55 as rated by technologists 1 and 2, respectively (p = 0.7113). Good/excellent anatomical segmentation quality (grade 3/4) was seen in 97% of exams. Each rated one exam as moderate quality (grade 2). 95% received a majority image quality score of good/excellent by three physicians. Ostial PV measurements correlated moderate to excellently with CTA (ICCs range 0.52-0.86). No difference in SNR was observed between IR and SR. High quality PV CE-MRA is possible in under 4 min using iNAV bolus timing/motion correction and VD-CASPR.

Reduction of cocaine self-administration and D3 receptor-mediated behavior by two novel dopamine D3 receptor-selective partial agonists, OS-3-106 and WW-III-55.

Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0-5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.

A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model.

A potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease.

The muscarinic receptor antagonist tropicamide suppresses tremulous jaw movements in a rodent model of parkinsonian tremor: possible role of M4 receptors.

RATIONALE: Nonselective muscarinic acetylcholine antagonists have been used for several years as antiparkinsonian drugs. However, there are at least five subtypes of muscarinic receptor (M1-5). Neostriatal M4 receptors have been implicated in aspects of motor function, and it has been suggested that M4 antagonists could be used as treatments for parkinsonism. OBJECTIVE: Currently, there is a lack of highly selective M4 antagonists that readily penetrate the blood brain barrier. Thus, the present studies focused upon the effects of tropicamide, a muscarinic acetylcholine receptor antagonist with moderate binding selectivity for the M4 receptor subtype. MATERIALS AND METHODS: Tremulous jaw movements were used as a model of parkinsonian tremor in these studies, and the effects of tropicamide were compared with those of the nonselective muscarinic antagonist atropine. RESULTS: Tropicamide suppressed the tremulous jaw movements induced by the muscarinic agonist pilocarpine and the dopamine antagonist pimozide. Analysis of the dose-response curves indicated that tropicamide showed approximately the same potency as atropine for suppression of pilocarpine-induced jaw movements but was more potent than atropine on the suppression of pimozide-induced jaw movements. In contrast, atropine was more potent than tropicamide in terms of impairing performance on visual stimulus detection and delayed nonmatch-to-position tasks. CONCLUSIONS: These studies demonstrate that tropicamide, which currently is used clinically for ophthalmic purposes, can exert actions that are consistent with antiparkinsonian effects. Moreover, the different pattern of effects shown by tropicamide compared to those of atropine on motor vs cognitive tasks could be due to the modest M4 selectivity shown by tropicamide.

Validation of the tremulous jaw movement model for assessment of the motor effects of typical and atypical antipychotics: effects of pimozide (Orap) in rats.

Drug-induced tremulous jaw movements (TJMs) in rats have been used as a model of parkinsonian tremor. Previous studies demonstrated that the typical antipsychotic haloperidol induced TJMs after acute or subchronic administration, while atypical antipsychotics did not. Moreover, it has been suggested that the relative potency for suppression of tacrine-induced TJMs relative to the suppression of lever pressing can be used to discriminate between typical and atypical antipsychotics. In order to validate this model with additional drugs, the present studies assessed the effects of the typical antipsychotic pimozide. In the first series of experiments, the effects of acute pimozide on tacrine-induced TJMs and lever pressing were examined. As with haloperidol, pimozide failed to suppress tacrine-induced TJMs, even at doses considerably higher than those that suppressed lever pressing. In the second group of experiments, rats were given single daily injections of pimozide (0.125-1.0 mg/kg) or tartaric acid vehicle for 13 days, and were observed for TJMs on days 1, 7, and 13. Pimozide induced TJMs in a dose-related manner on all days. The jaw movements occurred largely in the 3-7 Hz frequency range characteristic of parkinsonian tremor. These data support the hypothesis that typical antipsychotics can induce TJMs in rats, and demonstrate that chronic administration of typical antipsychotics is not necessary for induction of TJMs. TJMs induced by acute or subchronic pimozide may be related to early-onset motor syndromes such as drug-induced parkinsonism.

Increases in dopamine D3 receptor binding in rats receiving a cocaine challenge at various time points after cocaine self-administration: implications for cocaine-seeking behavior.

Previous research suggests that cocaine dysregulates dopamine D3 receptors. The present study examined the time course of changes in dopamine D3 receptor binding after terminating a cocaine self-administration regimen. [125I]-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino]-tetralin was used to label dopamine D3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31-32 days after their last cocaine self-administration session. The results indicated a time-dependent increase in D3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D3 receptor binding in cocaine-experienced rats killed at the 2- or 8-day time points relative to controls, but there was an increase in D3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31- to 32-day time point. In a subsequent experiment, we replicated the increase in D3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats.

RATIONALE: D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). OBJECTIVES: The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. METHODS: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. RESULTS: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. CONCLUSIONS: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.

Accumbens dopamine and the regulation of effort in food-seeking behavior: modulation of work output by different ratio or force requirements.

It has been suggested that depletions of accumbens dopamine (DA) make rats more sensitive to work-related response costs. One way of controlling work costs in operant tasks has been to use fixed-ratio (FR) schedules with different ratio requirements. In addition to using ratio requirements to control response costs, investigators also can employ different force requirements. In the present study, different groups of rats were trained on two schedules (FR 1 and FR 5) and weights were placed on the levers 2 days each week. In the FR 5 studies, two different weights were used (32 or 64 g), while three different weights were used in the FR 1 studies (32, 64, or 96 g). After baseline training, rats received intra-accumbens injections of either 6-OHDA to deplete DA, or ascorbate vehicle as the control. The effects of DA depletions were highly schedule-dependent. DA-depleted animals on the FR 5 schedule showed reductions in responding across the different weight conditions. In contrast, DA depletion did not significantly suppress FR 1 responding under any conditions. Addition of weights to the levers reduced responding on the FR 1 and FR 5 schedules, but did not enhance sensitivity to DA depletion. Thus, rats with accumbens DA depletions were sensitive to different ratio requirements, yet they were relatively insensitive to different force requirements within the range tested. These studies indicate that DA depletions make animals sensitive to temporal or rate components of work that greatly influence responding on ratio schedules.

Role of the prelimbic subregion of the medial prefrontal cortex in acquisition, extinction, and reinstatement of cocaine-conditioned place preference.

Previous research suggests that the prelimbic subregion of the medial prefrontal cortex (mPFC) is necessary for acquisition of cocaine-conditioned place preference (CPP). Recently, it has been shown that extinguished cocaine-CPP can be reinstated by cocaine priming injections, and that this effect reflects the incentive motivational effects of the cocaine prime. To determine whether the prelimbic cortex is necessary for cocaine-reinstated CPP, rats received bilateral infusions of quinolinic acid (lesion group) or vehicle (sham group) into the prelimbic cortex and were later tested for acquisition, extinction, and reinstatement of cocaine-CPP. Both sham and lesion rats exhibited robust CPP established by systemic injections of cocaine (15 mg/kg, i.p.) following either one or three drug-environment pairings. Following repeated exposure to the cocaine- and saline-paired environments, sham and lesion rats showed similar rates of extinction of cocaine-CPP. In contrast, reinstatement of cocaine-CPP by cocaine priming injections (5 and 10 mg/kg, i.p.) was attenuated in rats with prelimbic cortex lesions relative to sham controls. This finding suggests that the prelimbic cortex is involved in the incentive motivational effects of cocaine priming.

Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats.

Incentive motivation for cocaine, elicited by cocaine-associated stimuli, is thought to be involved in craving and relapse. To examine the role of the basolateral amygdala complex (BLC) in this phenomenon, we assessed the effects of post-training BLC lesions on extinction of cocaine-seeking behavior and cocaine-conditioned place preference (CPP) and the effects of pre-training BLC lesions on acquisition of cocaine-CPP. In Experiment 1, rats were first trained to self-administer cocaine and then received bilateral infusions of the excitotoxin, N-methyl-D-aspartic acid (NMDA, 0.12 M; 0.3 microl/side), or vehicle into the BLC. They were then tested repeatedly for extinction of cocaine-seeking behavior (i.e. nonreinforced responses in the presence of cocaine-paired stimuli). Subsequently, they were trained and tested for acquisition of cocaine-CPP (i.e. increased time spent in a previously cocaine-paired, relative to a saline-paired, environment). Locomotion and compartment entries were also measured. In Experiment 2, rats were first trained and tested for cocaine-CPP, and then received NMDA or vehicle infusions into the BLC. Subsequently, they were tested repeatedly for extinction of cocaine-CPP. Post-training BLC lesions retarded extinction of cocaine-seeking behavior and cocaine-CPP, whereas pre-training lesions disrupted acquisition of cocaine-CPP. These effects did not appear to be related to changes in general activity. We suggest that pre-training BLC lesions disrupted acquisition of cocaine-CPP by impairing assignment of incentive value to cocaine-paired stimuli, whereas post-training BLC lesions disrupted extinction of cocaine-conditioned behaviors by impairing the assessment of the current incentive value of cocaine-paired stimuli.

Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration.

Effects of the D2-like dopamine agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), on cocaine-seeking behavior and re-establishment of cocaine self-administration were examined. Rats were trained to lever press for cocaine infusions (0.25 mg/kg iv). Some were then tested for cocaine-seeking behavior (i.e., lever presses in the absence of cocaine re-inforcement) immediately following acute 7-OH-DPAT (0.001, 0.01, 0.1, or 1.0 mg/kg sc) or saline administration. Others were tested immediately or 2-23 h following repeated daily 7-OH-DPAT (1.0 mg/kg sc) or saline administration for extinction of cocaine-seeking behavior, cocaine re-instatement of cocaine-seeking behavior, and re-establishment of cocaine self-administration following extinction. 7-OH-DPAT-induced changes in locomotion were also assessed. Cocaine-experienced animals exhibited cross-tolerance to the transient hypoactivity produced by acute 7-OH-DPAT administration. Acute administration of low doses (0.01-0.1 mg/kg) of 7-OH-DPAT attenuated cocaine-seeking behavior, whereas the highest dose (1.0 mg/kg) initially attenuated, then increased, cocaine-seeking behavior. In animals tested immediately following one of the repeated administrations, 7-OH-DPAT did not alter cocaine self-administration, but sensitized locomotion. Repeated 7-OH-DPAT administration also increased cocaine-seeking behavior when administered 0 h, but not 2 or 4 h, before cocaine priming (15 mg/kg ip) and testing. In animals tested 17-23 h following one of the repeated administrations, cocaine-seeking behavior and re-establishment of cocaine self-administration were attenuated, but maintenance of self-administration following re-establishment, cocaine re-instatement of extinguished cocaine-seeking behavior, and spontaneous locomotion were unaltered. The findings suggest that following repeated administration, 7-OH-DPAT produces a transient increase (<2 h) in incentive motivation for cocaine that is followed by a protracted decrease in incentive motivation for cocaine.

Review of the legal obligations of the doctor to discuss Sudden Unexplained Death in Epilepsy (SUDEP)--a cohort controlled comparative cross-matched study in an outpatient epilepsy clinic.

INTRODUCTION: Acknowledging informed consent and warning of material risk, the present study examined the current debate regarding early discussion of Sudden Unexplained Death in Epilepsy (SUDEP). It sought to confirm the profile of those prone to SUDEP and to determine the basis for disclosure to patients. METHODS: Patients with SUDEP attending an Australian outpatient epilepsy clinic between 1985 and 2000 were compared to an age, gender and epilepsy type cross-matched control group to ascertain risk factors for SUDEP and similarities to published parameters. These were evaluated as the basis for actions in negligence for either disclosure or failure to disclose. RESULTS: Twenty-one SUDEP patients were identified: aged 18-70 years; the majority had localisation-related epilepsy (13:8, 62%); male to female ratio was 3:1; and 15/21 used polypharmacy, compared with 8/21 controls (P = 0.02951). Handedness, alcohol use or deterioration of epilepsy were unrelated. DISCUSSION: This population mirrored the literature and confirmed an absence of risk factors amenable to modification. As discussion of SUDEP with males with localisation-related epilepsy on polypharmacy could not alter outcome it is unlikely that failure to disclose could be causal and hence successful in an action for negligence. Conversely, disclosure, in the absence of the patient seeking the information, may causally adversely affect quality of life hence providing successful action in negligence. Duty of care dictates open and frank discussion with those seeking the information. Thus, each case must be managed individually and doctors are advised to document the decision-making process.

A pilot study of compassionate use of Levetiracetam in patients with generalised epilepsy.

Levetiracetam (LEV) has proven effective for partial seizures, suggesting the need to trial it in generalised epilepsy. Ten patients with generalised epilepsy were given compassionate use of LEV as a pilot study, attending 7 visits with seizure count (using diary) and compliance checked (pill count) with option for long term use. Seizure frequency was compared to baseline mean of the last 2 months and mean of follow-up. Patients were commenced on 500 mg I b.d, and titrated to a maximum of 3 g/day. There were 10 patients (7 females), aged 28-48, of whom 6 had primary generalised epilepsy (PGE) and 4 Lennox-Gastaut syndrome (LGS). At 7 month evaluation: 1 was seizure-free, 1 was 70% reduced, 3 were > or = 50% reduced, 2 were 30-35% reduced; 1 had no change; 1 was 10% increased and 1 was excluded because confounding pseudo seizures. Follow-up was 8-17 months (mean 13.8). The seizure-free patient became pregnant and had 2 seizures, but has been seizure-free for 2 months, at time of submission. A 16 months are three months seizure-free. One was 50% reduced at months 6 and 7, was 2 months seizure-free but then reverted to 50% per baseline. With respect to LGS, 1 withdrew due to aggression, 2 had 40% and 35% reduction at 13 and 15 months respectively and 1 had 25% increase (10% at 7 months). All patients were compliant. These data suggest that LEV may be effective for generalised epilepsy with a need for a larger clinical trial.

A new criterion for acquisition of nicotine self-administration in rats.

BACKGROUND: Acquisition of nicotine self-administration in rodents is relatively difficult to establish and measures of acquisition rate are sometimes confounded by manipulations used to facilitate the process. This study examined acquisition of nicotine self-administration without such manipulations and used mathematical modeling to define the criterion for acquisition. METHODS: Rats were given 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0-0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined for individual rats by the higher likelihood of reinforcers obtained across sessions fitting a logistic over a constant function according to the corrected Akaike Information Criterion (AICc). RESULTS: For rats that acquired self-administration, an AICc-based multi-model comparison demonstrated that the asymptote (highest number of reinforcers/session) and mid-point of the acquisition curve (h; the number of sessions necessary to reach half the asymptote) varied by nicotine dose, with both exhibiting a negative relationship (the higher the dose, the lower number of reinforcers and the lower h). CONCLUSIONS: The modeling approach used in this study provides a way of defining acquisition of nicotine self-administration that takes advantage of all data from individual subjects and the procedure used is sensitive to dose differences in the absence of manipulations that influence acquisition (e.g., food restriction, prior food reinforcement, conditioned reinforcers).

Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues.

Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.

Stimulation of medial prefrontal cortex serotonin 2C (5-HT(2C)) receptors attenuates cocaine-seeking behavior.

Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

Ratio and time requirements on operant schedules: effort-related effects of nucleus accumbens dopamine depletions.

Accumbens dopamine (DA) depletions produce deficits that are related to the ratio requirement of the operant schedule; however, it is also possible that time without reinforcement is a factor. The present study examined the effects of accumbens DA depletions in rats using variable interval (VI) schedules with additional fixed ratio (FR) requirements. Four VI schedules were used (VI 60/FR 1, VI 120/FR 1, VI 60/FR 10, VI 120/FR 10). Attachment of the additional work requirement increased response rates under control conditions. After surgery, there was no interaction between interval level (i.e. 60 vs. 120 s) and DA depletion, but there was a significant interaction between ratio requirement (i.e. 1 vs. 10) and DA depletion within the first week after surgery. DA depletions substantially impaired performance on the schedules with added FR 10 requirements, an effect that was largely dependent upon a reduction in fast responses (i.e. inter-response times less than 1.0 s). There was little effect of DA depletion on overall responding on VI 60/FR 1 and VI 120/FR 1 schedules. DA depletions also increased the tendency to take long pauses in responding (i.e. > 20.0 s), and this effect was evident across all schedules tested. Thus, accumbens DA depletions interact with work requirements and blunt the rate-enhancing effects of moderate size ratios, and also enhance the tendency to pause. Attachment of ratio requirements to interval schedules is a work-related response cost that provides a challenge to the organism, and DA in nucleus accumbens appears to be necessary for adapting to this challenge.