Early diagnosis of anastomotic leakage after colorectal surgery by the Dutch leakage score, serum procalcitonin and serum C-reactive protein: study protocol of a prospective multicentre observational study by the Italian ColoRectal Anastomotic Leakage (iC.

BACKGROUND: Anastomotic leakage (AL) is a dreaded major complication after colorectal surgery. There is no uniform definition of anastomotic dehiscence and leak. Over the years many risk factors have been identified (distance of anastomosis from anal verge, gender, BMI, ASA score) but none of these allows an early diagnosis of AL. The DUtch LeaKage (DULK) score, C reactive protein (CRP) and procalcitonin (PCT) have been identified as early predictors for anastomotic leakage starting from postoperative day (POD) 2-3. The study was designed to prospectively evaluate AL rates after colorectal resections, in order to give a definite answer to the need for clear risk factors, and testing the diagnostic yeld of DULK score and of laboratory markers. Methods and analysis. A prospective enrollment for all patients undergoing elective colorectal surgery with anastomosis carried out from September 2017 to September 2018 in 19 Italian surgical centers. OUTCOME MEASURES: preoperative risk factors of anastomotic leakage; operative parameters; leukocyte count, serum CRP, serum PCT and DULK score assessment on POD 2 and 3. Primary endpoint is AL; secondary endpoints are minor and major complications according to Clavien-Dindo classification; morbidity and mortality rates; readmission and reoperation rates, length of postoperative hospital stay (Retrospectively registered at ClinicalTrials.gov Identifier: NCT03560180, on June 18, 2018). Ethics. The ethics committee of the "Comitato Etico Regionale delle Marche - C.E.R.M." reviewed and approved this study protocol on September 7, 2017 (protocol no. 2017-0244-AS). All the participating centers submitted the protocol and obtained authorization from the local Institutional Review Board.

The effect of cannabis edibles on driving and blood THC.

BACKGROUND: Cannabis has been shown to impact driving due to changes produced by delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis. Current legal thresholds for blood THC while driving are based predominantly on evidence utilizing smoked cannabis. It is known that levels of THC in blood are lower after eating cannabis as compared to smoking yet the impact of edibles on driving and associated blood THC has never been studied. METHODS: Participants drove a driving simulator before and after ingesting their preferred legally purchased cannabis edible. In a counterbalanced control session, participants did not consume any THC or cannabidiol (CBD). Blood was collected for measurement of THC and metabolites as well as CBD. Subjective experience was also assessed. RESULTS: Participants consumed edibles with, on average, 7.3 mg of THC, which is less than the maximum amount available in a single retail package in Ontario, providing an ecologically valid test of cannabis edibles. Compared to control, cannabis edibles produced a decrease in mean speed 2 h after consumption but not at 4 and 6 h. Under dual task conditions in which participants completed a secondary task while driving, changes in speed were not significant after the correction for multiple comparison. No changes in standard deviation of lateral position (SDLP; 'weaving'), maximum speed, standard deviation of speed or reaction time were found at any time point or under either standard or dual task conditions. Mean THC levels were significantly increased, relative to control, after consuming the edible but remained relatively low at approximately 2.8 ng/mL 2 h after consumption. Driving impairment was not correlated with blood THC. Subjective experience was altered for 7 h and participants were less willing/able to drive for up to 6 h, suggesting that the edible was intoxicating. INTERPRETATION: This is the first study of the impact of cannabis edibles on simulated driving. Edibles were intoxicating as revealed by the results of subjective assessments (VAS), and there was some impact on driving. Detection of driving impairment after the use of cannabis edibles may be difficult.

Anal vector volume analysis: an effective tool in the management of pelvic floor disorders.

INTRODUCTION: Different trials have investigated the role of conventional anal manometry in the diagnosis of pelvic floor disorders. The aim of the present study is to define the role and the effectiveness of vector anal manometry and vector asymmetry index scoring in the assessment of pelvic floor disorders i.e. fecal incontinence and obstructed defecation. METHODS: Between 2005 and 2007, 387 patients underwent clinical and manometric evaluation in the Department of Surgery, University Hospital Tor Vergata, Rome, Italy, and were included in the present prospective cohort study. All the patients underwent clinical examination, Wexner incontinence scoring, and anal vector manometry and were classified into three groups. Group I included patients with normal resting anal pressure values (195 patients). Groups II and III consisted of patients with resting anal pressure higher and lower than normal values, respectively (90 and 102 patients, respectively). All patients were classified into asymmetric and non-asymmetric according to the vector asymmetry index using a cut-off of 20%. We investigated the correlation between anal asymmetry and pelvic floor disorders, i.e. fecal incontinence due to sphincter injury, rectal prolapse, and obstructed defecation. RESULTS: In Group III, the number of asymmetric patients was significantly higher than non-asymmetric ones (P < 0.0001). Asymmetry values were significantly higher in group III than in groups I and II considering squeeze (P < 0.0001) or resting pressures (P < 0.0001). Furthermore, there was a statistically significant association between anal asymmetry and both anal incontinence (P < 0.0001) and rectal prolapse (P = 0.0270). No such association was found between anal asymmetry and obstructed defecation. CONCLUSION: Anal vector manometry using vector analysis of resting and squeeze pressures is complementary to endoanal ultrasonography, as it provides information on anal sphincter function and integrity. The vector asymmetry index >20% correlates with fecal incontinence due to anal sphincter lesions. Therefore, anal vector manometry may be useful as an independent method of screening for pregnant women at risk of sphincter injury and for patients undergoing anorectal surgery with risk factors for incontinence, like previous anorectal surgery or a history of two or more previous vaginal deliveries.

Role of the prelimbic cortex in the acquisition, re-acquisition or persistence of responding for a drug-paired conditioned reinforcer.

The medial prefrontal cortex has been suggested to play a role in drug addiction due to its involvement in the reinstatement of drug seeking. In the present study, the role of the prelimbic cortex in persistent responding maintained by the earned presentations of a drug-paired conditioned reinforcer was studied. Temporary inactivation of the prelimbic, prefrontal cortex of rats had no effect on this persistent response, but did impair its initial acquisition, maintained by the drug-paired conditioned reinforcer. The lesion also impaired re-acquisition of this response after extinction by omission of the contingent conditioned reinforcer. These results suggest that the prelimbic cortex has a selective role in the acquisition, or re-acquisition, of instrumental responses for drug-paired conditioned reinforcers, that may be important in relapse to drug seeking. Anatomical controls with placements in the infralimbic cortex showed longer-lasting impairments in the acquisition of this response, consistent with the suggestion that the prelimbic and infralimbic cortices mediate different aspects of behavior, with the infralimbic being more specialized for habits. The implications of the present findings toward the understanding of drug seeking and relapse behaviors and the separate brain systems that may underlie them are discussed.

Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of pavlovian approach behavior.

Stimuli paired with primary rewards can acquire emotional valence and the ability to elicit automatic, Pavlovian approach responses that have been shown to be mediated by the nucleus accumbens. The present experiment investigated the effects of infusions of glutamatergic or dopaminergic receptor antagonists into the core of the nucleus accumbens on the acquisition and performance of Pavlovian discriminated approach to an appetitive conditioned stimulus. Rats were trained on an autoshaping task in which a conditioned stimulus (CS+; a lever) was inserted into the operant chamber for 10 sec, after which a food pellet was delivered. Presentation of another lever (CS-) was never followed by food. Subjects developed a conditioned response of approaching and contacting the CS+ selectively, although food delivery was not in any way contingent on the animals' response. A triple dissociation in the effects of AP-5, LY293558 [(3SR, 4aRS, 6RS, 8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid], and alpha-flupenthixol infused into the nucleus accumbens core on the acquisition and performance of this conditioned response was observed. The AMPA/kainate receptor antagonist LY293558 disrupted discriminated approach performance but not acquisition, as evidenced by increased approaches to the CS-. In contrast, the NMDA receptor antagonist AP-5 impaired only the acquisition, but not performance, of autoshaping whereas the dopamine D1/D2 receptor antagonist alpha-flupenthixol decreased approaches to the CS+ during both acquisition and performance. The data are discussed with reference to dissociable interactions of these receptor types with limbic cortical and dopaminergic afferents to the nucleus accumbens core during the acquisition and expression of Pavlovian conditioned approach.

Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior.

The purpose of the present experiment was to investigate the involvement of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell in the control over cocaine-seeking behavior by drug-associated cues. Rats were trained under a second-order schedule of reinforcement for cocaine with five infusions of cocaine being available in each daily session. The NMDA receptor antagonist AP-5 and the AMPA/KA receptor antagonist LY293558 were infused directly into the core or shell. LY293558 infused into the core produced a dose-dependent decrease in responding during both the first, cocaine-unaffected interval and also after cocaine had been self-administered in subsequent intervals. By contrast, AP-5 infused into the core had no effect on responding. Infusion of AP-5 into the shell had the limited effect of decreasing responding during the second interval only. There were no effects of LY293558 infused into the shell. These results indicate that NMDA and AMPA receptor-mediated glutamate transmission in the core and shell are dissociably involved in cocaine-seeking behavior controlled in part by drug-associated cues.

Quantitation of lymphocytes in endomyocardial biopsies: use and limitations of antibodies to leukocyte common antigen.

The difficulty in distinguishing lymphocytes from other cells in the myocardial interstitium on hematoxylin-eosin-stained sections has contributed to the variable incidence of myocarditis diagnosed by endomyocardial biopsy. We investigated the value of immunoperoxidase staining using antibodies to leukocyte common antigen (LCA) for identifying interstitial mononuclear cells in formalin-fixed, paraffin-embedded, endomyocardial biopsy samples of the right ventricle obtained by bioptome from 50 consecutive autopsies. In 42 cases with nonspecific findings or no disease, two observers independently quantitated interstitial lymphocytes on hematoxylin-eosin-stained sections and LCA-positive cells on immunoperoxidase sections. Mean values for lymphocytes on hematoxylin-eosin-stained sections were significantly different for the two observers (5.8/mm2 vs. 8.9/mm2, P less than 0.001). In contrast, mean values for LCA-positive cells on immunoperoxidase sections were similar (13.8/mm2 vs. 15.1/mm2, P = not significant). Interobserver concordance was excellent for LCA-immunoperoxidase sections (r = 0.83), exceeding that obtained for hematoxylin-eosin-stained sections (r = 0.63). Intraobserver correlations between lymphocytes identified on hematoxylin-eosin-stained sections and LCA-positive cells on immunoperoxidase sections were poor (r = 0.28 and 0.14). LCA-immunoreactive cells included, in addition to lymphocytes, mast cells and histiocytes. We conclude that there is considerable interobserver discordance in identifying lymphocytes on hematoxylin-eosin-stained sections of endomyocardial biopsy samples. While LCA-immunoperoxidase staining reduces interobserver variability, results must be interpreted with caution since this antibody stains other leukocytes in addition to lymphocytes.

Villous adenoma presenting as a vaginal polyp in a rectovaginal tract.

A 72-year-old woman had a villous adenoma of endodermal derivation involving the rectovaginal septum and contiguous mucosal surfaces that presented clinically as a vaginal polypoid tumor. To explain the vaginal involvement, we postulate that the adenoma traversed a tract of developmental origin within the rectovaginal septum. This is the first report of such a unique constellation of findings.

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats.

Rats were prepared with jugular catheters and assigned randomly to one of three groups: intravenous (IV) self-administration of cocaine, yoked administration of cocaine or vehicle. Rats experienced intermittent administration of cocaine (0.75 mg/kg per injection) or vehicle (0.1 ml/injection) for six test sessions, in accordance with the pattern of injections made by the self-administration group. Sensitization of motor activity between pre-and post-treatment challenges of cocaine (3 mg/kg, IV) was observed after both self- and yoked administration of cocaine but not in the yoked-vehicle group. These data indicate that sensitization as a consequence of drug self-administration may be an important factor in the etiology of addiction.

Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats.

The present experiment employed chronoamperometry with stearate-graphite paste electrodes to monitor dopamine efflux in the nucleus accumbens during extinction and subsequent reinstatement of bar-pressing for a conditioned stimulus (CS) following presentation of a CS or following a systemic injection of d-amphetamine. Rats self-administered d-amphetamine (0.25 mg/kg per infusion) for 3 h a day on 6 consecutive days. Each infusion was paired with a flashing light CS. On the 7th day, rats self-administered d-amphetamine for 1 h, followed by 10 h of extinction. Presentation of the CS 2 days following extinction induced small and transient increases in responding for the CS, with no significant associated increases in DA efflux. Lower rates of responding were observed in rats that had received random presentations of the CS during d-amphetamine self-administration, and in an experimentally-naïve control group. A subsequent systemic injection of d-amphetamine increased dopamine efflux in the nucleus accumbens in all groups and was most effective in reinstating bar-pressing in the CS-d-amphetamine paired group. This is consistent with the hypothesis that exposure to psychostimulant drugs, and a drug-paired CS, can reinstate drug-seeking behavior. Together, these findings suggest that enhanced DA efflux may contribute to the reinstatement of drug-seeking behavior induced by the single administration of a psychostimulant drug, but not transient reinstatement induced by presentation of a drug-paired CS alone following extinction.

Changes in dopamine oxidation currents in the nucleus accumbens during unlimited-access self-administration of d-amphetamine by rats.

In-vivo chronoamperometry in conjunction with stearate-modified carbon paste electrodes was used to monitor changes in dopamine (DA) oxidation currents in the nucleus accumbens during extended 24h and 48h sessions of i.v. self-administration of d-amphetamine (0.1mg/infusion) by rats. Animals in two control groups received "yoked" administration of d-amphetamine or saline vehicle. In a separate experiment, microdialysis with probes adjacent to the electrochemical electrodes was employed to estimate the sensitivity of these electrodes to different extracellular concentrations of DA reverse dialyzed at the probe surface in the presence of pharmacological blockade of the DA transporter. During unlimited access to d-amphetamine self-administration, several distinct changes in basal DA oxidation currents were observed: 1) a significant elevation that peaked after asymptotically equal to 4h; 2) a steady decline to values that were not significantly different from the values in the "yoked" vehicle group at asymptotically equal to 9h; 3) a further decline below control levels, reaching a nadir at asymptotically equal to 24h; 4) in the 48h session, a second phase of increased DA oxidation currents accompanied the reinstatement of a second bout of d-amphetamine self-administration, which followed an abstinence period. Examination of chronoamperometric records for individual rats, before, during and after the abstinence periods revealed 1) a significant reduction in basal DA oxidation currents in the self-administration group, relative to both "yoked" groups; 2) resumption of self-administration when DA currents were still attenuated; 3) an increase in DA currents following reinitiation of d-amphetamine self-administration. Comparison of changes in DA oxidation currents between groups revealed 1) significantly greater increases with self-administration vs "yoked" d-amphetamine administration; 2) a significant decrease in the self-administration vs the "yoked" d-amphetamine group during abstinence and 3) a circadian variation in the "yoked" vehicle group that was out of phase with the groups receiving the drug.

Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine.

Changes in extracellular concentrations of dopamine (DA) were measured in vivo in the nucleus accumbens of the rat during intravenous self-administration of either cocaine (0.25, 0.5, 1.0mg/infusion) or d-amphetamine (0.05, 0.1, 0.2mg/infusion). Drug intake was limited to 12 self-administered infusions per session for each drug/dose combination. Changes in extra-cellular DA concentrations were measured by two different techniques: chronoamperometry in conjunction with chronically-implanted stearate-modified carbon paste electrodes, or intracerebral microdialysis with off-line analyses using high performance liquid chromatography with electrochemical detection (HPLC-ED). Significant increases in extracellular DA concentrations were observed with both in vivo techniques during self-administration of each dose of cocaine or d-amphetamine. For each drug, the magnitude of change during the first hour of the test session was comparable across doses. However, the change observed over the first 2h period, as measured by microdialysis and HPLC-ED, revealed a dose effect for cocaine, but no dose-response effect for d-amphetamine. The duration of the drug-induced elevation was increased significantly as a function of dose with both cocaine and d-amphetamine. Data from the microdialysis experiments indicated that the high dose of d-amphetamine (0.2mg/infusion) produced a significantly greater increase in extracellular DA concentrations in the nucleus accumbens than did the high dose of cocaine (1.0mg/infusion), but that comparable changes were induced by doses of 0.1mg/infusion of d-amphetamine and 1.0mg/infusion of cocaine, respectively. Each dose of both psychostimulant drugs also produced a significant decrease in dihydroxyphenylacetic acid (DOPAC) levels. The latter finding indicated that the electrochemical signal measured in these studies was not due to the oxidation of DOPAC. These results confirm that self-administration of cocaine or d-amphetamine by the rat is accompanied by a significant increase in extracellular DA concentrations in the nucleus accumbens. The fact that two different psychomotor stimulant drugs of abuse have qualitatively similar neurochemical correlates when self-administered, adds credence to the hypothesis that their reinforcing properties are related to dynamic changes in DA concentrations in the ventral striatal region of the brain.

A signet-ring cell carcinoma of the ampulla of Vater.

We describe a variant of carcinoma of the ampulla of Vater, which, to our knowledge, has not been previously described. Classic signet-ring cells represented the predominant cell type, and were admixed with more poorly differentiated tumor cells that were chromogranin positive. These findings raise the possibility of an amphicrine tumor of the ampulla.

Acquired immunodeficiency syndrome with disseminated toxoplasmosis presenting as an acute pulmonary and gastrointestinal illness.

Encephalitis due to the protozoan Toxoplasma gondii has emerged as a common cause of central nervous system disease in patients with acquired immunodeficiency syndrome. Extraneural disease is less common and more difficult to diagnose. We report a case of widely disseminated toxoplasmosis that presented as acute gastrointestinal and pulmonary disease in a patient without a prior diagnosis of acquired immunodeficiency syndrome. The diagnosis of toxoplasmosis was made only at autopsy. Antemortem diagnosis of disseminated T gondii infection requires a high degree of clinical suspicion and the prompt utilization of appropriate diagnostic testing. Since toxoplasmosis is a potentially treatable opportunistic infection, diagnosis allows the swift institution of anti-Toxoplasma therapy.

Deep vein thrombosis as debut of cytomegalovirus infection associated with type II cryoglobulinemia, with antierythrocyte specificity in a kidney transplant recipient: a case report.

Immunologic alterations, such as cryoglobulinemia, have been described in the acute phase of primary cytomegalovirus (CMV) infections in immunocompetent patients. There are few references about these influences of a primary CMV infection in an at-risk kidney transplant recipient (donor positive/recipient negative-D(+)/R(-)). Herein we have described the case of a 46-year-old man, who was naive for CMV and underwent renal transplantation from a CMV+ cadaveric donor, thereby at high risk for disease transmission. The immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and steroids. The recipient was not treated with CMV prophylaxis, but rather regularly screened for possible pre-emptive treatment. At 35 days after transplantation, he was admitted because of deep vein thrombosis (DVT) in the transplant ipsilateral lower limb accompanied by oliguria, fever, and epigastric pain accompanied by type II cryoglobulinemia and acute CMV infection. The direct antiglobulin test (DAT) for C3d was positive. The cryoglobulins displayed anti-red blood cell specificity, with maximum activity at 4°C. The DVT was successfully treated with locoregional thrombolysis in combination with anticoagulant therapy. The DAT improved with CMV treatment and increased steroid therapy. The urine output and renal function tests improved with resolution of the thrombosis, achieving complete recovery without sequelae. Our hypothesis was that CMV infection triggered cryoglobulinemia. The blood disorder caused hyperviscosity, inducing DVT. This case, of CMV infection showed associated cryoglobulinemia presenting with antierythrocyte specificity in a kidney transplant recipient.

Everolimus and enteric-coated mycophenolate sodium ab initio after liver transplantation: midterm results.

BACKGROUND AND AIM: Everolimus (EVR) use in liver transplantation (OLT) has been prescribed with calcineurin inhibitors (CNIs), steroids, and monoclonal antibodies. The aim of our study was to evaluate the safety, feasibility, and impact on renal function of EVR ab initio, in combination with enteric-coated mycophenolate sodium (EC-MPS) without the use of induction treatment, steroids, or CNIs. PATIENTS AND METHODS: We retrospective analyzed nine consecutive patients who underwent OLT at our institution. The initial dose of EVR (1.5 mg/d) was adjusted to achieve trough levels of 8 to 12 ng/mL. EC-MPS introduced at 1080 mg/d was maintained at the same dose over time. RESULTS: At a mean follow-up of 21.48 (standard deviation [SD] 1.4) months from OLT, 7/9 recipients were alive with stable graft function. The 2-year patient and graft survivals were 77%. One recipient died due to cerebral hemorrhage and one, lung failure. No clinical evidence of an acute rejection episode was observed. Mean estimated glomerular filtration rate value, according to the Modification of Diet in Renal Disease formula increased from 59.5 (SD 9.89) mL/min/1.73 m(2) at OLT to 100.2 (SD 47.5) mL/min/1.73 m(2) (P = .03) after 12 months and 98.71 (SD 33.74) mL/min/1.73 m(2) (P = .03) after 24 months' follow-up. CONCLUSION: A double immunosuppression therapy with EVR and EC-MPS ab initio seemed to be efficacions and safe, representing a valid alternative to CNIs to prevent renal failure after OLT.

Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports.

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.

Acquisition of instrumental conditioned reinforcement is resistant to the devaluation of the unconditioned stimulus.

The associative mechanisms responsible for the efficacy of Pavlovian stimuli during first- and second-order conditioning have been extensively studied, but little is known about the representations underlying instrumental conditioned reinforcement. The present study investigated the associative structure underlying conditioned reinforcement, by employing an unconditioned stimulus (US) devaluation procedure on a commonly used instrumental task: the acquisition of a new response with conditioned reinforcement. Whilst US-directed behaviour was abolished following devaluation, the conditioned stimulus acting as a conditioned reinforcer supported the acquisition of instrumental responding. In this preparation then, the conditioned reinforcer appears to be impervious to devaluation of its associated US, suggesting that the underlying representation maintaining behaviour is independent of the current value of the US and may reflect the activation of a central appetitive motivational state.

Reinstatement and spontaneous recovery of cocaine-seeking following extinction and different durations of withdrawal.

Stimuli paired with drug use can acquire powerful motivational properties that are believed to induce relapse to drug-seeking in abstinent humans. Behavioural interventions for drug addiction, that have attempted to reduce the probability of relapse by extinguishing the motivational impact of drug-associated conditioned stimuli (CS), have had limited success. One explanation for the ready propensity to relapse to drug-seeking even following extinction of these stimuli may be that abstinence by humans can increase the ability of conditioned stimuli and drug primes to reinstate responding. In the present study, we sought to determine the effects on cocaine-seeking of imposing different periods of drug unavailability on rats, with or without extinction of the drug-seeking response and non-reinforced exposure to drug-associated stimuli. Rats were trained to self-administer cocaine under a second-order schedule of reinforcement, under which high response rates are maintained by drug-paired conditioned reinforcers, prior to extinction of the operant response alone or in combination with contingent presentation of the CS. Comparison of cocaine-seeking behaviour during a test session conducted either 1 day or 21 days after a 7-day period of extinction revealed that responding was significantly decreased the day after extinction, but spontaneously recovered following a further imposed period of 21 days during which cocaine and cocaine cues were not available. Self-administered cocaine further potentiated reinstated responding following all withdrawal periods. These findings are discussed with reference to interactions between drug unavailability, conditioned stimuli and cocaine self-administration, on the reinstatement of drug-seeking and the potential utility of extinction therapies for drug addiction.

Conditioned changes in dopamine oxidation currents in the nucleus accumbens of rats by stimuli paired with self-administration or yoked-administration of d-amphetamine.

In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked- or self-administered intravenous injections of the psychostimulant d-amphetamine. Daily conditioning trials began with a non-contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d-amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4-7, and on each trial, intravenous d-amphetamine (0.25 mg/kg per injection) self-administration produced a significant maximal increase in mean dopamine oxidation currents of approximately 8 nA above baseline. Dopamine oxidation currents in rats receiving yoked d-amphetamine were approximately 5 nA above baseline by the fourth day of drug administration and reached approximately 8 nA on the seventh and final day of drug administration. On day 9 the first presentation of the vehicle injection and conditioned stimulus, in combination with illumination of the house lights, induced an immediate increase in nucleus accumbens dopamine oxidation currents in all rats that had previously received d-amphetamine. Subsequent presentations of the conditioned stimulus at 30 min intervals induced further increases in extracellular dopamine oxidation currents in both drug-treated groups. By the end of the 3 h session, both groups had similar maximal conditioned increases in dopamine oxidation currents of approximately 6 nA. These data are discussed with relation to the neurochemistry of drug craving.