Restoration of the coagulation cascade on CPB: a case report.

Coagulopathy can sometimes be observed when CPB times are prolonged. Correction of coagulopathy post CPB can present the surgical team with a number of challenges, including right ventricular volume overload, hemodilution, anemia and excessive cell salvage with further loss of coagulation factors. Restoration of the coagulation cascade on CPB may help to avoid these issues. This case report is of a 64-year-old male with a delayed diagnosis of aortic dissection. The patient presented to the cardiac surgery operating room with hepatic and renal shock/failure, with the resulting coagulopathy. The described technique is representative of a technique that we sometimes employ to restore the clotting mechanism before separating from bypass.

Association of Upper GI Surgery of Great Britain and Ireland (AUGIS) Delphi consensus recommendations on the adoption of robotic upper GI surgery.

BACKGROUND: The adoption of robotic platforms in upper gastrointestinal (GI) surgery is expanding rapidly. The absence of centralised guidance and governance in adoption of new surgical technologies may lead to an increased risk of patient harm. METHODS: Surgeon stakeholders participated in a Delphi consensus process following a national open-invitation in-person meeting on the adoption of robotic upper GI surgery. Consensus agreement was deemed met if >80% agreement was achieved. RESULTS: Following two rounds of Delphi voting, 25 statements were agreed on covering the training process, governance and good practice for surgeons' adoption in upper GI surgery. One statement failed to achieve consensus. CONCLUSIONS: These recommendations are intended to support surgeons, patients and health systems in the adoption of robotics in upper GI surgery.

Outcomes of emergency laparoscopy in the elderly.

INTRODUCTION: This paper assessed the association between operative approach and postoperative in-hospital mortality in elderly patients undergoing emergency abdominal surgery. Patients undergoing emergency laparotomy have high morbidity and mortality rates. One-third of patients requiring emergency surgery are over 75 years old, and their in-hospital mortality rate exceeds 17%. Fewer than 20% of emergency abdominal operations in the UK are attempted laparoscopically, and only 10% are completed laparoscopically. Little is known about how laparoscopic emergency surgery in the elderly might affect outcomes. METHODS: An observational UK study was performed using the prospectively maintained National Emergency Laparotomy Audit (NELA) database. Operative approach, NELA risk-prediction score and in-hospital mortality were recorded. The effect of operative approach on in-hospital mortality was analysed, both on a national basis and in a high-volume laparoscopic centre. RESULTS: A total of 47,667 patients were included in the study, of whom 15,068 were over 75 years of age. Nationally, surgery was completed by the laparoscopic approach in 7.8% of patients aged over 75; both crude mortality (9.2%) and risk-adjusted mortality (7.1%) were significantly reduced (p<0.0001). In our unit, surgery was completed laparoscopically in 48.4% of patients aged over 75; both crude mortality (6.6%) and risk-adjusted mortality (3.3%) were significantly reduced (p<0.0001). CONCLUSION: Laparoscopy in emergency surgery has been shown in this study to significantly reduce in-hospital mortality in elderly patients and should be embraced in every centre dealing with emergency abdominal surgery.

Comparison of the effects of 2,5-dimethoxy-4-iodoamphetamine and D-amphetamine on the ability of rats to discriminate the durations and intensities of light stimuli.

Rats' ability to discriminate durations is disrupted by the monoamine-releasing agent D-amphetamine and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). It is unknown whether this effect is specific for temporal discrimination or reflects general disruption of stimulus control. This experiment addressed this question by comparing the effects of D-amphetamine and DOI on temporal discrimination and discrimination along a nontemporal dimension, light intensity. Twelve rats responded on a schedule in which a light (intensity 22 cd/m) was presented for t seconds (2.5-47.5 s), after which levers A and B were presented. Responses on A were reinforced when t was less than 25 s, and responses on B were reinforced when t was greater than 25 s. Twelve rats responded on a similar schedule in which a light of intensity i (3.6-128.5 cd/m) was presented for 25 s. Responses on A were reinforced when i was less than 22 cd/m, and responses on B were reinforced when i was greater than 22 cd/m. Logistic functions were fitted and psychophysical parameters estimated [T50, I50 (central tendency of temporal or light-intensity discrimination); Weber fraction (relative discriminative precision)]. D-Amphetamine (0.2-0.8 mg/kg) increased the Weber fraction for temporal and light-intensity discrimination; DOI (0.625-0.25 mg/kg) increased it for temporal discrimination only. Both drugs increased T50; neither altered I50. D-Amphetamine and DOI have similar effects on temporal discrimination but different effects on light-intensity discrimination. The increase in T50 may reflect the impairment of sustained attention during prolonged stimulus presentation.

High concentrations of glutathione in glandular stomach: possible implications for carcinogenesis.

In laboratory rodents, concentrations of reduced glutathione (GSH) are exceedingly high (up to 7 to 8 millimolar) in the glandular gastric tissue compared to concentrations in other portions of the gastrointestinal tract or to those of most other organs. Gastric GSH varies diurnally, with the highest levels occurring in the late afternoon or early evening. Starvation, treatment with diethyl maleate, or cold-restraint stress all caused marked decreases in stomach GSH, whereas treatment with cobaltous chloride caused an increase in the GSH concentrations. The physiological significance of the high gastric GSH is unknown, but because this endogenous compound may strongly modulate (decrease or increase) the macromolecular binding of certain chemicals capable of inducing stomach tumors, the possible role of glutathione in the pathogenesis of chemically induced gastric cancer should be considered.

Quantitative analysis of the effect of lesions of the subthalamic nucleus on intertemporal choice: further evidence for enhancement of the incentive value of food reinforcers.

Recent evidence suggests that the subthalamic nucleus (STN) is involved in regulating the incentive value of food reinforcers. The objective of this study was to examine the effect of lesions of the STN on intertemporal choice (choice between reinforcers differing in size and delay). Rats with bilateral quinolinic acid-induced lesions of the STN (n = 15) or sham lesions (n = 14) were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B(50)) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B(50)) vs. d(A)) were derived. The STN-lesioned group showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) than the sham-lesioned group; the intercepts did not differ between the groups. The results agree with recent evidence for a role of the STN in incentive value. Unlike some earlier studies, these results do not indicate a role of the STN in delay discounting.

Effect of reinforcer magnitude on performance maintained by progressive-ratio schedules.

This experiment examined the relationship between reinforcer magnitude and quantitative measures of performance on progressive-ratio schedules. Fifteen rats were trained under a progressive-ratio schedule in seven phases of the experiment in which the volume of a 0.6-M sucrose solution reinforcer was varied within the range 6-300 microl. Overall response rates in successive ratios conformed to a bitonic equation derived from Killeen's (1994) Mathematical Principles of Reinforcement. The "specific activation" parameter, a, which is presumed to reflect the incentive value of the reinforcer, was a monotonically increasing function of reinforcer volume; the "response time" parameter, delta, which defines the minimum response time, increased as a function of reinforcer volume; the "currency" parameter, beta, which is presumed to reflect the coupling of responses to the reinforcer, declined as a function of volume. Running response rate (response rate calculated after exclusion of the postreinforcement pause) decayed monotonically as a function of ratio size; the index of curvature of this function increased as a function of reinforcer volume. Postreinforcement pause increased as a function of ratio size. Estimates of a derived from overall response rates and postreinforcement pauses showed a modest positive correlation across conditions and between animals. Implications of the results for the quantification of reinforcer value and for the use of progressive-ratio schedules in behavioral neuroscience are discussed.

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice.

RATIONALE: The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. OBJECTIVE: This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105-172). MATERIALS AND METHODS: Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r2 > 0.92). The motor parameter, delta, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. CONCLUSIONS: The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.

Effect of disconnecting the orbital prefrontal cortex from the nucleus accumbens core on inter-temporal choice behaviour: a quantitative analysis.

Previous experiments showed that destruction of the orbital prefrontal cortex (OPFC) or the nucleus accumbens core (AcbC) in rats altered choice between two delayed food reinforcers. Application of a quantitative model of inter-temporal choice suggested that lesions of either structure increased the delay-dependent degradation of reinforcer value (delay discounting); destruction of the OPFC (but not the AcbC) also increased the relative value of the larger reinforcer. This experiment examined the effect of disconnecting the OPFC from the AcbC on inter-temporal choice. Rats received excitotoxin-induced contralateral lesions of the OPFC and AcbC (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection+callosotomy) or sham lesions. They were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B50) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B50)vs. d(A)) were derived. The disconnection+callosotomy group showed a lower intercept of the indifference function (implying a higher rate of delay discounting) than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas the callosotomy group did not differ significantly from the sham-lesioned group. The results suggest that OPFC-AcbC connections are involved in delay discounting of food reinforcers, but provide no evidence for an involvement of OPFC-AcbC connections in regulating sensitivity to reinforcer size.

Tolerance to the effect of 2,5-dimethoxy-4-iodoamphetamine (DOI) on free-operant timing behaviour: interaction between behavioural and pharmacological mechanisms.

RATIONALE: The psychostimulant d-amphetamine, the D(2/3) dopamine receptor agonist quinpirole and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behaviour. There is evidence that tolerance develops to the effects of psychostimulants on timing performance during chronic treatment; this tolerance is generally attributed to behavioural adaptation rather than to pharmacological desensitisation. There have been no previous investigations of tolerance to the effect of DOI on free-operant timing behaviour. OBJECTIVE: To demonstrate tolerance to DOI's effect on timing performance and to examine the nature of this tolerance. MATERIALS AND METHODS: Rats were trained under the free-operant psychophysical procedure to press two levers (A and B) in 80-s trials in which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 8-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices (T (50) [time corresponding to %B = 50]; Weber fraction). RESULTS: In experiment 1, DOI (0.25 mg kg(-1)) reduced T (50) compared to vehicle; tolerance to this effect was seen after repeated daily treatments with DOI if the rats were exposed to behavioural training during the period of treatment but not if the repeated treatments took place during a 'holiday' from behavioural training. In experiment 2, repeated treatment with DOI resulted in tolerance to the effect of DOI on T (50) and cross-tolerance to the effect of d-amphetamine (0.4 mg kg(-1)), but no cross-tolerance was seen to the effect of quinpirole (0.08 mg kg(-1)). CONCLUSIONS: The results indicate that behavioural adaptation is involved in the development of tolerance to DOI's effect on timing. The finding of cross-tolerance to d-amphetamine but not to quinpirole suggests that the reduction of T (50) in the free-operant psychophysical procedure may be brought about by two distinct pharmacological mechanisms, one activated by DOI and d-amphetamine, and the other by quinpirole.

Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis.

RATIONALE: There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. AIM: We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size. MATERIALS AND METHODS: Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after d(B). d(B) increased across blocks of trials, while d(A) was manipulated across phases of the experiment. Indifference delay d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d(B(50)) vs d(A)) derived. RESULTS: d(B(50)) increased linearly with d(A) (r(2) > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC. CONCLUSIONS: The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.

Evidence for the sensitivity of operant timing behaviour to stimulation of D1 dopamine receptors.

RATIONALE: Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Previous studies using the fixed-interval peak procedure implicated D(2)-like dopamine receptors in these effects. However, recent findings suggest that d-amphetamine alters timing performance on the free-operant psychophysical procedure via D(1)-like receptors. It is not known whether this effect of d-amphetamine is mimicked by direct D(1)-like receptor stimulation. OBJECTIVE: The effects of a D(1)-like receptor agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine (SKF-81297) on performance on the free-operant psychophysical procedure and the interaction between SKF-81297 and a D(1)-like receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566) and a D(2)-like receptor antagonist haloperidol, were examined. MATERIALS AND METHODS: Rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data (percent responding on B [%B] vs time from trial onset [t]) under each treatment condition, and quantitative indices of timing (T(50) [value of t corresponding to %B = 50] and the Weber fraction [(T(75)-T(25))/2T(50); T(25) and T(75) are values of t corresponding to %B = 25 and %B = 75] were compared among treatments. RESULTS: SKF-81297 (0.8 mg kg(-1)) reduced T(50); this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) but not by haloperidol (0.05, 0.1 mg kg(-1)). CONCLUSIONS: Stimulation of D(1)-like dopamine receptors affects performance in the free-operant psychophysical procedure.

Effect of quinpirole on timing behaviour in the free-operant psychophysical procedure: evidence for the involvement of D2 dopamine receptors.

RATIONALE: Operant timing behaviour is sensitive to dopaminergic manipulations. It has been proposed that this effect is mediated principally by D(2)-like dopamine receptors. However, we recently found that the effect of d-amphetamine on timing in the free-operant psychophysical procedure was mediated by D(1)-like dopamine receptors. It has not been established whether stimulation of D(2)-like receptors affects timing in this schedule. OBJECTIVE: To examine the effects of a D(2)-like receptor agonist quinpirole on second-range timing and the ability of dopamine receptor antagonists to reverse quinpirole's effects. MATERIALS AND METHODS: Rats responded on two levers (A and B) under a free-operant psychophysical schedule in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rates [percent responding on B (%B) vs time (t)] under each treatment; quantitative timing indices [T (50) (value of t when %B = 50) and Weber fraction] were compared among treatments. RESULTS: Quinpirole (0.04, 0.08 mg kg(-1)) reduced T (50). This effect was attenuated by D(2)-like receptor antagonists haloperidol (0.05, 0.1 mg kg(-1)), eticlopride (0.04, 0.08 mg kg(-1)) and sulpiride (30, 60 mg kg(-1)), but not by the D(3) receptor-preferring antagonist nafadotride (0.5, 1 mg kg(-1)), the D(4) receptor antagonist L-745870 (1, 3 mg kg(-1)) or the D(1)-like receptor antagonist SKF-83566 (0.015 mg kg(-1)). CONCLUSIONS: Results suggest that quinpirole reduced T (50) via an action at D(2) receptors. D(1)-like and D(2)-like receptors may mediate behaviourally similar but pharmacologically distinct effects on timing behaviour.

Effects of d-amphetamine and DOI (2,5-dimethoxy-4-iodoamphetamine) on timing behavior: interaction between D1 and 5-HT2A receptors.

RATIONALE: The dopamine-releasing agent d-amphetamine and the 5-HT(2) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) have similar effects on free-operant timing behavior. The selective D(1) dopamine receptor antagonist 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), but not the D(2) dopamine receptor antagonist haloperidol, can antagonize the effect of d-amphetamine, and the selective 5-HT(2A) receptor antagonist (+/-)2,3-dimethoxyphenyl-1-(2-(4-piperidine)-methanol (MDL-100907) can antagonize the effect of DOI. However, it is not known whether the effect of d-amphetamine can be reversed by MDL-100907 and the effect of DOI by dopamine receptor antagonists. OBJECTIVE: The objective of this work is to examine the interactions of d-amphetamine and DOI with MDL-100907, SKF-83566, and haloperidol on timing performance. MATERIALS AND METHODS: Rats (n = 12-15 per experiment) were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data from each rat for the derivation of timing indices [T (50) (time corresponding to %B = 50); Weber fraction]. Rats were treated systemically with d-amphetamine or DOI, alone and in combination with haloperidol, SKF-83566, or MDL-100907. RESULTS: d-Amphetamine (0.4 mg kg(-1)) reduced T (50) compared to vehicle; this effect was antagonized by SKF-83566 (0.03 mg kg(-1)) and MDL-100907 (0.5 mg kg(-1)), but not by haloperidol (0.05, 0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced T (50); this effect was reversed by MDL-100907 (0.5 mg kg(-1)), but not by SKF-83566 (0.03 mg kg(-1)) or haloperidol (0.05 mg kg(-1)). CONCLUSIONS: The results suggest that both 5-HT(2A) and D(1) receptors, but not D(2) receptors, are involved in d-amphetamine's effect on timing behavior in the free-operant psychophysical procedure. DOI's effect on timing is mediated by 5-HT(2A) receptors, but neither D(1) nor D(2) receptors are involved in this effect.

Evidence for a role of D1 dopamine receptors in d-amphetamine's effect on timing behaviour in the free-operant psychophysical procedure.

RATIONALE: Temporal differentiation of operant behaviour is sensitive to dopaminergic manipulations. Studies using the fixed-interval peak procedure implicated D2 dopamine receptors in these effects. Less is known about the effects of dopaminergic manipulations on temporal differentiation in other timing schedules. OBJECTIVE: To examine the effects of a D1 antagonist,8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SKF-83566), and a D2 antagonist, haloperidol, on performance on the free-operant psychophysical procedure, and the ability of these antagonists to reverse the effects of the catecholamine-releasing agent, d-amphetamine on performance. The antagonists' ability to reverse d-amphetamine-induced hyperlocomotion was also examined. MATERIALS AND METHODS: Rats responded on two levers (A and B) under a free-operant psychophysical schedule, in which reinforcement was provided intermittently for responding on A during the first half, and B during the second half, of 50-s trials. Logistic functions were fitted to the relative response rate data (percent responding on B [%B] vs time [t]) in each treatment condition, and quantitative timing indices [T50 (value of t corresponding to %B=50) and Weber fraction] were compared among treatments. Effects of the treatments on locomotion were measured in a separate experiment. RESULTS: SKF-83566 (0.015, 0.03, 0.06 mg kg(-1)) did not affect timing performance. Haloperidol (0.025, 0.05 mg kg(-1)) had no effect; a higher dose (0.1 mg kg(-1)) reduced T (50). d-Amphetamine (0.4 mg kg(-1)) reduced T50; this effect was antagonised by SKF-83566 but not by haloperidol. Both antagonists reduced d-amphetamine-induced hyperlocomotion. CONCLUSIONS: The results suggest that d-amphetamine's effect on performance in the free-operant psychophysical procedure is mediated by D1 rather than D2 receptors.

Effects of 5-HT1A and 5-HT2A receptor stimulation on temporal differentiation performance in the fixed-interval peak procedure.

We examined the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) on performance on the fixed-interval peak procedure, and the sensitivity of these effects to 5-HT1A and 5-HT2A receptor antagonists (N-[2-(4-[2-methoxyphenyl]-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide [WAY-100635] and ketanserin). Rats were trained to press a lever for food reinforcement in 50 min sessions consisting of 32 trials in which the lever was continuously available, separated by 10 s inter-trial intervals. In 16 trials, reinforcement was delivered following the first response after 30 s had elapsed since trial onset (fixed-interval 30 s). In 16 randomly interposed (peak/probe) trials, reinforcement was omitted, and the lever remained in the operant chamber for 120 s. Response rate in probe trials was plotted against time from trial onset. Time to peak response rate (t(peak)) and the Weber fraction were derived from modified Gaussian curves fitted to each rat's data. 8-OH-DPAT (0.05 mg kg(-1)) reduced t(peak) and increased the Weber fraction; the effect on t(peak) was antagonized by WAY-100635 (0.1 mg kg(-1)). DOI (0.25 mg kg(-1)) also reduced t(peak) and increased the Weber fraction; the reduction of t(peak) was antagonized by ketanserin (2 mg kg(-1)). Stimulation of 5-HT1A and 5-HT2A receptors alters temporal differentiation in qualitatively similar ways.

Evidence that the effect of 5-HT2 receptor stimulation on temporal differentiation is not mediated by receptors in the dorsal striatum.

5-HT2 receptor stimulation alters temporal differentiation in free-operant timing schedules. The anatomical location of the receptor population responsible for this effect is unknown. We examined the effect of a 5-HT2 receptor agonist and antagonists, injected systemically and into the dorsal striatum, a region that is believed to play a major role in interval timing. Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5s epochs of the trials; logistic functions were fitted to the data from each rat to derive timing indices (T50: time corresponding to %B = 50; Weber fraction: [T75-T25]/2T50, where T75 and T25 are the times corresponding to %B = 75 and %B = 25). Systemic treatment with the 5-HT(2A/2C) receptor agonist 2,5,-dimethoxy-4-iodo-amphetamine (DOI) (0.25 mg/kg, s.c.) reduced T50; the 5-HT2A receptor antagonist MDL-100907 (0.5 mg/kg, i.p.) did not affect performance, but completely blocked the effect of DOI. DOI (1 and 3 microg) injected bilaterally into the dorsal striatum did not alter T50. The effect of systemic treatment with DOI (0.25 mg/kg, s.c.) was not altered by intra-striatal injection of MDL-100907 (0.3 microg) or the 5-HT2C receptor antagonist RS-102221 (0.15 microg). The ability of systemically administered MDL-100907 to reverse DOI's effect on T50 confirms the sensitivity of temporal differentiation to 5-HT2A receptor stimulation. The failure of intra-striatal MDL-100907 to antagonize the effects of DOI suggests that 5-HT2A receptors in the dorsal striatum are unlikely to be primarily responsible for DOI's effects on timing. Furthermore, the results provide no evidence for a role of striatal 5-HT2C receptors in DOI's effect on timing.

Quantitative analysis of the effects of some "atypical" and "conventional" antipsychotics on progressive ratio schedule performance.

RATIONALE: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the value or "efficacy" of reinforcers. A mathematical model affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. According to this model, the relation between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, alpha, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, delta, expresses the minimum time needed to execute a response, and is regarded as an index of "motor capacity". In a previous experiment we found that the "atypical" antipsychotic clozapine increased alpha, indicating an increase in the efficacy of a food reinforcer. OBJECTIVE: We examined the effects of four "atypical" and four "conventional" antipsychotics on progressive ratio schedule performance. METHODS: Rats responded for a sucrose reinforcer (0.6 M, 50 microl) on a time-constrained progressive ratio schedule (50-min sessions). After 90 preliminary training sessions, they received acute doses of antipsychotics (doses in mg kg(-1)): atypical: clozapine (2, 4, 8, IP; n=15), quetiapine (1.25, 2.5, 5, 10, SC; n=23), olanzapine (0.25, 0.5, 1, IP; n=15), ziprasidone (0.625, 1.25, 2.5, IP, n=15); conventional: haloperidol (0.025, 0.05, 0.1, IP, n=15), pimozide (0.125, 0.25, 0.5, IP; n=15), raclopride (0.25, 0.5, 1, SC; n=12), cis-flupenthixol (0.2, 0.4, 0.8, SC; n=15). Values of a and delta were estimated from the response rate functions obtained under each treatment condition, and were compared between drug and vehicle-alone treatments. RESULTS: The atypical antipsychotics significantly increased alpha (indicating enhancement of reinforcer efficacy), and also increased delta (indicating reduction of motor capacity). Haloperidol, pimozide and raclopride significantly increased delta; none of the conventional antipsychotics significantly altered alpha. CONCLUSIONS: The results extend previous findings with clozapine to other atypical antipsychotics and suggest that enhancement of the efficacy of reinforcers may be a common feature of atypical antipsychotics not shared by conventional antipsychotics.

Comparison of the effects of clozapine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on progressive ratio schedule performance: evidence against the involvement of 5-HT1A receptors in the behavioural effects of clozapine.

RATIONALE: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105-172) affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, delta, expresses the minimum time needed to execute a response, and is regarded as an index of 'motor capacity'. Previously we found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine's behavioural effects are mediated by agonistic action at 5-HT(1A) receptors. OBJECTIVE: This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. METHODS: Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute doses of clozapine (4 mg kg(-1)) and 8-OH-DPAT (100 microg kg(-1)), alone and in combination with the 5-HT(1A) receptor antagonist N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 microg kg(-1)). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg(-1)) and 8-OH-DPAT (25, 50 and 100 microg kg(-1)) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT). RESULTS: In both experiments, clozapine and 8-OH-DPAT increased a and delta. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and delta, but did not alter clozapine's effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not differ between sham-lesioned and 5,7-DHT-lesioned rats. CONCLUSIONS: The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. 8-OH-DPAT's effects are probably mediated by post-synaptic 5-HT(1A) receptors; clozapine's effects are mediated by a different mechanism, which does not appear to involve 5-HT(1A) receptors and which does not depend upon an intact 5-HTergic pathway.