From safety to frustration: The neural substrates of inhibitory learning in aversive and appetitive conditioning procedures.

Inhibitory associative learning counters the effects of excitatory learning, whether appetitively or aversively motivated. Moreover, the affective responses accompanying the inhibitory associations are of opponent valence to the excitatory conditioned responses. Inhibitors for negative aversive outcomes (e.g. shock) signal safety, while inhibitors for appetitive outcomes (e.g. food reward) elicit frustration and/or disappointment. This raises the question as to whether studies using appetitive and aversive conditioning procedures should demonstrate the same neural substrates for inhibitory learning. We review the neural substrates of appetitive and aversive inhibitory learning as measured in different procedural variants and in the context of the underpinning excitatory conditioning on which it depends. The mesocorticolimbic dopamine pathways, retrosplenial cortex and hippocampus are consistently implicated in inhibitory learning. Further neural substrates identified in some procedural variants may be related to the specific motivation of the learning task and modalities of the learning cues. Finally, we consider the translational implications of our understanding of the neural substrates of inhibitory learning, for obesity and addictions as well as for anxiety disorders.

Strain comparisons in inhibitory discrimination learning and novel object recognition procedures.

Strain differences in visual abilities and exploratory tendencies can confound rats' performance in cognitive tests of learning and memory. In the present study we compared the performance of albino Wistar and pigmented Lister Hooded rats in appetitive conditioning and recognition memory procedures, specifically within-subjects inhibitory learning (A+ /AX-) and novel object recognition (NOR) variants. The inhibition task included an excitatory training stage and summation and retardation tests. Difference scores were used to help control for individual variation in baseline nosepoke responding. NOR was tested after a 10 min delay, following 24hr delay and using a recency variant. Discrimination ratios were used to control for individual variation in exploratory activity. In the inhibitory learning procedure, Lister Hooded showed more magazine activity prior to stimulus presentations than Wistar rats but this was a transient effect restricted to day 1 of excitatory training. There was no strain difference in associative learning at the excitatory training stage. The Wistars went on to show some performance advantage at the inhibitory discrimination stage and marginally stronger retardation test performance. In the NOR tasks, there was no significant effect of strain on cognitive performance, but the Wistars showed some advantage in the 10 min delay variant, whereas in the 24hr delay and relative recency NOR variants, the Lister Hooded rats showed some advantage. Overall the results of the present study confirm the suitability of Wistar rats for use in associative learning and basic NOR procedures.

The phase-resolved photoacoustic method to indicate chemical assignments of paracetamol.

In this work, the phase-resolved photoacoustic method was applied to provide specific information on the chemical assignments of paracetamol in the near-infrared region. Two broad bands, centered at 1370 and 1130 nm, were well-resolved using this method, making it possible to assign the peaks centered at 1398, 1355 and 1295 nm to a C-H combination from a CH3 structure and the peak at 1305 nm to a C-H combination from the aromatic ring. This information represents a new finding in chemical studies regarding this medicament.

Pentraxin 3 in plasma and vaginal fluid in women with preterm delivery.

OBJECTIVE To investigate the role of pentraxin 3 (PTX3), an acute-phase protein produced by cells of innate immunity in response to inflammatory signals, in spontaneous preterm delivery (PTD). DESIGN Cohort study. SETTING Department of Obstetrics and Gynecology of the University of Milano-Bicocca. POPULATION Forty-six pregnant women with preterm rupture of membranes (n=33) or preterm labour with intact membranes (n=13) delivering at <34 weeks of gestation and 34 women with uncomplicated pregnancies (control group). METHODS We compared plasma and vaginal PTX3 levels between study group and controls, and in women with versus women without clinical or histologic evidence of intrauterine infection using statistical analysis. MAIN OUTCOME MEASURES Peak PTX3 concentration. RESULTS Peak PTX3 concentration in plasma samples of study group was significantly higher than that in controls (1175, 0-9630 versus 650, 0-1450 pg/ml; P=0.0003) but not in vaginal swabs (1660, 0-6604 versus 457, 0-4649 pg/ml; P=0.386). PTX3 levels in plasma were significantly higher in women with placenta vasculopathy compared with that in women with no placental lesions (2910, 0-9630 versus 636, 0-5692 pg/ml; P=0.04). Peak plasma and vaginal PTX3 concentrations were not significantly different in women with versus women without intrauterine infection (1168, 0-7110 versus 845, 0-9630 pg/ml, P=0.34 and 1975, 471-6604 versus 1919, 0-4150 pg/ml, P=0.38, respectively). CONCLUSIONS Spontaneous PTD is associated with a significant increase of maternal plasma concentrations of PTX3. PTX3 seems to be a marker of placenta vasculopathy rather than intrauterine infection.

Palliative surgery for recurrent bowel obstruction due to advanced ovarian cancer.

AIM: Intestinal obstruction is a frequent event in patients affected by ovarian carcinoma. Little data on repeat palliative surgery for recurrent bowel obstruction are available. The aim of this study was to analyze postoperative and long term outcomes of ovarian cancer patients who underwent reoperation for recurrent intestinal obstruction. METHODS: We retrospectively evaluated the records of these patients treated at our Department between 1992 and 2002. RESULTS: Nine women with a mean age of 56 years (range 37-72) were identified. All patients had undergone previous abdominal surgery for bowel obstruction from ovarian cancer. All patients underwent exploratory laparotomy. In 4 patients (Group A) because of advanced disease, only exploratory surgery was carried out. A surgical correction was achieved in the other 5 patients (Group B), but only 3 patients had a successful palliation, defined as the ability to tolerate an oral intake for at least 60 days postoperatively. Postoperative mortality was nil, morbidity was 44.4%; particularly 2 patients developed an enterocutaneous fistula. Mean survival of Group A and B patients were 36.7 and 96.2 days respectively. The 3 successful palliated patients died of disease after 3.5, 4 and 5 months, in 2 cases for recurrent bowel obstruction. CONCLUSIONS: Repeat surgery for recurrent bowel obstruction in advanced ovarian carcinoma may achieve successful palliation in few cases and is associated with high postoperative morbidity and limited survival. In these patients non surgical approaches based on medical treatment, percutaneous endoscopic gastrostomy and stent placement should be considered.

Alteration of hypothalamus-pituitary-adrenal gland axis in colorectal cancer patients. Preliminary report.

AIM: In advanced cancer patients a cell-mediated immunological impairment, both at baseline and during postoperative period, is often found and is associated with poor prognosis. Cortisol is strictly involved in the response to major surgical stress, is an immunosuppressor and causes a redistribution of immunological population cells in different tissues. The aim of the study was to verify serum levels and circadian rhythm of cortisol in patients with colorectal cancer at baseline before surgery and in the postoperative period, and relate it to the immune status. METHODS: In 21 patients with colorectal cancer undergoing surgery we evaluated the assessment of total lymphocytes, CD4+, cortisolemia, circadian rhythm of cortisol (11 p.m. and 8 a.m.) at baseline and in 3(rd) and 7(th) postoperative days. RESULTS: Increase of cortisolemia, as decrease of total and CD4+ lymphocytes in the postoperative period versus baseline was statistically significant. Patients with an altered circadian rhythm were 47% and 36% at 3rd and 7th postoperative days, respectively. At baseline 19% of patients had an altered cortisol circadian rhythm and it was more frequent in patients with nodal involvement (p<0.05) and with metastasis (p<0.01). No relations between lymphocytopenia and alteration of cortisolemia and cortisol circadian rhythm were found, either at baseline or postoperatively (p<0.05). CONCLUSION: Lymphocytopenia in cancer patients seems not to be associated with cortisol level and circadian rhythm alteration, either at baseline or after surgical stress. An impairment of circadian rhythm of cortisol was found at baseline in 19% of patients. It was significantly associated with the presence of metastatic disease.

Dorsal hippocampal lesions impair appetitive classical conditioning to localized cues.

Three experiments examined appetitive classical conditioning in rats with small electrolytic lesions of the dorsal hippocampus. In all the experiments, the reinforcer was food delivery and the conditioned response (CR) entry to the food tray; the three experiments differed in the nature of the conditioned stimulus (CS). When this was a small light located inside the food tray, conditioning was impaired in lesioned animals, but when the CS was a general increase in illumination, they learned at the same rate as controls. With a white noise as the CS, learning was significantly faster in lesioned subjects. These data demonstrate that lesions of the dorsal hippocampus can produce impairments in appetitive delay conditioning, but only with certain types of CS. It is suggested that deficits are found with CSs that are localized in space.

Enhanced stimulus-reward learning by intra-amygdala administration of a D3 dopamine receptor agonist.

The amygdala is considered to be a critical neural substrate underlying the formation of stimulus-reward associations, and is known to receive substantial innervation from dopaminergic neurons located within the ventral mesencephalon. However, relatively little is known about the function of the mesoamygdaloid dopamine projection in stimulus-reward learning. Recently, we have found post-session intra-amygdala microinjections of d-amphetamine to enhance appetitive Pavlovian conditioning as assessed in a discriminative approach task. In the present study, we have examined the effects of dopamine receptor agonists possessing relative selectivity for the D1, D2 and D3 receptor subtypes in order to examine more fully the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Thus, subjects were trained to associated an initially neutral stimulus (CS+) with 10% sucrose reward (US). A second, control stimulus (CS-) was also presented but never paired with sucrose reward. In order to measure specifically the conditioned response to CS+/CS- presentation, responding during CS and US presentations was measured separately. Immediately following each training session, subjects received bilateral intra-amygdala infusion of 0.1, 1 or 10 nmol/side of SKF-38393, quinpirole or 7-OH-DPAT. Infusions of SKF-38393 or quinpirole were without effect on CS+ approach. However, post-session intra-amygdala infusions of 7-OH-DPAT enhanced selectively CS+ approach in a dose-dependent fashion. No dose of any drug affected CS- approach, US behaviours, or measures of extraneous behaviour. Subsequent acquisition of a novel conditioned instrumental response was also unaffected. Thus, the present data indicate a selective involvement of the D3 dopamine receptor subtype in the modulation of stimulus-reward learning by the mesoamygdaloid dopamine projection.

Contextual control of conditioned responding in rats with dorsal hippocampal lesions.

The control exerted by contextual cues over classically conditioned responding was assessed for rats with electrolytic lesions of the dorsal hippocampus and sham-operated controls. In 3 experiments the rats received initial training with 2 reinforced cues, each presented in its own distinctive context, followed by a nonreinforced test in which the cues were presented in the other context. Both control and operated subjects showed context specificity, as evidenced by less vigorous responding to these cues than to cues presented on test in their original contexts. The groups did not differ in their ability to learn an explicit discrimination in which a given cue was reinforced in one context and nonreinforced in a different context (although the groups did differ on a simple autoshaping task). It is concluded that a special role for the hippocampus in the contextual control of conditioned responding still remains to be demonstrated.

Role of stimulus ambiguity in conditional learning.

Three experiments using rats and the conditioned emotional response procedure examined the notion that when a conditioned stimulus (CS) is paired with a reinforcer (US), that CS must be ambiguous if the CS-US association is to become the target of conditional control. CS ambiguity was manipulated by varying whether the CS had been preexposed prior to conditioning. In Experiments 1 and 2, it was demonstrated that a cue that accompanied pairings of a CS and shock acquired conditional control over the CS-shock association when that CS had been preexposed, but not when it was novel. The measure of conditional control in Experiments 1 and 2 was the ability of the (conditional) cue to enhance responding to the target CS. Experiment 3 used a blocking procedure to show that this enhancement reflected an amplification of the target CS's effective associative strength. These findings extend existing knowledge of the conditions required for conditional cue formation.

Enhancement of latent inhibition in rats with electrolytic lesions of the hippocampus.

Two groups of rats--1 with electrolytic lesions of the hippocampus and 1 consisting of sham-operated controls--received flavor-aversion conditioning with 2 flavors. All subjects had received prior nonreinforced exposure to Flavor A. Latent inhibition was apparent in slower acquisition of the aversion to Flavor A than to Flavor B. Hippocampal lesions had no effect on acquisition to the nonpreexposed Flavor B but produced a marked enhancement of the latent inhibition effect. The contrast between this result and previous findings of an attenuation of latent inhibition in subjects with hippocampal lesions is discussed.

Discriminative inhibition is specific to the response-reinforcer association but not to the discriminative stimulus.

In 4 experiments an instrumental contingency between a response and a reinforcer was introduced in the presence of a discriminative stimulus. Then a discriminative inhibitor (S delta) was established that signaled that the instrumental contingency would no longer operate in the presence of that discriminative stimulus, so that the S delta suppressed operant responding. The degree to which the S delta, s inhibitory properties transferred to different discriminative stimuli and different response-reinforcer associations was then explored. In Experiments 1 and 2 the S delta, s effects transferred perfectly to a 2nd discriminative stimulus, whereas the results of Experiments 3 and 4 were consistent with the hypothesis that the S delta, s inhibitory properties were specific to the original response-reinforcer association. The theoretical implications of these findings are discussed.

Occasion-setting training renders stimuli more similar: acquired equivalence between the targets of feature-positive discriminations.

In two experiments rats received training on two concurrent appetitive feature-positive discriminations. A preliminary test in Experiment 1 confirmed previous demonstrations of the transfer of occasion-setting properties--the feature from one of these discriminations was better able to facilitate responding to the occasion-set target CS from the second discrimination than to a control stimulus that had not been the subject of occasion-setting. The source of this transfer was investigated in a second phase of training, and in Experiment 2. In both experiments one of the occasion-set CSs was paired with food, and generalization of appetitive conditioned responding from this stimulus to the second occasion-set CS, and to a control cue, was examined. There was more generalization from the first occasion-set CS to the second CS that had also been occasion-set than to the control cue. This is taken as evidence that occasion-set CSs are rendered more similar as a result of their common training history. The implications of these findings for explaining transfer of occasion setting are discussed.

Acquired equivalence between cues trained with a common antecedent.

In Experiment 1, rats experienced 2 stimuli (A and N) each preceded by the same event (food) or by different events (food preceded 1 but not the other). N was then paired with shock, and the generalization of conditioned suppression to A was assessed. Generalization was more marked when A and N had been experienced along with a common antecedent. In Experiment 2, 3 stimuli (A, B, and N) were presented in initial training. For 1 group, A and N were preceded by food and B was not; for a 2nd group A alone was preceded by food. In each group, suppression generalized more readily from N to the stimulus that had received the same initial training as had been given to N. Experiment 3 found that generalization was not enhanced between stimuli when 1 had preceded food in initial training and 1 had followed it. These results demonstrate that stimuli that have shared a common antecedent will come to be treated as equivalent.

Negative priming in associative learning: evidence from a serial-conditioning procedure.

Three experiments investigated the suggestion that a predicted or primed stimulus commands less processing and consequently elicits a weaker conditioned response (CR) than a stimulus that is not primed. In each experiment rats received initial training in which the presentation of each of 2 serial compounds, A-X and B-Y, was followed by the delivery of food. Subsequently, X's capacity to elicit the CR, approaching the site of food delivery, was assessed when X was preceded by Stimulus A (i.e., primed) or was presented after Stimulus B. Stimulus X elicited a more vigorous response when it was presented after B than when it followed A. These results show that the ability of one event to elicit its CR is reduced if its presentation has been predicted by some other event. This negative priming effect supports one aspect of Wagner's (1981) model of Pavlovian conditioning.

Inhibitory discriminative control is specific to both the response and the reinforcer.

In two experiments an S delta was established which signalled the absence of an instrumental contingency between a particular response, R1, and a particular reinforcer, Rf1. The S delta suppressed operant responding, and the specificity of this suppression to the elements of the response-reinforcer association, R1 and Rf1, was explored. Experiment 1 showed that the S delta suppressed performance of R1 more effectively than it suppressed performance of a second response, R2. Experiment 2 showed that the S delta suppressed performance of a response rewarded with Rf1 more effectively than it suppressed performance of a response that had been rewarded with a second reinforcer, Rf2. These results suggest that an S delta's suppressive effects are specific to the particular response and reinforcer, which were uncorrelated in its presence during training. The implications of these results for theories of inhibitory discriminative control and for theories of occasion setting are discussed.

[Althesin in anesthesia for neuroradiologic arteriographic studies]. / L'althesin nella anestesia delle indagini arteriografiche neuroradiologiche.

Following mention of problems of cerebral haemodynamics and the action of various anaesthetics on endocranial pressure, a personal anaesthesiological technique based on the use of althesin in drip form is reported and its advantages listed.