Prefrontal cortex and reversion of atropine-induced disruption of the degraded contingency effect by antipsychotic agents and N-desmethylclozapine in rats.

Interactive context processing is a cognitive ability that is altered in psychotic states, including schizophrenia. This deficit has been linked to prefrontal cortical dysfunction in humans. The degraded contingency effect (DCE) is a simple form of interactive context processing by which contextual information interferes with a target conditioned stimulus for control over conditioned responding. We have previously shown that the DCE was disrupted by the muscarinic receptor antagonist atropine and that this disruption was specifically restored by cholinergic drugs displaying an antipsychotic-like profile, such as physostigmine or xanomeline. The DCE was selectively associated with an increase in Fos immunoreactivity in the medial prefrontal cortex (mPFC), an increase that was not observed in the presence of atropine. Here, we set out to test the actions of typical, atypical and potential antipsychotics on atropine-induced disruption of the DCE and the related mPFC Fos-immunoreactivity profile. Low doses of haloperidol, olanzapine, clozapine and N-desmethylclozapine reversed atropine-induced disruption of the DCE, but with different dose-dependent curves (linear shapes for haloperidol and N-desmethylclozapine, inverted U shapes for olanzapine and clozapine). The level of Fos within the mPFC paralleled the pharmacological profile of the different drugs. Compared to contingent control groups, an increased level of Fos immunoreactivity within the mPFC was observed only with doses that reversed atropine-induced disruption of the DCE. These results suggest that the deficit of interactive context processing, which is a hallmark of psychotic states, might originate from a mere deficit of fundamental associative processes. This deficit might result from a cholinergic blockade of the PFC.

Delayed aversive effects of high-dose fentanyl. Prevention by a polyamine-deficient diet.

The present study aimed to examine the effects of an acute administration of the mu-opioid receptor fentanyl on affect as assessed by place-conditioning procedure in rats. We determined the affective properties of fentanyl not only immediately following its administration, but also 24h later. Experiments were performed using the dose of fentanyl (240 gamma/kg; four injections of 60 gamma/(ml kg) every 15 min, subcutaneously) for which secondary hyperalgesia has been previously described. Our results show that the acute administration of fentanyl display biphasic affective properties, with early rewarding and 24-h delayed aversive components. The 24-h delayed aversive effects of fentanyl were not observed in animals submitted to a polyamine-deficient diet, suggesting an NMDA-dependent mechanism.

Involvement of the basal cholinergic forebrain in the mediation of general (propofol) anesthesia.

BACKGROUND: Recent studies have pointed out the involvement of the basal forebrain gamma-aminobutyric acid-mediated system in mediating the effects of general anesthesia. In this study, the authors asked whether the basal forebrain cholinergic system is also involved in mediating the effects of general anesthetics such as propofol. METHODS: Cholinergic lesions were produced by administration of the selective immunotoxin 192 immunoglobulin G-saporin into the lateral ventricles, the medial septum, or the nucleus basalis magnocellularis. The anesthetic potency of propofol was determined using an anesthetic score with a crossover counterbalanced design. Animals were given intraperitoneal propofol (25 or 50 mg/kg) repeatedly every 15 min to set up a subanesthetic (low-dose) or anesthetic (high-dose) state. The anesthetic score was assessed for each cumulative dose. Control of the cholinergic depletion was performed using histochemical acetylcholinesterase staining on brain slices. RESULTS: A shift from a subanesthetic state to an anesthetic state was observed mainly in the rats with the immunotoxin injected into the lateral ventricles or the medial septum and vertical diagonal band of Broca, compared with controls. In those rats, the density of acetylcholinesterase reaction products was normal in the striatum and the thalamus, but reduced in the cortex and the hippocampus. CONCLUSION: The anesthetic potency of propofol was increased in all rats with hippocampal lesions, whatever the injection sites, compared with controls. These results demonstrate that a cholinergic dysfunction in the basal forebrain potentiates the anesthetic effects of propofol.

Reciprocal relationships between general (Propofol) anesthesia and circadian time in rats.

Several common postdischarge symptoms, such as sleep disorders, headache, drowsiness or general malaise, evoke disturbances of circadian rhythms due to jet lag (ie crossing time zones) or shift work rotation. Considering that general anesthesia is associated with numerous effects on the central nervous system, we hypothesized that it may also act on the circadian timing system. We first determined the effects of the circadian timing on general anesthesia. We observed that identical doses of propofol showed marked circadian fluctuations in duration of effects, with a peak at the middle of the resting period (ie 7 h after lights on). Then, we examined the effects of general anesthesia on circadian timing, by analysing stable free-running circadian rhythms (ie in constant environmental conditions), an experimental approach used widely in circadian biology. Free-running rats were housed in constant darkness and temperature to assess possible phase-shifting effects of propofol anesthesia according to the time of the day. When administered around (+/-2 h) the daily rest/activity transition point, a 30-min propofol anesthesia induced a 1-h phase advance in the free-running rest-activity rhythm, while anesthesia had no significant resetting effect at other times of the day. Anesthesia-induced hypothermia was not correlated with the phase-shifting effects of propofol anesthesia. From our results, anesthesia itself can reset circadian timing, and acts as a synchronizing cue for the circadian clock.

Fos immunolabelling evidence for brain regions involved in the Pavlovian degraded contingency effect and in its disruption by atropine.

Using a fear conditioning preparation, [Carnicella, S., Pain, L., Oberling, P., 2005a. Cholinergic effects on fear conditioning I: The degraded contingency effect is disrupted by atropine but reinstated by physostigmine. Psychopharmacology 178, 524-532] showed that the muscarinic receptor antagonist atropine disrupted the degraded contingency effect (DCE) in the rat, that is, the processes by which contextual memory competes with cued memory for the control over conditioned responding. Here, we investigated neural substrates involved in the expression of normal and atropine-disrupted DCE, using the protein Fos as a marker of neuronal activity. Compared to contingent conditioning, the DCE was associated with a decrease of the amount of Fos immunoreactive neurons within the auditory system and the amygdala and an increase within the medial prefrontal cortex (mPFC). Compared to the normal DCE, atropine-induced disruption of the DCE was associated with an increase of the amount of Fos immunoreactive neurons within the central nucleus of the amygdala. When atropine-induced suppression of the DCE, Fos pattern was modified in the mPFC with a change in Fos immunoreactivity, but no longer associated with the DCE. However, the mPFC was the unique structure studied in which the amount of Fos immunoreactive neurons was differentially affected according to both the conditioning procedure and the pharmacological treatment. These results are discussed in the framework of the cholinergic modulation of context processing in the rat and are put in parallel with an emerging set of studies in humans regarding the role of the PFC in such processing.

Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine.

RATIONALE: The cholinergic system has been shown to modulate contextual fear conditioning. However, with the exception of trace conditioning studies, most of the available data have focussed on independent context, i.e., context that do not compete with the conditioned stimulus to control for the conditioned response (interactive context). OBJECTIVE: In the present series of experiments, the effects of the muscarinic antagonist, atropine, were assessed when contextual fear memory interacts with cued fear memory to regulate conditioned response, using a Pavlovian degraded contingency preparation in rats. This preparation not only afforded an insight into simple Pavlovian associations but also enabled us to test for the processes of competition that made use of these associations to make an appropriate response to a stimulus [degraded contingency effect (DCE)]. METHODS: In experiment 1, three doses of atropine [2.5, 5.0, and 10.0 mg/kg, intraperitoneally (i.p.)] were evaluated on male Sprague-Dawley rats. In experiment 2, physostigmine (0.037-0.3 mg/kg, i.p.) was injected after the administration of 5 mg/kg of atropine. RESULTS: Experiment 1A and its partial replication (experiment 1B) showed that at asymptotic level of training, atropine did not alter contextual and cued fear memories when the subjects were directly tested for them, whereas it suppressed the DCE for a 5 mg/kg dose. Indeed, atropine-induced suppression of the DCE was found to be an inverted U-shaped dose-response curve. Experiment 2 showed that physostigmine caused a dose-dependent reversal of the atropine-induced alleviation of the DCE, without altering the expression of simple cued and contextual fear memories. CONCLUSION: These results evidence at asymptotic level of training a cholinergic modulation of the processing of interactive context, but not of independent ones. They are discussed in the framework of the mechanisms that are involved in both types of contextual processing.

Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect.

RATIONALE: In a companion study (Carnicella et al., 2005), we showed that the muscarinic antagonist atropine, when administered after extensive training during both conditioning and testing, affected neither cued nor contextual fear memories when both of them did not compete for the control of the overt behaviour. In contrast, atropine altered the degraded contingency effect (DCE), that is, the processes by which contextual fear memory competes with the cued one for the control of the conditioned response. Atropine-induced disruption of the DCE was fully reversed by the administration of the anticholinesterase inhibitor physostigmine, which suggests a direct cholinergic implication. OBJECTIVE: The present series of experiments was conducted in order to define more precisely the involvement of the cholinergic system in such an effect. METHODS: Oxotremorine (0.0, 0.0075, 0.015, or 0.03 mg/kg), pilocarpine (0.0, 0.3, 1, or 3 mg/kg), xanomeline (0.0, 2.5, 5.0, 10.0 or 20.0 mg/kg) and nicotine (0.0, 0.1, 0.2, or 0.4 mg/kg) were tested for reversal of the atropine-induced alteration of the DCE. RESULTS: Oxotremorine and pilocarpine did not reverse the atropine-induced alteration of the DCE. In contrast, xanomeline and nicotine reversed the effect of atropine on the DCE. CONCLUSION: The present series of experiments reveals complex pharmacological interactions within the cholinergic system when cued and contextual fear memories interact. Results are discussed in this connection and with regard to the relation between the properties of cholinergic agonists and their therapeutic values.

Associative deficit accounts of disrupted latent inhibition and blocking in schizophrenia.

Latent inhibition (attenuated responding to a signal due to signal-alone presentations preceding the signal-outcome pairings) and blocking (attenuated responding to Signal B due to Signal A being paired with the outcome prior to pairings of an AB compound with the outcome) are reportedly absent in acute schizophrenics. The common assumption that these phenomena reflect the normal functioning of attention and the observation that rats administered low doses of amphetamine show a similar disruption has resulted in the development of an animal model of attentional dysfunction in acute schizophrenia. Here, we selectively review the experimental and clinical literature concerning latent inhibition and blocking, their disruption in acute schizophrenia, and the current status of this model. We conclude that the construct validity of the model is compromised if latent inhibition and blocking are viewed in attentional terms because experimental data indicate both phenomena can be better understood in associative terms. We favor a framework in which disruption of latent inhibition and blocking in acute schizophrenics is viewed as an inability to compare and express stored representations (i.e. associative performance deficit). This change of perspective does not undermine the potential value of the model, but rather suggests that the nature of its validity should be reconsidered.

Effect of a nonsedative dose of propofol on memory for aversively loaded information in rats.

BACKGROUND: The effects of propofol on memory for aversive information are not well determined. The authors evaluated the effects of a minimal nonsedative dose of propofol or midazolam on memory in rats, using an apparatus composed of two compartments: a large bright anxiogenic one and a small dark neutral one. METHODS: Groups of rat received propofol (9 mg/kg, intraperitoneally) or midazolam (3 mg/kg). Anxiety was assessed in rats placed in the anxiogenic compartment as the time before the animals entered the neutral compartment. Memory for an aversive event was assessed in rats placed in the anxiogenic compartment as the time to enter the neutral one where they previously experienced foot shocks (fear conditioning). To assess the memory for a nonaversive event, rats were placed in the neutral compartment with no shocks (preexposure). The following day, rats were placed in it and they experienced foot shocks. As a result of the preexposure, rats exhibit less fear to enter it. RESULTS: Propofol and midazolam increased the time to enter the neutral compartment. Propofol or midazolam was given to rats before experiencing foot shocks in the neutral compartment. When later tested, the time to enter it was decreased. Propofol or midazolam was given to rats before the preexposure to the neutral compartment. When later tested, the latency to enter it was not modified by the preexposure. CONCLUSIONS: Propofol and midazolam impaired memory for aversive and for nonaversive experiences at equianxiolytic doses that do not produce locomotor impairment in rats.

In vivo dopamine measurements in the nucleus accumbens after nonanesthetic and anesthetic doses of propofol in rats.

UNLABELLED: There is growing evidence that propofol acts on affective and reward processes. We designed this study to assess the effect of propofol on the concentration of dopamine in the nucleus accumbens, a main component of the mesolimbic system. The concentration of dopamine in the nucleus accumbens was assessed by using in vivo brain microdialysis in freely moving rats. A microdialysis probe was placed within guide cannulae previously placed during stereotaxic surgery. Fluid was perfused through the probe, and samples were collected every 20 min for measuring concentrations by high-pressure liquid chromatography. All rats served as their own controls and were randomized to four different doses of propofol, injected intraperitoneally: 0, 9, 60, or 100 mg/kg, according to a within design. Compared with the baseline value, dopamine concentration was decreased at the smallest dose of 9 mg/kg, whereas concentration was largely increased at the subanesthetic (60 mg/kg) and anesthetic (100 mg/kg) doses. This increase was of the same magnitude (+90%) for subanesthetic and anesthetic doses but was more prolonged at the anesthetic dose. Data show that only subanesthetic and anesthetic doses of propofol increase the concentration of dopamine in the nucleus accumbens, as previously described with drugs of potential abuse. IMPLICATIONS: Depending on the dose, propofol either increased or decreased the concentration of dopamine in the nucleus accumbens, as assessed during microdialysis in freely moving rats. Only large doses which display a pharmacological profile, such as propofol, may show promise.