Clozapine-induced potentiation of latent inhibition is due to its action in the conditioning stage: implications for the mechanism of action of antipsychotic drugs

Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its non-reinforced pre- exposure. LI is impaired in some subsets of schizophrenic patients and in rats treated with amphetamine. Antipsychotic drugs (APDs) potentiate LI under conditions that are insufficient to produce LI in control animals, namely, low number of pre-exposures or high number of conditioning trials. The present experiments tested the proposition that LI potentiation under both conditions stems from the action of APDs in the conditioning stage. Experiments 1-3 used 10 pre-exposures and 2 conditioning trials, and tested the effects of 2.5, 5, and 10 mg/kg clozapine, respectively. Experiments 4-6 used 40 pre-exposures and 5 conditioning trials, with clozapine doses as above. Clozapine was administered in either the pre-exposure, the conditioning stage, or in both. In all the experiments, vehicle controls did not show LI. Overall, clozapine administration in conditioning, irrespective of drug condition in pre-exposure, produced LI. The implications of these results for the mechanism of action of antipsychotic drugs are discussed.     

Effects of clozapine on latent inhibition in the rat

In the present study we have examined the effect of clozapine, an atypical antipsychotic drug, on latent inhibition (LI) using the conditioned emotional response (CER) procedure. In this procedure, ten pre-exposures to the to-be-conditioned stimulus result in weak or no LI whereas 30 pre-exposures produce robust LI. Three different experimental protocols were used to study the effects of clozapine: facilitation of LI in animals subjected to ten pre-exposures to the to-be-conditioned stimulus; antagonism of the disruptive effect of amphetamine (1mg/kg, s.c.) on LI in animals receiving 30 pre-exposures; antagonism of the disruptive effect of nicotine (0.6mg/kg, s.c.) on LI in animals receiving 30 pre-exposures. High doses of clozapine (3 and 10mg/kg, s.c.) disrupted the CER in non pre-exposed animals. Despite this, clozapine significantly facilitated the development of LI at 1 and 10mg/kg and significantly attenuated the disruptive effects of nicotine at 0.3 and 1mg/kg and of amphetamine at 2 and 5mg/kg. These results demonstrate that clozapine is active in the LI model and further support the utility of this model in the study of mechanisms of action of antipsychotic drugs.     

Disruption and potentiation of latent inhibition by risperidone: the latent inhibition model of atypical antipsychotic action.

Latent inhibition (LI), that is, retarded conditioning to a stimulus following its nonreinforced pre-exposure, is impaired in some subsets of schizophrenia patients and in amphetamine-treated rats. Potentiation of LI by antipsychotic drugs (APDs) given in conditioning, under conditions that do not lead to LI in controls, is a well-established index of antipsychotic activity. Recently, we have shown that the atypical APD, clozapine, in addition disrupts LI if administered in pre-exposure, under conditions that lead to LI in controls. This study demonstrates the same behavioral profile for the atypical APD risperidone. LI was measured in a thirst-motivated conditioned emotional response procedure by comparing suppression of drinking in response to a tone previously paired with a foot shock in rats that received nonreinforced exposure to the tone prior to conditioning (pre-exposed (PE)) and rats for whom the tone was novel (non-pre-exposed (NPE)). We show that under conditions that did not yield LI in vehicle controls (40 pre-exposures and five conditioning trials), risperidone (0.25, 0.5, and 1.2 mg/kg) led to LI when administered in conditioning. Under conditions that led to LI in vehicle controls (40 pre-exposures and two conditioning trials), risperidone (0.25, 0.5, and 2.5 mg/kg) abolished LI when administered in pre-exposure; the latter effect was not evident with haloperidol. In addition, the effects of risperidone administered in both the pre-exposure and conditioning stages were dose-dependent so that the pre-exposure-based action was manifested at lower but not at higher doses. It is concluded that atypical APDs exert in the LI model a dual pattern of effects, which enables detection of their 'typical' action (conditioning-based LI potentiation) as well as a dissociation from typical APDs by their 'atypical' action (pre-exposure-based LI disruption). It is suggested that the former and latter effects are subserved by D2 and 5HT2A antagonism, respectively.     

Comparison of toluene-induced locomotor activity in four mouse strains

The mechanisms by which abused inhalants exert their neurobehavioral effects are only partially understood. In research with other drugs of abuse, specific inbred mouse strains have been useful in exploring genetic loci important to variation in behavioral reactions to these drugs. In the present investigation, mice from three inbred strains (Balb/cByj, C57BL/6J and DBA/2J) and one outbred strain (Swiss Webster) were studied for their acute and chronic sensitivity to toluene-induced changes in locomotor activity. Mice were exposed to toluene (0, 100, 2000, 8000, and 10,000 ppm) for 30 min in static exposure chambers equipped with activity monitors. In the acute condition, concentrations of toluene < 8000 ppm increased ambulatory distance while the concentrations of ≥ 8000 ppm induced temporally biphasic effects with initial increases in activity followed by hypoactivity. Between-group differences in absolute locomotor activity levels were evident. The inbred Balb/cByj and DBA/2J strains as well as the outbred Swiss Webster strain of mice showed greater increases in activity after an acute challenge exposure to 2000 ppm than the inbred C57BL/6J strain. The same animals were then exposed 30 min/day to 8000 ppm toluene for 14 consecutive days. Re-determination of responses to 2000-ppm challenge exposures revealed that sensitization developed in locomotor activity and that the DBA/2J strain showed the greatest increase in sensitivity. These baseline differences in acute sensitivity and the differential shifts in sensitivity after repeated exposures among the inbred mouse strains suggest a genetic basis for the behavioral effects to toluene. The results support the notion that like for other drugs of abuse, using various strains of mice may be useful for investigating mechanisms that underlie risk for inhalant abuse.     

Strain differences in haematological response to chloramphenicol succinate in mice: implications for toxicological research.

Much toxicological research continues to be done using genetically undefined "outbred" stocks of mice and rats, although the case for using isogenic strains has been made repeatedly in the literature over a period of more than two decades. Also, very few studies are conducted using more than one strain, with the result that genetic variation in response is seldom apparent to the investigator. Here we report qualitative and quantitative strain differences in the haematological response to chloramphenicol succinate (CAPS) when administered by gavage at 500-2500 mg/kg for 7 days, to four inbred strains of mouse (C3H/He, CBA/Ca, BALB/c and C57BL/6) and one outbred stock (CD-1). CAPS caused anaemia and reticulocytopenia in all mouse strains, and leucopenia in the inbred strains but not in the outbred CD-1 stock. All four inbred strains showed significant (P<0.01) responses to CAPS at lower dose levels than in CD-1 mice, which were phenotypically more variable than the inbred animals. A simulated experiment, using a sample of records from the present study, showed that the use of two mice at each dose level using CD-1, CBA, BALB/c and C57BL/6 (48 total mice), would have given a more sensitive experiment than the use of 47 CD-1 mice alone, and would also have shown that the response is partly strain dependent. These studies provide additional evidence that inbred strains, because of their greater sensitivity and other valuable properties, should be more widely used in toxicology.     

Inherent differences in sensitivity to methylxanthines among inbred mice

The behavioral effects of caffeine, theophylline, paraxanthine, and theobromine on locomotor activity were analyzed in four strains of inbred mice that were previously shown to differ in their acute toxic responses to caffeine administered at high dosages. Dose response curves for the effects of caffeine, theophylline, paraxanthine and theobromine on locomotor activity were established in CBA/J, C57BL/6J, DBA/2J and SWR/J strains of inbred mice. Paraxanthine was the maximally effective methylxanthine in the CBA/J, DBA/2J and SWR/J strains, while in the C57BL/6J strain, caffeine was the maximally effective methylxanthine. Theophylline failed to stimulate locomotor activity in the C57BL/6J strain and theobromine failed to stimulate activity in all of the strains tested. Decreases in locomotor activity were seen at the 100 mg/kg dose of caffeine in the C57BL/6J mice and at the 100 mg/kg dose of theophylline in the C57BL/6J, DBA/2J and SWR/J strains. Theobromine produced decreases in locomotor activity in the C57BL/6J, DBA/2J and SWR/J strains of mice. In contrast to the other methylxanthines, paraxanthine failed to decrease activity across the range of doses tested (1.0-150 mg/kg). These data suggest that the methylxanthines have genetically specified multiple modes of action upon locomotor activity and that the use of genetically distinct strains of mice may have important value in the neurochemical and pharmacological dissection of methylxanthine-induced behavioral effects.     

Reexamination of the relationship between alcohol preference and brain monoamines in inbred strains of mice including senescence-accelerated mice

The relationship between voluntary alcohol consumption and brain monoamine levels was studied in the inbred strains of C57BL/6N, C57BL/6J, A/J, BALB/cA, CBA/N, C3H/He and DBA/2cr mice; the congeneric mouse strain, B10.Br/Sg, and the senescence accelerated mouse (SAM P1, SAM P2). The C57BL strains exhibited a high alcohol preference whereas the other strains exhibited a low alcohol preference. A clear positive relationship was found between alcohol intake (g/kg/day) and brain norepinephrine level (r = 0.683, p less than 0.05), and a clear negative relationship between alcohol intake and brain serotonin level (r = -0.628, p less than 0.05). The content of brain dopamine was not clearly correlated with alcohol intake (r = -0.206, p greater than 0.05). These findings suggest that in mice voluntary alcohol preference is influenced by brain norepinephrine and serotonin levels genetically.     

SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents

SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment β_25-35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.     

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol

Abstract Rationale. Latent inhibition (LI) refers to retarded conditioning to a stimulus as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat is considered to model an attentional deficit in schizophrenia. Blockade of NMDA receptor transmission, which produces behavioral effects potentially relevant to schizophrenic symptomatology in several animal models, has been reported to spare LI. Objectives. To show that systemic administration of the non-competitive NMDA antagonist MK-801 will lead to an abnormally persistent LI which will emerge under conditions that disrupt LI in controls, and that this will be reversed by the atypical neuroleptic clozapine but not by the typical neuroleptic haloperidol, as found for other NMDA antagonist-induced models. Methods. LI was measured in a thirst-motivated conditioned emotional response (CER) procedure by comparing suppression of drinking in response to a tone in rats which previously received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two (experiment 1) or five (experiments 2–5) tone – foot shock pairings. Results. MK-801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect on suppression was seen at the 0.05 mg/kg dose. At the latter dose, intact LI was seen with parameters that produced LI in controls (40 pre-exposures and two conditioning trials). Raising the number of conditioning trials to five disrupted LI in control rats, but MK-801-treated rats continued to show LI, and this abnormally persistent LI was due to the action of MK-801 in the conditioning stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was reversed by clozapine but not by haloperidol administered in pre-exposure. Conclusion. MK-801-induced perseveration of LI is consistent with other reports of perseverative behaviors, suggested to be particularly relevant to negative symptoms of schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration may model impaired attentional set shifting associated with negative symptoms of schizophrenia. Moreover, the finding that the action of MK-801 on LI and the action of clozapine are exerted in different stages of the LI procedure suggests that the MK-801-based LI model may provide a unique screening tool for the identification of novel antipsychotic compounds, whereby the schizophrenia-mimicking LI abnormality is drug-induced, but the detection of the antipsychotic action is not dependent on the mechanism of action of the pro-psychotic drug. Electronic Publication     

Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

Rationale Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. Objective To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. Materials and methods LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. Results Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. Conclusions These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.     

Differences in adenosine A-1 and A-2 receptor density revealed by autoradiography in methylxanthine-sensitive and insensitive mice

Two strains of inbred mice, CBA/J and SWR/J, have been identified which are, respectively, sensitive and insensitive to the behavioral and toxic effects of methylxanthines. Autoradiographic analyses of brain adenosine receptors were conducted with [3H]CHA to label adenosine A-1 receptors and [3H]NECA, in the presence of 50 nM CPA, to label adenosine A-2 receptors. For both mouse strains, adenosine A-1 receptors were most highly concentrated in the hippocampus and cerebellum whereas adenosine A-2 receptors were selectively localized in the striatum. CBA/J mice displayed a 30% greater density of adenosine A-1 receptors in the hippocampal CA-1 and CA-3 regions and in the cerebellum as compared to the SWR/J mice. The number of A-2 receptors (Bmax) was 40% greater in the striatum and olfactory tubercle of CBA/J as compared to SWR/J mice. No significant regional differences in A-1 or A-2 receptor affinities were observed between these inbred strains of mice. These results indicate that the differential sensitivity to methylxanthines between these mouse strains may reflect a genetically mediated difference in regional adenosine receptor densities.     

Modulators of the glycine site on NMDA receptors, <Emphasis Type="SmallCaps">d</Emphasis>-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia

Rationale Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.Objectives This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, d-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801.Methods C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise–foot shock pairings.Results Clozapine (3 mg/kg) and d-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by d-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, d-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801.Conclusions d-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.     

Potency and efficacy of dopamine agonists in mouse strains differing in dopamine cell and receptor number.

The potency and efficacy of the selective dopamine D2 receptor agonist quinpirole, the mixed D1/D2 agonist apomorphine, and the selective D1 receptor agonist SKF 38393 in producing hypothermia and changes in locomotor activity were evaluated in four strains of mice: CBA/J, C57BL/6J, ICR Swiss and CF1. CBA/J mice previously have been shown to be deficient in dopamine cell and receptor number relative to other strains such as C57BL/6J mice, whereas ICR Swiss and CF1 are commonly used strains of mice. Quinpirole (0.125 to 1.0 mg/kg) was equiefficacious and equipotent in producing hypothermia in all 4 strains. Apomorphine (0.125 to 16 mg/kg) was equiefficacious in producing hypothermia in all 4 strains, but was approximately four-fold less potent in CBA/J mice than in the other strains. SKF 38393 had little effect on body temperature in any of the 4 strains. Basal motor activity was lowest in CBA/J mice, and tended to be highest in ICR Swiss mice. Quinpirole (0.125 to 32 mg/kg) had no effect on motor activity in CBA/J mice, but decreased motor activity in the other 3 strains. Apomorphine (1 to 16 mg/kg) produced modest increases in motor activity in all 4 strains. The magnitude of the changes produced by apomorphine was comparable in all strains when expressed as change from mean control values. SKF 38393 (8 to 64 mg/kg) also increased motor activity in all 4 strains, with comparable increases when expressed as change from mean control values. The present results are consistent with the interpretation that inherited deficiencies in dopamine cell and receptor number in CBA/J mice produce functional decrements in D2, but not D1, dopamine receptor function.     

Genotype and test experience determine responsiveness to morphine

Initial responsiveness to morphine was studied in two inbred strains of mice, C57BL/6J and DBA/2J, and their F₁ hybrid, using both a hot-plate analgesia test and a locomotor-activity test. Three dose levels of morphine were used, 0 mg/kg, 5 mg/kg, and 15 mg/kg. The inclusion of the 0 mg/kg group revealed differences between the inbred strains in the effects of test experience. These data also led to some new conclusions about the differences in responsiveness to morphine between the strains studied. On both tests, the DBA mice showed no effect of morphine, the C57 mice showed large effects, and the F₁ mice showed an intermediate effect.     

The role of the genotype in the cataleptogenic effect of neuroleptics]

The cataleptogenic effects of three neuroleptics from one chemical group was investigated in 8 mice strains (CBA, A/He, C57B1/6, C3H/He, BALB/c, AKR, DD, and CC57Br. Despite significant interstrain, differences in the action of the drugs, haloperidol (0.5 mg/kg) and trifluperidol (0.5 mg/kg) produced much greater cataleptogenic action than fluspirilene (2 mg/kg). At the same time the intensity of catalepsy in various mice strains after haloperidol was not coincident with that after trifluperidol (r = 0.22): CBA mice displayed the maximum catalepsy, but AKR, DD and CC57Br mice, the minimum when haloperidol was given; with trifluperidol, the maximum catalepsy was observed in AKR mice, but absent in DD mice. Fluspirilene induced catalepsy only in CBA and A/He mice. Thus, the presence of catalepsy, a side effect of most neuroleptics, is largely predetermined by hereditary factors.     

The effects of cocaine on operant responding for food in several strains of mice

 The availability of numerous genetically homogenous mouse strains permits the analysis of genetic influences on behavior and also behavioral sensitivity (responsivity) to drugs of abuse. The current study was conducted to characterize discriminated operant responding for food in four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, SJL/J), an F1 Hybrid (C57BL/6×SJL), and one outbred strain (CD1) of mouse. The effect of cocaine on this operant behavior was also examined. Initially, all animals were trained to nosepoke for food on a continuous reinforcement schedule. The minimum response requirement for reinforcement was increased every 5 days until the animals were responding on an FR-15 schedule of reinforcement. All strains increased operant responding as the schedule of reinforcement was raised. However, significant differences in response rate and discrimination learning were observed among the various strains of mice. Cocaine administration reduced operant responding for food in Balb/cByJ, C57BL/6J, C57BL/6×SJL/J and CD1 mice at a dose of 15.0 mg/kg, whereas higher doses were required in DBA/2J mice (30.0 mg/kg) and SJL/J mice (56.0 mg/kg). These results suggest that operant performance and the effect of cocaine on this behavior is differentially influenced by genetic make-up. Received: 20 December 1996 / Final version: 4 April 1997     

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolt's test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.     

A mouse model of early social interactions after prenatal drug exposure: a genetic investigation

The aim of the present study was to (i) characterise the mouse behavioural profile (particularly social interactions) during the preweaning period, (ii) assess the effects of prenatal exposure to an anticonvulsant drug widely used in clinical practice, (iii) examine possible genetic differences both in baseline behavioural profiles and in sensitivity to drug-induced effects. Following a balanced intra-strain fostering procedure, the offspring of C57BL/6J and CBA inbred mouse strains from mothers exposed during pregnancy to either phenobarbitone (PHB, 60 mg/kg) or vehicle (VEH) given intraperitoneally (IP) during days 10–16 of gestation, were observed for early social interactions in the home cage during the last part of the preweaning period (days 20 and 21). The behavioural repertoires of the two strains differed markedly, in that C57 pups were more involved in Play soliciting, Locomotor-rotational play, and in Maintenance activities, while CBA mice spent much more time being inactive or exploring the environment. C57 and CBA mice also differed in the sensitivity to PHB exposure. On the whole, time spent in Investigative/Affiliative behaviours was increased, while the frequency of Play soliciting patterns was reduced in PHB-treated mice. The treatment of the fostering mother had only negligible effects, suggesting that PHB-induced changes in behaviour were largely due to direct effects of the substance on the foetus. These results indicate that specific items of the preweaning behavioural profile, and particularly social interactions, are influenced by early PHB exposure, and that the responses are heavily affected by the genotype.Preliminary results have been presented at the Joint Meeting of the British Association for Psychopharmacology and the European Behavioural Pharmacology Society, 2–7 August 1992, Cambridge, UK     

7-OH-DPAT effects on latent inhibition: low dose facilitation but high dose blockade: implications for dopamine receptor involvement in attentional processes

7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.     

Towards an animal model of an antipsychotic drug-resistant cognitive impairment in schizophrenia: scopolamine induces abnormally persistent latent inhibition, which can be reversed by cognitive enhancers but not by antipsychotic drugs

Schizophrenia symptoms segregate into positive, negative and cognitive, which exhibit differential sensitivity to drugs. Recent efforts to identify treatments targeting cognitive impairments in schizophrenia have directed attention to the cholinergic system for its well documented role in cognition. Relatedly, muscarinic antagonists (e.g. scopolamine) produce an 'antimuscarinic syndrome', characterized by psychosis and cognitive impairments. Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its non-reinforced pre-exposure. LI indexes the ability to ignore irrelevant stimuli and aberrations of this capacity produced by pro-psychotic agents (e.g. amphetamine, MK-801) are used extensively to model attentional impairments in schizophrenia. We recently showed that LI was disrupted by scopolamine at low doses, and this was reversed by typical and atypical antipsychotic drugs (APDs) and the acetylcholinesterase inhibitor physostigmine. Here, at a higher dose (1.5 mg/kg), scopolamine produced an opposite pole of attentional impairment, namely, attentional perseveration, whereby scopolamine-treated rats persisted in expressing LI under strong conditioning that prevented LI expression in controls. Scopolamine-induced persistent LI was reversed by cholinergic and glycinergic cognitive enhancers (physostigmine and glycine) but was resistant to both typical and atypical APDs (haloperidol and clozapine). The latter sets scopolamine-induced persistent LI apart from scopolamine- and amphetamine-induced disrupted LI, which are reversed by both typical and atypical APDs, as well as from other cases of abnormally persistent LI including MK-801-induced persistent LI, which is reversed by atypical APDs. Thus, scopolamine-induced persistent LI may provide a pharmacological LI model for screening cognitive enhancers that are efficient for the treatment of APD-resistant cognitive impairments in schizophrenia.