Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine

Rationale.: Psychomotor stimulants can induce psychotic states in humans that closely resemble those observed in patients with idiopathic schizophrenia. Attentional and sensorimotor gating impairments are observed in schizophrenic patients using the latent inhibition (LI) and prepulse inhibition (PPI) behavioral assays, respectively. Our previous studies demonstrated that after 4days of withdrawal from a period of amphetamine (AMPH) administration, animals exhibited disrupted LI but normal PPI. Objective.: The aim of the present study was to test PPI in AMPH-withdrawn rats under experimental conditions similar to those used to best demonstrate locomotor sensitization following AMPH withdrawal. Methods.: We examined the effects on PPI of (1) pairing drug injections with PPI test-associated cues, (2) administration of a low-dose dopamine agonist challenge and (3) testing following longer withdrawal periods (23, 30, 60days). Results.: Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn rats, we did observe that the acoustic startle response was reduced during a restricted time period following AMPH withdrawal. Similar to our previous findings, AMPH-withdrawn animals showed disrupted LI on day16 of withdrawal and locomotor sensitization to a challenge injection of AMPH after 62days of withdrawal. Conclusion.: We conclude that the effects of repeated AMPH on PPI are not modulated by the same experimental parameters known to be important for eliciting locomotor sensitization and that withdrawal from the schedule of AMPH administration used in this study models only specific cognitive dysfunctions linked to schizophrenic symptoms, since LI was disrupted but PPI was not affecte

Haloperidol and clozapine antagonise amphetamine-induced disruption of latent inhibition of conditioned taste aversion

Rationale: Latent inhibition (LI) describes a process by which repeated pre-exposure of a stimulus without any consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that LI is impaired in rats and in humans by injections of the indirect dopamine agonist amphetamine (AMPH), and that this disruption can be prevented by co-administration of either the typical neuroleptic haloperidol (HAL) or the atypical neuroleptic clozapine (CLZ). Objectives: Most of what is known of the pharmacology of LI is derived from studies using either the conditioned emotional response or the conditioned active avoidance paradigm. The goal of the present study was to determine whether these results would generalize to the conditioned taste aversion assay. Methods: We tested whether AMPH (0.5mg/kg) pretreatment would disrupt LI of a conditioned aversion to sucrose, and if so, which stage of the procedure is critical for mediating the disruption; in addition, we tested whether HAL (0.2mg/kg) or CLZ (5.0mg/kg) could restore such an expected LI disruption. Results: We determined that AMPH disrupted LI when it was injected before pre-exposure and prior to conditioning, but not if the rats were injected before either stage alone. When HAL or CLZ was given 40min before AMPH (before both pre-exposure and conditioning), it blocked LI disruption. Conclusion: These results are in line with the pharmacology of LI as derived from other conditioning paradigms. We conclude that the pharmacological regulation of LI in the CTA paradigm is similar to what has been observed previously in the conditioned emotional response and the conditioned active avoidance paradigm

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact

Rationale: Schizophrenia has been associated with dysregulation of dopamine (DA) transmission and impairment in a number of experimental tasks, including sensorimotor gating assessed using prepulse inhibition (PPI) and selective attention assessed using latent inhibition (LI). We have demonstrated in previous studies that after withdrawal from escalating (ESC) dosages of amphetamine (AMPH), animals exhibited disruption of LI but no alteration of PPI. Moreover, these animals always showed behavioural sensitization to an AMPH challenge. Objective: In this study, we were interested in testing whether a different administration schedule would elicit disruption of both LI and PPI. Methods: Animals were treated with continuous AMPH release (via osmotic mini-pumps at a dosage of 10mg kg−1 day−1 for 7 days) and tested for their performance in L and PPI during withdrawal in a drug free state. Rats received AMPH treatment during the induction phase in their home cages or in the activity chambers. Following withdrawal, the expression of behavioural sensitization to an AMPH challenge was tested in both cases in the activity chambers. Results: Animals pretreated with AMPH from both groups did not exhibit behavioural sensitization. Withdrawal from continuous administration induced LI attenuation with no effect on PPI. Conclusions: These findings are similar to what was previously found with respect to an ESC AMPH regime. The only difference between the schedules was that the ESC AMPH schedule led to behavioural sensitization whereas the continuous AMPH did not. It is suggested that the expression of sensitization may not be a prerequisite for observed LI disruptio

Influence of Early Stress on Social Abilities and Serotonergic Functions across Generations in Mice

Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations

FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

Rationale: 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives: In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods: Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results: A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30mg/kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D2 receptor antagonism, but a partial involvement of 5-HT2- and α1-receptors cannot be ruled out at present. Conclusions: We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristic

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine

ISSN:0033-3158ISSN:1432-207

IntelliCage: the development and perspectives of a mouse- and user-friendly automated behavioral test system

IntelliCage for mice is a rodent home-cage equipped with four corner structures harboring symmetrical double panels for operant conditioning at each of the two sides, either by reward (access to water) or by aversion (non-painful stimuli: air-puffs, LED lights). Corner visits, nose-pokes and actual licks at bottle-nipples are recorded individually using subcutaneously implanted transponders for RFID identification of up to 16 adult mice housed in the same home-cage. This allows for recording individual in-cage activity of mice and applying reward/punishment operant conditioning schemes in corners using workflows designed on a versatile graphic user interface. IntelliCage development had four roots: (i) dissatisfaction with standard approaches for analyzing mouse behavior, including standardization and reproducibility issues, (ii) response to handling and housing animal welfare issues, (iii) the increasing number of mouse models had produced a high work burden on classic manual behavioral phenotyping of single mice. and (iv), studies of transponder-chipped mice in outdoor settings revealed clear genetic behavioral differences in mouse models corresponding to those observed by classic testing in the laboratory. The latter observations were important for the development of home-cage testing in social groups, because they contradicted the traditional belief that animals must be tested under social isolation to prevent disturbance by other group members. The use of IntelliCages reduced indeed the amount of classic testing remarkably, while its flexibility was proved in a wide range of applications worldwide including transcontinental parallel testing. Essentially, two lines of testing emerged: sophisticated analysis of spontaneous behavior in the IntelliCage for screening of new genetic models, and hypothesis testing in many fields of behavioral neuroscience. Upcoming developments of the IntelliCage aim at improved stimulus presentation in the learning corners and videotracking of social interactions within the IntelliCage. Its main advantages are (i) that mice live in social context and are not stressfully handled for experiments, (ii) that studies are not restricted in time and can run in absence of humans, (iii) that it increases reproducibility of behavioral phenotyping worldwide, and (iv) that the industrial standardization of the cage permits retrospective data analysis with new statistical tools even after many years

Withdrawal from continuous amphetamine administration abolishes latent inhibition but leaves prepulse inhibition intact

ISSN:0033-3158ISSN:1432-207

Haloperidol and clozapine antagonise amphetamine-induced disruption of latent inhibition of conditioned taste aversion

ISSN:0033-3158ISSN:1432-207