RenaSci

Evaluation of Antipsychotics

Condiitoned Avoidance Response Model

 

Schizophrenia is a clinical syndrome of unknown aetiology that occurs in approximately 1% of the adult population in most countries. Schizophrenia usually develops during young adulthood and is characterised by a range of symptoms including disordered thought, social dysfunction, hallucinations (aural and visual) and delusions of persecution. The syndrome is chronic and generally progressive. Antipsychotic drugs are typically used for the long-term maintenance of psychotic symptoms and are often prescribed temporarily during episodes of mania.

RenaSci has validated and routinely performs a variety of assays for evaluating the potential efficacy and side-effect profile of novel antipsychotic drugs in rats and mice.

 

The Rat Conditioned Avoidance Response Model

 

The rat conditioned avoidance response model (CAR) is a gold standard preclinical model for assessing the antipsychotic activity of novel compounds. Rats are trained in sound-attenuated two-chambered shuttle-boxes to associate the presentation of a conditioned stimulus (eg light and a tone) with a mild foot-shock applied to the side where the animal is located during the conditioned stimulus. Thus, animals learn to avoid the shock upon presentation of the conditioned stimulus by crossing to the other chamber (a conditioned avoidance response). Crossing to the other compartment during presentation of the shock is defined as an escape response. Failure to move to the other side on presentation of the shock is defined as an escape failure and indicative of sedation.

Disruption of conditioned avoidance responses, but not escape responses, is a selective characteristic of all marketed antipsychotics but not other CNS-active drugs. The efficacy of a drug to suppress conditioned avoidance responding in rats correlates with its ability to reduce psychosis in man. The conditioned avoidance response model is therefore a crucial animal model in the development of new drugs to treat schizophrenia.

Disruption of Conditioned Avoidance Responding in Rats by Aripiprazole


We have recently validated the conditioned avoidance response model in-house using the typical antipsychotic, haloperidol, and the atypical antipsychotics, aripiprazole, olanzapine and risperidone. All drugs reduced avoidance responses, but not escape responses, in the model.

For further validation data please see our Conditioned Avoidance Response flyer.

 

Pre-pulse Inhibition of Acoustic Startle

 

We have 8 acoustic startle boxes (TSE Systems) which can be used to measure pre-pulse inhibition (PPI) of acoustic startle in rats. In brief, the acoustic startle reflex is a basic response to marked external noise stimuli. It can be inhibited by exposure to a weak stimulus (pre-pulse) before the loud acoustic stimulus. PPI is evident in a number of animal species including man. Importantly, deficits in PPI are associated with numerous neuropsychiatric conditions characterised by sensory gating disturbances, including schizophrenia and Tourette Syndrome (ie the effect of the pre-pulse is limited and the startle response is maintained even in the presence of the pre-pulse).

It is well-established that PPI inhibition of the startle response can be inhibited by direct and indirect dopaminergic agonists and NMDA receptor antagonists in rats. We have shown that amphetamine, apomorphine and PCP inhibit PPI of acoustic startle in these animals as expected. We are currentlly validating the methodology by testing the ability of antipsychotic agents and a range of other drugs to normalise the deficits in PPI produced by psychotomimetic drugs in rats.

Please contact us for further information about this model. 

 

Reversal of Amphetamine-, PCP- or MK-801-induced Hyperactivity

 

A variety of simple screens for antipsychotic activity have been developed based on observations that compounds such as amphetamine and the NMDA receptor antagonists, PCP and MK-801, produce psychotic symptoms resembling schizophrenia in man. These models generally involve reversal of the hyperactivity and stereotyped behaviour produced by psychostimulants in rats and mice. These behaviours can be easily measured using automated activity chambers and established behavioural scoring systems.

 
Models offered by RenaSci include :-

     •     Reversal of amphetamine-induced hyperactivity (reversal of amphetamine-induced
           stereotypy can be examined in the same animals if required)

     •     Reversal of PCP- and MK-801-induced hyperactivity


We have validated these assay using both typical and atypical antipsychotics.

Reversal of PCP-induced Hyperactivity in Mice by Olanzapine

Attenuation of d-amphetamine induced locomotor activity in rats by xanomeline

 

For further information please see our Evaluation of Antipsychotics and Three Component Test flyers.

 

DOI-induced Head Twitch

 

Certain psychoactive drugs are able to induce head-twitch behaviour in rats or mice (a characteristic rotational flick of the head, ears and neck) and this ability can be directly related to the capacity for the drug to produce hallucinations in man.  Thus, the 5-HT2A receptor agonist, DOI, induces a robust head twitch response in mice and rats.  This behaviour can be reversed by the 5-HT2A receptor antagonist, M100907, and by typical and atypical antipsychotic drugs (eg olanzapine). 

 

Reversal of DOI-induced Head Twitch in Mice by M100907

 

Reversal of DOI-induced Head Twitch in Mice

DOI-induced head twitch in mice or rats can therefore be used as an additional assay to screen for antipsychotic activity.


Catalepsy Testing

 

Catalepsy, a condition characterised by muscular rigidity and the maintenance of an externally imposed posture for a prolonged duration, is produced by typical antipsychotics such as haloperidol in mice and rats and has been widely used as a screen to predict whether novel antipsychotics will produce extrapyramidal side effects in man. RenaSci offers catalepsy testing in both mice and rats.

Haloperiodol-induced Catalepsy

Haloperidol-induced catalepsy can also be used as a model of the extrapyramidal symptoms seen in Parkinson’s disease. Please contact us for further information.

 

Antipsychotic-induced Weight Gain

 

Atypical (second generation) antipsychotics have improved the treatment of schizophrenia but many produce weight gain. A significant number of these drugs also produce insulin resistance, impaired glucose tolerance and type 2 diabetes. Schizophrenia itself is almost certainly casual in many endocrine and metabolic disturbances therefore schizophrenic patients are particularly vulnerable to antipsychotic-induced weight gain (neuroleptic-induced weight gain) and its metabolic consequences.


Animal models can be used to predict the ability of novel antipsychotic drugs to produce weight gain and the effects of chronic administration of antipsychotic drugs on glycaemic control and adiposity. Our rodent model of antipsychotic-induced weight gain can also be used to investigate whether the increase in body weight can be attenuated by antiobesity drugs. For further information please see our Antipsychotic-induced Weight Gain Flyer.

 

Antipsychotic-induced Increases in Plasma Prolactin

 

It is well-established that antipsychotic drugs can increase circulating prolactin levels in rats and man. This is an undesirable side-effect as prolactin can interfere with the normal function of reproductive, endocrine and metabolic systems. We offer a plasma prolactin assay which can be used to assess whether novel antipsychotics are likely to produce hyperprolactinaemia. 

Please contact us for further information about measurement of circulating levels of prolactin.