[1][4][2][7] Drugs that selectively suppress conditioned avoidance responses without affecting escape behavior are considered to have antipsychotic-like activity.
[1] The effects of drugs that are active in the test are thought to be mediated by inhibition of signaling in the nucleus accumbens or ventral striatum of the mesolimbic pathway.
[2][20][5] In the two-way active avoidance test, an animal is placed in a two-compartment shuttle box with an open doorway.
[1][5] Drugs that are considered to show antipsychotic-like effects selectively suppress the avoidance response without affecting escape behavior.
[4][2][6][21] The CAR test is considered to have high predictive validity in the identification of potential antipsychotics and is frequently used in drug development.
[4][1][7] Moreover, a described major limitation of the model is that drugs active in the test work by impairing a normal self-preservation function; that is, avoiding an unpleasant or painful stimulus.
[1][2][32][13][33] Dopamine D1 receptor antagonists have either shown no effect in the CAR, for instance ecopipam (SCH-39166), or have inhibited both avoidance and escape responses at the same doses, such as SCH-23390.
[22][23] The effects of drugs that are active in the CAR test, suppression of conditioned avoidance responses without affecting escape behavior, are thought to be mediated specifically by modulation of signaling in the nucleus accumbens shell or ventral striatum, part of the mesolimbic pathway.
[2][1][14] This area of the brain plays a major role in behavioral activation and in appetitive and aversive motivational processes.
[15][16][17][18] Drugs active in the CAR test may work by dampening behavioral responses to motivationally salient stimuli.
[37] Some academics, such as Joanna Moncrieff and David Healy, maintain that antipsychotics do not actually directly treat psychotic symptoms or delusions, but rather simply induce a state of psychic indifference or blunted emotions and resultant behavioral suppression (e.g., of agitation), thereby helping to reduce the functional consequences of psychotic symptoms.
[38][39][40][41][42][43] This interpretation is notably consistent with the behavioral effects of antipsychotics in the CAR test, in which treated animals lose their interest or motivation in preemptively avoiding an unpleasant stimulus.
[8][9][46] The dopamine depleting agent tetrabenazine can strongly and almost completely inhibit acquisition of conditioned avoidance responses in the shuttle box and also results in a very high rate of escape failures.
[5] In addition, the CAR test may be inducing more of a behavioral reflex rather than involving higher-order memory associated with areas like the prefrontal cortex.
[12] Drugs that induce such effects include dopaminergic agents like amphetamine and apomorphine and NMDA receptor antagonists like dizocilpine (MK-801).