Principles and Role in Psychopharmacology

Background

It was found early that antipsychotic drugs for the treatment of ► schizophrenia had the ability to produce a selective suppression of active avoidance/conditioned avoidance behavior in rats (Cook and Weidley 1957). Later, as more antipsychotic drugs came on the market, it was found that this was a unique property among antipsychotics that was not shared by other classes of pharmacological agents, and that the selective suppression of conditioned avoidance response (CAR) produced by the antipsychotic drugs correlated with their main therapeutic mechanism of action namely brain dopamine D2 receptor blockade (Arnt 1982).

History and Procedures

The active avoidance procedure has connections back to classical conditioning (as first presented by I.P. Pavlov in 1927) (► Classical (Pavlovian) conditioning). The concept was further developed by the experimental psychologist B.F. Skinner. Skinner showed that a certain behavior could be maintained by the consequences it produced, and called this type of behavior operant behavior (► Operant behavior in animals). Thus, operant behavior (such as active avoidance response) can be defined as behavior that is maintained by its consequences.

The basic principle ofactive avoidance is that an animal (usually rodent) is trained (conditioned) to make a specific response within a fixed time interval when presented with an auditory, or visual, stimulus (CS). During training, incorrect responses (i.e., late responses) will trigger a negative reinforcer (unconditioned stimulus; UCS), usually a weak electric footshock presented in a grid floor, that will be active together with the CS until a correct response occurs. Thus, the animal terminates the negative reinforcer (together with the CS) by making the appropriate response. If the response, expected to be performed by the animal, is to move from one place to another upon presentation of the CS, the procedure is said to be using the active avoidance paradigm. Active avoidance procedures using a negative reinforcer typically record three dependent variables: avoidance (correct move within stipulated time frame), escape (correct, but late, move following onset of negative reinforcer), and escape failure (failure to perform a correct move despite the onset of negative reinforcer within a certain cut-off time) (see e.g., Wadenberg et al. 2007).

The active avoidance paradigm can be carried out mainly in two different ways: (1) one-way active avoidance; (2) two-way active avoidance. The one-way active avoidance procedure has the experimenter placing the animal in a chamber with a metal grid floor (for the electric shock, UCS), and upon presentation of the CS, the animal is required to move from the starting chamber into another (safe) compartment of the experimental box or jump onto a wooden pole hanging down from the ceiling of the box. The experimenter then has to move the animal back into the starting chamber for the next trial. In the two-way active avoidance procedure on the other hand, the animal moves back and forth (shuttles) between two compartments of equal size and appearance in the box via an opening in the partition dividing the box into the two compartments (shuttle-box) (Fig. 1). Here, the animal has to learn that upon presentation of the CS, it is always supposed to cross over to the other empty compartment in the box. Training and experimental sessions typically consist of a fixed number of trials over a certain time interval. The two-way active avoidance procedure has over time become the most commonly used procedure, most likely in part because this procedure can be set up as a computer-assisted apparatus with several boxes run simultaneously by one computer, thus saving time and money.

The training phase (typically needing three to four consecutive training days) in the active avoidance paradigm can be considered an acquisition phase (i.e., acquisition of avoidance performance), while, following training, animals that perform well show retention (over time) of the acquired avoidance performing ability. Screening for novel, potentially antipsychotic drugs uses well-trained, high avoidance performing animals. The marker for potential antipsychotic activity thus is the ability of an acutely

Active Avoidance. Fig. 1. The figure shows a conventional two-way active avoidance apparatus (schematic drawing by Sofia I Wadenberg).

administered drug to selectively, and temporarily, suppress the retention of avoidance performance in the animals.

Evaluation and Use of the Active Avoidance Test

Animal behavioral tests (so-called animal models), used in the development of novel drugs for pharmacological treatment of diseases, are typically evaluated and rated for their fulfillment of validity criteria such as (1) predictive, construct and face validity; (2) their reliability; and (3) how they fare in terms of producing false positives or negatives. The active avoidance test is commonly considered to have high predictive validity, since all clinically effective antipsychotics, but not other classes of drugs, show the ability to selectively suppress avoidance behavior with a positive correlation between doses needed for the selective suppression of avoidance and their clinical potency for the effective treatment of schizophrenia (Seeman et al. 1976). More recently it was also found that antipsychotics produce selective suppression of avoidance in doses that result in a brain striatal dopamine D2 receptor occupancy around 65-75% in the rat (Wadenberg et al. 2001), which is also the percentage of dopamine D2 receptor occupancy usually needed for therapeutic response to occur in schizophrenic individuals following antipsychotic treatment. In other words, the active avoidance test identifies potential antipsychotic activity of new drugs tested with high predictive certainty. The active avoidance test has also been shown to have some construct validity (i.e., selective suppression of avoidance may mimic a blockade of some pathophysiological mechanisms in schizophrenia). Thus, the local application of an antipsychotic-related dopamine D2 receptor blocking agent, (-)sulpiride, into various brain areas in the rat, produced selective suppression of avoidance only when injected into the nucleus accumbens/ventral striatum (Wadenberg et al. 1990), a brain area that has a prominent role in the dopamine mesolimbic pathway that is commonly thought to be involved in the psychotic symptoms in schizophrenia (Laruelle et al. 1996) (► Aminergic hypotheses for schizophrenia). The active avoidance test has, however, no face validity, as it does not mimic any behavioral core symptoms of schizophrenia. The active avoidance test also shows high reliability, as there is a high degree of agreement between laboratories as to which compounds produce antipsychotic-like effects and in what dose range that occurs. Finally, to the best of the Author's knowledge, the active avoidance test produces few, if any, false positives or negatives. Thus, there is no antipsychotic, known to be clinically effective, that does not produce a selective suppression of active avoidance within a clinically relevant dose range. In addition, drugs that have failed in clinical trials, or studies, for antipsy-chotic activity (such as for example, selective serotonin2A antagonists, selective dopamine D1 or D4 receptor antagonists) also, either showed no effect on active avoidance, or failed to produce a dose dependent suppression of avoidance without concomitant inhibition also of the escape variable (i.e., producing failures).

Based on the properties listed above, the active avoidance test falls into the category of so-called screening tests. A screening test is used by drug companies to evaluate synthesized molecules for a specific therapeutic property. When the screening test is an animal behavioral test, drug companies usually label the procedure in vivo pharmacology. Effects in these tests should occur following an acute administration of test drug, and only molecules that are effective against a particular disease should produce the specific effect that constitutes the marker for clinical activity - in this case selective suppression of avoidance within a clinically relevant dose range is produced.

The Active Avoidance Test and Identification of Drug Pharmacological Properties

There is no doubt that active avoidance behavior is strongly associated with brain dopamine neural transmission, and that the suppression of avoidance performance correlates significantly with the degree of striatal dopamine D2 receptor occupancy produced by D2 receptor blocking antipsy-chotic drugs. However, the active avoidance test not only identifies traditional, mainly dopamine D2 blocking anti-psychotics such as haloperidol (Fig. 2a), but is also equally sensitive in detecting the antipsychotic activity of the newer, so-called atypical, antipsychotics with a different mechanism of action such as combined lower dopamine D2/high serotonin2 receptor blockade (e.g., olanzapine, risperidone) (Fig. 2b,c), or being partial agonists at dopa-mine D2 receptors rather than pure D2 antagonists (i.e., aripiprazole).

In addition, data from clinical studies (Litman et al. 1996; Schubert et al. 2006) are in line with, and support,

Active Avoidance. Fig. 2. Shown are typical dose-response effects on active avoidance response (selective suppression of avoidance) by the typical antipsychotic haloperidol (a), and the atypical antipsychotics risperidone (b), and olanzapine (c) in rats. Data are presented as medians ± semi-interquartile range (n=6-9).

experimental data showing that the active avoidance test also reliably detects sufficient antipsychotic activity obtained by adjunct treatment with some non-D2 blocking agents (such as alpha2 adrenoceptor antagonists or acetylcholinesterase inhibitors) to a low dose of an anti-psychotic not giving sufficient dopamine D2 occupancy alone to produce antipsychotic activity (Wadenberg and Karlsson 2007; Wadenberg et al. 2007). Thus, the ability of the active avoidance test to detect antipsychotic activity does not seem to be solely limited to the detection of drugs with direct dopamine D2 receptor blocking properties. This certainly increases the value of this test as a screening tool in further development of new antipsy-chotic drugs, since many current development strategies, in order to minimize side effects and improve therapeutic efficacy, aim at moving away from molecules with mainly strong dopamine D2 receptor blocking properties.

Alternative Use of the Active Avoidance Test

The active avoidance test is primarily a test for detecting antipsychotic activity, that is, the ability of tested compounds to counteract psychotic symptoms in patients. However, since there is an element of training and learning (acquisition) associated with this test, there have been attempts to investigate if the test may be used also as a model for the detection of compounds that will enhance learning (effects on acquisition) or memory (effects on retention). Such attempts have overall not produced any consistent data. In fact, drugs that normally would impair memory (such as for example, drugs blocking brain neural transmission of acetylcholine) do not suppress avoidance behavior. Furthermore, the administration of a dopamine D2 receptor blocking antipsychotic to the animals during the training/acquisition phase does not impair the final outcome of avoidance performance in the absence of drug. This would suggest that suppressive effects on avoidance performance are not related to the impairment of memory, but rather to a temporary attenuation of the conditioned reflex, or urge, to hurry over to the other side in order to avoid getting a footshock. Indeed, gross observations of the behavior in animals given an antipsychotic drug strongly indicate that upon presentation of the CS, these animals still remember exactly what they are supposed to do; they just do not care enough to move within the time frame. Another way of explaining this phenomenon, although somewhat speculative, could be that the reason why active avoidance does not seem to work as a memory test, is because the acquisition and retention performance of active avoidance seem to primarily involve the brain subcortical mesolim-bic system in general considered to be mediating behavior associated with basic reward and survival factors (i.e., survival reflexes), rather than recruiting higher order brain structures, such as for example, the prefrontal cortex, that are involved in memory processes ofhigher order events (Wadenberg et al. 1990).

Advantages and Limitations of the Active Avoidance Test

The active avoidance test has proven to be a unique and very useful screening test for the detection of drugs with antipsychotic activity with high predictive validity as well as excellent reliability. However, individuals suffering from schizophrenia do not only present with psychotic symptoms, but also have features of social withdrawal and cognitive impairment. These symptoms have a crucial impact on the quality of life for these individuals, and unfortunately, many of the currently used antipsychotics do not adequately improve these symptoms. Therefore, novel compounds showing antipsychotic-like effects in the active avoidance test, need to be tested also in an animal model of cognition as a complementary investigation of their potential cognitive enhancing activity compared with currently used antipsychotics. A major improvement in the field would be the development of an animal behavioral screening test that identifies both antipsychotic and cognitive enhancing activity of tested drugs.

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