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Conditioned avoidance response test

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The conditioned avoidance response (CAR) test, also known as the active avoidance test, is an animal test used to identify drugs with antipsychotic-like effects.[1][2][3][4][5] It is most commonly employed as a two-way active avoidance test with rodents.[6][2][5] The test assesses the conditioned ability of an animal to avoid an unpleasant stimulus.[1][4][2][7] Drugs that selectively suppress conditioned avoidance responses without affecting escape behavior are considered to have antipsychotic-like activity.[1][4][2] Variations of the test, like testing for enhancement of avoidance and escape responses, have also been used to assess pro-motivational and antidepressant-like effects of drugs.[8][9][10][11]

Dopamine D2 receptor antagonists, like most classical antipsychotics, are active in the CAR test once occupancy of the dopamine D2 receptor reaches around 70%.[1][2] Dopamine D2 receptor partial agonists like aripiprazole are likewise active in the test.[1][12] Serotonin 5-HT2A receptor antagonists like volinanserin (MDL-100907) and ritanserin can enhance suppression of conditioned avoidance responses in the test.[1][13] Various other types of drugs have also been found to be active in the CAR test.[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][1][14]

The CAR test was developed in the 1950s soon after the discovery of antipsychotics.[2][15] It is one of the oldest animal tests of antipsychotic-like activity.[4][2] Other animal tests that are used to evaluate antipsychotic-like activity include inhibition of drug-induced hyperactivity or stereotypy, reversal of drug-induced prepulse inhibition deficits, and restoration of latent inhibition.[4][12][7]

Description

There are several variations of the CAR test, the most common of which is the two-way active avoidance test.[6][2][5] In this test, an animal is placed in a two-compartment shuttle box with an open doorway.[12][1][4][2][7][6] Then, the animal is trained to avoid an aversive stimulus (unconditioned stimulus), usually an electric footshock, on presentation of a neutral stimulus (conditioned stimulus), usually an auditory or visual stimulus like a tone or light, that shortly precedes it.[12][1][4][2][7][6] The animal does this by performing a specific behavioral response, like moving to the other compartment of the box, and this response is referred to as "avoidance" or "conditioned avoidance".[12][1][4][2][7][6] If the animal is late in performing the avoidance, the aversive stimulus is presented until the animal responds by moving to the compartment.[1] This is referred to as "escape".[1] If the animal does not escape within a certain amount of time, it is designated "escape failure".[1] As such, there are three variables that can be measured in the CAR test: avoidance, escape, and escape failure.[1][5]

Drugs that are considered to show antipsychotic-like effects selectively suppress the avoidance response without affecting escape behavior.[4][1][2][5] Conversely, drugs that do not have antipsychotic-like effects either have no effect in the CAR test or suppress both avoidance behavior and escape behavior at the same doses.[2][4][1] Examples of drugs that inhibit both avoidance and escape responses include sedatives like benzodiazepines, barbiturates, and meprobamate and antidepressants like many tricyclic antidepressants (TCAs).[4][2][6][16]

The CAR test is considered to have high predictive validity in the identification of potential antipsychotics and is frequently used in drug development.[1] However, its face validity and construct validity have been described as low or absent.[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 stimulus.[7]

Active drugs

The test can detect antipsychotic-like activity both in the case of dopamine D2 receptor antagonists and in the case of drugs lacking D2 receptor antagonism.[1][2][6] The occupancy of the D2 receptor by antagonists of this receptor required to inhibit the CAR is around 65 to 80%, which is similar to the occupancy at which therapeutic antipsychotic effects occur in humans with these drugs.[1][4] Both typical antipsychotics and atypical antipsychotics are active in the CAR test.[1][2] Similarly to dopamine D2 receptor antagonists, dopamine depleting agents like reserpine and tetrabenazine suppress conditioned avoidance responses and hence are active in the CAR test.[2][17][18]

Selective serotonin 5-HT2A receptor antagonists can enhance the suppression of conditioned avoidance responses by dopamine D2 receptor antagonists.[1] Serotonin 5-HT1A receptor agonism, for instance with buspirone, 8-OH-DPAT, or antipsychotics with concomitant 5-HT1A receptor agonism, may also enhance suppression of conditioned avoidance responses.[1][19][20] Dopamine D2 receptor partial agonists like aripiprazole, brexpiprazole, and bifeprunox suppress conditioned avoidance responses in the CAR test similarly to dopamine D2 receptor antagonists.[1][12][21]

Other drugs that may produce or enhance suppression of conditioned avoidance responses include serotonin 5-HT2C receptor agonists like CP-809101, WAY-163909, and meta-chlorophenylpiperazine (mCPP), α1-adrenergic receptor antagonists like prazosin, α2-adrenergic receptor antagonists like idazoxan, acetylcholinesterase inhibitors (and hence indirect cholinergics) like galantamine, the muscarinic acetylcholine receptor agonist xanomeline (used clinically as xanomeline/trospium),[22][23] AMPA receptor antagonists like GYKI-52466 and LY-326325, metabotropic glutamate mGlu2 and mGlu3 receptor agonists like pomaglumetad (LY-404039), and phosphodiesterase inhibitors like the PDE4 inhibitor rolipram and the PDE10A inhibitors papaverine, mardepodect (PF-2545920), and balipodect (TAK-063).[1][2][24][13][25]

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.[1][5] However, different findings have also been reported, for instance ecopipam being effective in the CAR test.[12][26] In contrast to dopamine D2 receptor antagonists, clinical trials of dopamine D1 receptor antagonists, including ecopipam and NNC 01-0687, have found that they were ineffective in the treatment of psychosis.[12][27][28]

Many antidepressants, like a variety of tricyclic antidepressants (TCAs) as well as the selective serotonin reuptake inhibitor (SSRI) fluoxetine, reduce both avoidance and escape responses in the CAR test.[6][16]

Reversal agents

Dopaminergic agents, like the dopamine precursor levodopa (L-DOPA), the dopamine releasing agents amphetamine and methamphetamine, the dopamine reuptake inhibitors methylphenidate, bupropion, and nomifensine, the non-selective dopamine receptor agonist apomorphine, and the indirect dopaminergic agent amantadine, can all markedly reverse the effects of drugs like reserpine that are active in the CAR test and restore conditioned avoidance responses.[2][17][18] Selective dopamine D1 receptor agonists. like SKF-38,393, and selective dopamine D2 receptor agonists, like quinpirole, are only weakly effective in reversing the effects of reserpine in suppressing conditioned avoidance responses when given individually.[17] However, they are synergistic and robustly effective when administered in combination.[17] Similarly, anticholinergics like atropine and scopolamine increase rates of conditioned avoidance responses.[2] In contrast to dopaminergic agents, non-dopaminergic antidepressants, like many tricyclic antidepressants (TCAs), are generally ineffective in antagonizing agents that are active in the test.[17][18]

Mechanism

The effects of drugs 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]

History

The test was developed in the 1950s soon after the discovery of antipsychotics.[2][15][29] It is one of the oldest and most classical tests of antipsychotic-like activity.[4][2][29] By 1998, its popularity had declined somewhat, but it continues to be frequently employed.[28][1][3]

Pro-motivational or antidepressant-like activity test

See also: Tetrabenazine § Animal model of motivational dysfunction, Motivation-enhancing drug, and Animal models of depression

The CAR test can also be used to assess behavioral activity or drive and associated learning.[8][9][30] The dopamine depleting agent tetrabenazine can strongly and almost completely inhibit acquisition of conditioned avoidance responses in the shuttle box and results in a very high rate of escape failures.[9][31][8] Dopaminergic agents like the catecholaminergic activity enhancers selegiline, phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP) can reverse the effects of tetrabenazine and enhance learning in this test.[8][31][9][30][32]

In addition, the CAR test, by testing the capacity of drugs to enhance escape responses and thereby reverse learned helplessness, has been used as a test of antidepressant-like activity.[10][11] κ-Opioid receptor antagonists like norbinaltorphimine have been found to be active in this test.[10][11]

Since there is a learning (acquisition) phase, there have also been attempts to use the CAR test to assess activity of drugs in enhancing learning and memory.[5] However, there have been no consistent data for this use.[5] In addition, the CAR test may be inducing more of a reflex than triggering higher-order memory involving areas like the prefrontal cortex.[5]

Other tests of antipsychotic-like activity

Other animal tests used to evaluate antipsychotic-like activity of drugs include inhibition of drug-induced stereotypy, inhibition of drug-induced hyperlocomotion or climbing behavior, and reversal of drug-induced prepulse inhibition or startle response deficits.[12] Drugs that induce such effects include dopaminergic agents like amphetamine and apomorphine and NMDA receptor antagonists like dizocilpine (MK-801).[12] Another test of antipsychotic-like activity is restoration of latent inhibition.[7]

References

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  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x Wadenberg ML, Hicks PB (1999). "The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?". Neurosci Biobehav Rev. 23 (6): 851–862. doi:10.1016/s0149-7634(99)00037-8. PMID 10541060.
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  18. ^ a b c Voith, K.; Herr, F. (1971). "The effect of various antidepressant drugs upon the tetrabenazine-suppressed conditioned avoidance response in rats". Psychopharmacologia. 20 (3). Springer Science and Business Media LLC: 253–265. doi:10.1007/bf00402101. ISSN 0033-3158.
  19. ^ Yocca, Frank; Altar, C. Anthony (2006). "Partial agonism of dopamine, serotonin and opiate receptors for psychiatry". Drug Discovery Today: Therapeutic Strategies. 3 (4). Elsevier BV: 429–435. doi:10.1016/j.ddstr.2006.10.014. ISSN 1740-6773.
  20. ^ Newman-Tancredi A, Kleven MS (August 2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties". Psychopharmacology (Berl). 216 (4): 451–473. doi:10.1007/s00213-011-2247-y. PMID 21394633.
  21. ^ Aftab A, Gao K (October 2017). "The preclinical discovery and development of brexpiprazole for the treatment of major depressive disorder". Expert Opin Drug Discov. 12 (10): 1067–1081. doi:10.1080/17460441.2017.1354849. PMID 28718334.
  22. ^ Paul SM, Yohn SE, Popiolek M, Miller AC, Felder CC (September 2022). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". Am J Psychiatry. 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. PMID 35758639.
  23. ^ Mirza NR, Peters D, Sparks RG (2003). "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Rev. 9 (2): 159–186. doi:10.1111/j.1527-3458.2003.tb00247.x. PMID 12847557.
  24. ^ Svensson TH (March 2000). "Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs". Brain Res Brain Res Rev. 31 (2–3): 320–329. doi:10.1016/s0165-0173(99)00048-x. PMID 10719159.
  25. ^ Neef J, Palacios DS (September 2021). "Progress in mechanistically novel treatments for schizophrenia". RSC Med Chem. 12 (9): 1459–1475. doi:10.1039/d1md00096a. PMID 34671731.
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  30. ^ a b Miklya I (November 2016). "The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)". Mol Psychiatry. 21 (11): 1499–1503. doi:10.1038/mp.2016.127. PMID 27480491.
  31. ^ a b Knoll J (2001). "Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain". CNS Drug Rev. 7 (3): 317–345. doi:10.1111/j.1527-3458.2001.tb00202.x. PMID 11607046.
  32. ^ Gaszner P, Miklya I (January 2006). "Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane". Prog Neuropsychopharmacol Biol Psychiatry. 30 (1): 5–14. doi:10.1016/j.pnpbp.2005.06.004. PMID 16023777.
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