Social: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 by checking if they limit the animals' will.[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 other drug effects, like pro-motivational and antidepressant-like effects.[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 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] This is a major brain area involved in behavioral activation and motivation.[15][16][17][18]

The CAR test was developed in the 1950s soon after the discovery of antipsychotics.[2][19] 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.[6][2][5][20] The most common form of the test is the two-way active avoidance test (also known as the two-way discriminated shuttle box procedure).[6][2][5][20] Other variations of the test include the one-way active avoidance test (also known as the one-way discriminated pole jump procedure or the pole-jumping test) and the non-discriminated operant continuous avoidance procedure (also known as the continuous avoidance test, the Sidman avoidance test, or simply the Sidman procedure).[2][20][5]

In the two-way active avoidance 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 are not considered to 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][21]

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 or painful stimulus.[7]

Another limitation of the CAR test is that selective suppression of avoidance responses by drugs is procedure-specific.[20] In procedures besides the one-way discriminated pole jump procedure and the two-way active avoidance test, such as the Sidman procedure, antipsychotics block avoidance behavior and escapes at almost the same doses.[20] Conversely, benzodiazepines selectively suppress avoidance behavior without affecting escape behavior in the Sidman procedure.[20] This is opposite to what is generally described as reflecting antipsychotic-like activity.[20] Hence, selective suppression of avoidance responses is not a specific predictor of antipsychotic efficacy, or at best, selective suppression of avoidance responses as a predictor of antipsychotic activity is dependent on the specific CAR procedure employed.[20]

Drugs affecting the test

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][22][23]

Selective serotonin 5-HT2A receptor antagonists like volinanserin (MDL-100907) and ritanserin 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][24][25] 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][26]

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; norepinephrine reuptake inhibitors like reboxetine;[27] acetylcholinesterase inhibitors (and hence indirect cholinergics) like galantamine;[28] the muscarinic acetylcholine receptor agonist xanomeline (used clinically as xanomeline/trospium);[29][30] κ-opioid receptor agonists like spiradoline;[31] AMPA receptor antagonists like GYKI-52466 and tezampanel (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][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.[1][5] However, different findings have also been reported, for instance ecopipam being effective in the CAR test.[12][34] 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][35][36]

Inactive drugs

Various antidepressants, like tricyclic antidepressants (TCAs) as well as the selective serotonin reuptake inhibitor (SSRI) fluoxetine, reduce both avoidance and escape responses in the CAR test and hence are not considered to be active since they are not selective for avoidance responses.[6][21]

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][22][23] 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.[22] However, they are synergistic and robustly effective when administered in combination.[22] 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.[22][23]

Mechanism

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.[43][44]

History

The CAR test was developed in the 1950s soon after the discovery of antipsychotics.[2][19][45] It is one of the oldest and most classical tests of antipsychotic-like activity.[4][2][45] The test was originally performed as the one-way active avoidance or pole-jumping test, but subsequently the two-way active avoidance test was introduced and became more commonly used.[2][5][20] By 1998, the popularity of the CAR test had declined somewhat, but it continues to be frequently employed.[36][1][3]

Test of other drug effects

The CAR test can additionally be used to assess behavioral activity or drive and associated learning.[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.[9][47][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][47][9][46][48]

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]

Acquisition of conditioned avoidance responses has been used as a test of anxiolytic and anxiogenic drug effects.[49]

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 behavioral reflex rather than involving higher-order memory associated with 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]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 "Conditioned avoidance response in the development of new antipsychotics". Curr Pharm Des 16 (3): 358–370. January 2010. doi:10.2174/138161210790170085. PMID 20109144. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 "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. 1999. doi:10.1016/s0149-7634(99)00037-8. PMID 10541060. 
  3. ↑ 3.0 3.1 "Animal models for the evaluation of antipsychotic agents". Fundam Clin Pharmacol 37 (3): 447–460. June 2023. doi:10.1111/fcp.12855. PMID 36410728. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 "Animal models for predicting the efficacy and side effects of antipsychotic drugs". Braz J Psychiatry 35 Suppl 2: S132–S139. 2013. doi:10.1590/1516-4446-2013-1164. PMID 24271225. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 Wadenberg, Marie-Louise G. (2011). "Schizophrenia Key Essays: Active Avoidance". in Fleischhacker, W. Wolfgang; Stolerman, Ian P.. Encyclopedia of Schizophrenia. Tarporley: Springer Healthcare Ltd.. pp. 5–12. doi:10.1007/978-1-907673-96-2_1. ISBN 978-1-907673-17-7. https://books.google.com/books?id=T3UeBAAAQBAJ&pg=PA5. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 "Current and novel approaches to the drug treatment of schizophrenia". J Med Chem 44 (4): 477–501. February 2001. doi:10.1021/jm0002432. PMID 11170639. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Animal Models of Psychosis: Current State and Future Directions". Curr Behav Neurosci Rep 1 (2): 100–116. June 2014. doi:10.1007/s40473-014-0013-2. PMID 25215267. 
  8. ↑ 8.0 8.1 8.2 8.3 "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochem Res 28 (8): 1275–1297. August 2003. doi:10.1023/a:1024224311289. PMID 12834268. 
  9. ↑ 9.0 9.1 9.2 9.3 "The Psychopharmacology of Life and Death. Interview with Joseph Knoll.". The Psychopharmacologists, Vol. III: Interviews. London: Arnold. 2000. pp. 81–110. doi:10.4324/9781003058892-3. ISBN 978-0-340-76110-6. https://books.google.com/books?id=NJEBEAAAQBAJ&pg=PT109. 
  10. ↑ 10.0 10.1 10.2 "Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents". Curr Neuropharmacol 4 (4): 277–291. October 2006. doi:10.2174/157015906778520773. PMID 18654637. 
  11. ↑ 11.0 11.1 11.2 "Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects". J Neurochem 90 (5): 1258–1268. September 2004. doi:10.1111/j.1471-4159.2004.02589.x. PMID 15312181. 
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 Ginovart, Nathalie; Kapur, Shitij (19 September 2009). "Dopamine Receptors and the Treatment of Schizophrenia". The Receptors. Totowa, NJ: Humana Press. pp. 431–477. doi:10.1007/978-1-60327-333-6_16. ISBN 978-1-60327-332-9. 
  13. ↑ 13.0 13.1 Svensson, Torgny H. (2003). "Preclinical effects of conventional and atypical antipsychotic drugs: defining the mechanisms of action". Clinical Neuroscience Research (Elsevier BV) 3 (1–2): 34–46. doi:10.1016/s1566-2772(03)00017-3. ISSN 1566-2772. 
  14. ↑ 14.0 14.1 "Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats". Behav Brain Res 422. March 2022. doi:10.1016/j.bbr.2022.113759. PMID 35051488. 
  15. ↑ 15.0 15.1 "Mesolimbic Dopamine and the Regulation of Motivated Behavior". Behavioral Neuroscience of Motivation. Current Topics in Behavioral Neurosciences. 27. 2016. pp. 231–257. doi:10.1007/7854_2015_383. ISBN 978-3-319-26933-7. 
  16. ↑ 16.0 16.1 "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol 75: 1–32. January 2024. doi:10.1146/annurev-psych-020223-012208. PMID 37788571. 
  17. ↑ 17.0 17.1 "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev 70 (4): 747–762. October 2018. doi:10.1124/pr.117.015107. PMID 30209181. 
  18. ↑ 18.0 18.1 "The mysterious motivational functions of mesolimbic dopamine". Neuron 76 (3): 470–485. November 2012. doi:10.1016/j.neuron.2012.10.021. PMID 23141060. 
  19. ↑ 19.0 19.1 "Half a century of antipsychotics and still a central role for dopamine D2 receptors". Prog Neuropsychopharmacol Biol Psychiatry 27 (7): 1081–1090. October 2003. doi:10.1016/j.pnpbp.2003.09.004. PMID 14642968. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 Castagné, Vincent; Moser, Paul C.; Porsolt, Roger D. (2009). "Preclinical Behavioral Models for Predicting Antipsychotic Activity". Advances in Pharmacology. 57. Elsevier. pp. 381–418. doi:10.1016/s1054-3589(08)57010-4. ISBN 978-0-12-378642-5. 
  21. ↑ 21.0 21.1 "The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats". Pharmacol Biochem Behav 22 (2): 261–264. February 1985. doi:10.1016/0091-3057(85)90388-0. PMID 3983218. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 "Effects of dopaminergic agents on reversal of reserpine-induced impairment in conditioned avoidance response in rats". Pharmacol Biochem Behav 58 (4): 829–836. December 1997. doi:10.1016/s0091-3057(97)98984-x. PMID 9408183. 
  23. ↑ 23.0 23.1 23.2 Voith, K.; Herr, F. (1971). "The effect of various antidepressant drugs upon the tetrabenazine-suppressed conditioned avoidance response in rats". Psychopharmacologia (Springer Science and Business Media LLC) 20 (3): 253–265. doi:10.1007/bf00402101. ISSN 0033-3158. PMID 5565256. 
  24. ↑ Yocca, Frank; Altar, C. Anthony (2006). "Partial agonism of dopamine, serotonin and opiate receptors for psychiatry". Drug Discovery Today: Therapeutic Strategies (Elsevier BV) 3 (4): 429–435. doi:10.1016/j.ddstr.2006.10.014. ISSN 1740-6773. 
  25. ↑ "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties". Psychopharmacology (Berl) 216 (4): 451–473. August 2011. doi:10.1007/s00213-011-2247-y. PMID 21394633. 
  26. ↑ "The preclinical discovery and development of brexpiprazole for the treatment of major depressive disorder". Expert Opin Drug Discov 12 (10): 1067–1081. October 2017. doi:10.1080/17460441.2017.1354849. PMID 28718334. 
  27. ↑ "Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat". Neuropsychopharmacology 27 (5): 691–698. November 2002. doi:10.1016/S0893-133X(02)00350-0. PMID 12431844. 
  28. ↑ "Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor". Int J Neuropsychopharmacol 14 (5): 644–654. June 2011. doi:10.1017/S1461145710000921. PMID 20701827. 
  29. ↑ "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". Am J Psychiatry 179 (9): 611–627. September 2022. doi:10.1176/appi.ajp.21101083. PMID 35758639. 
  30. ↑ "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Rev 9 (2): 159–186. 2003. doi:10.1111/j.1527-3458.2003.tb00247.x. PMID 12847557. 
  31. ↑ Wadenberg, M-L. G. (2003). "A Review of the Properties of Spiradoline: A Potent and Selective k-Opioid Receptor Agonist". CNS Drug Reviews (Wiley) 9 (2): 187–198. doi:10.1111/j.1527-3458.2003.tb00248.x. ISSN 1080-563X. PMID 12847558. 
  32. ↑ "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. March 2000. doi:10.1016/s0165-0173(99)00048-x. PMID 10719159. 
  33. ↑ "Progress in mechanistically novel treatments for schizophrenia". RSC Med Chem 12 (9): 1459–1475. September 2021. doi:10.1039/d1md00096a. PMID 34671731. 
  34. ↑ "Highlights of D1 dopamine receptor antagonist research". Neurochem Int 20 Suppl: 119S–122S. March 1992. doi:10.1016/0197-0186(92)90223-e. PMID 1365409. 
  35. ↑ "New drugs for the treatment of schizophrenic patients". Acta Psychiatr Scand Suppl 388: 24–30. 1995. doi:10.1111/j.1600-0447.1995.tb05941.x. PMID 7604735. 
  36. ↑ 36.0 36.1 "Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence". Neuropsychopharmacology 18 (2): 63–101. February 1998. doi:10.1016/S0893-133X(97)00112-7. PMID 9430133. 
  37. ↑ "How antipsychotics work-from receptors to reality". NeuroRx 3 (1): 10–21. January 2006. doi:10.1016/j.nurx.2005.12.003. PMID 16490410. 
  38. ↑ "Experiences of taking neuroleptic medication and impacts on symptoms, sense of self and agency: a systematic review and thematic synthesis of qualitative data". Soc Psychiatry Psychiatr Epidemiol 55 (2): 151–164. February 2020. doi:10.1007/s00127-019-01819-2. PMID 31875238. 
  39. ↑ Belmaker, Robert Haim; Lichtenberg, Pesach (2023). "Antipsychotic Drugs: Do They Define Schizophrenia or Do They Blunt All Emotions?". Psychopharmacology Reconsidered: A Concise Guide Exploring the Limits of Diagnosis and Treatment. Cham: Springer International Publishing. pp. 63–84. doi:10.1007/978-3-031-40371-2_6. ISBN 978-3-031-40370-5. 
  40. ↑ Moncrieff, Joanna (2007). "What Do Neuroleptics Really Do? A Drug-Centred Account". The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment. Palgrave Macmillan London. pp. 100–117. doi:10.1007/978-0-230-58944-5_7. ISBN 978-0-230-57431-1. 
  41. ↑ Moncrieff, Joanna (2013). "The Patient's Dilemma: Other Evidence on the Effects of Antipsychotics". The Bitterest Pills. London: Palgrave Macmillan UK. pp. 113–131. doi:10.1057/9781137277442_7. ISBN 978-1-137-27743-5. 
  42. ↑ "The subjective experience of taking antipsychotic medication: a content analysis of Internet data". Acta Psychiatr Scand 120 (2): 102–111. August 2009. doi:10.1111/j.1600-0447.2009.01356.x. PMID 19222405. 
  43. ↑ 43.0 43.1 "Neuroleptics and psychic indifference: a review". J R Soc Med 82 (10): 615–619. October 1989. doi:10.1177/014107688908201018. PMID 2572700. 
  44. ↑ Healy, David (1990). "Schizophrenia: Basic, release, reactive and defect processes". Human Psychopharmacology: Clinical and Experimental (Wiley) 5 (2): 105–121. doi:10.1002/hup.470050203. ISSN 0885-6222. "Arguably, indeed, the fact that neuroleptics reduced agitation in schizophrenic subjects is the best evidence against a malfunctioning of dopamine systems in schizophrenia. That this effect is therapeutically useful in schizophrenia does not imply an abnormality of dopamine systems in schizophrenia, but rather that the behavioural state induced can be put to therapeutic use in this illness. Such a behavioural effect is consistent with the known effects of neuroleptics on conditioned avoidance paradigms in experimental animals, where they appear to inhibit the engagement of motor responses or operant behaviour with learned associations (Beninger, 1983; Mason, 1984), leading to extinction-like effects in learning paradigms (Beninger, 1983; Crow and Deakin, 1985; Gallistel, 1986). These effects, unlike clinical recovery, correlate closely with potency in blocking D2 receptors. They are also of acute onset and are consistent with the induction of a state of psychic indifference in humans.". 
  45. ↑ 45.0 45.1 Willner, Paul (1990). "Animal models for Clinical Psychopharmacology: Depression, Anxiety, Schizophrenia". International Review of Psychiatry (Informa UK Limited) 2 (3–4): 253–276. doi:10.3109/09540269009026601. ISSN 0954-0261. 
  46. ↑ 46.0 46.1 "The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015)". Mol Psychiatry 21 (11): 1499–1503. November 2016. doi:10.1038/mp.2016.127. PMID 27480491. 
  47. ↑ 47.0 47.1 "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. 2001. doi:10.1111/j.1527-3458.2001.tb00202.x. PMID 11607046. 
  48. ↑ "Major depression and the synthetic enhancer substances, (-)-deprenyl and R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane". Prog Neuropsychopharmacol Biol Psychiatry 30 (1): 5–14. January 2006. doi:10.1016/j.pnpbp.2005.06.004. PMID 16023777. 
  49. ↑ "The early acquisition of two-way (shuttle-box) avoidance as an anxiety-mediated behavior: psychopharmacological validation". Brain Res Bull 26 (1): 173–176. January 1991. doi:10.1016/0361-9230(91)90205-x. PMID 1673080. 



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