title: Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies.
abstract: BACKGROUND
  Drug discrimination is an increasingly valuable behavioral assay for the preclinical development of antipsychotic drugs. The majority of studies have used the atypical antipsychotic clozapine because it displays robust discriminative stimulus properties and is the "prototypical" or "gold standard" atypical antipsychotic against which other antipsychotics will undoubtedly be compared for many years.
  
  
  OBJECTIVE
  Pharmacological mechanisms mediating the discriminative stimulus properties of antipsychotics used as training drugs and the usefulness of drug discrimination for distinguishing typical and atypical antipsychotics were reviewed.
  
  
  RESULTS
  Clozapine appears to have a compound cue involving antagonism of two or more receptors. While muscarinic receptor antagonism is a prominent factor for mediation of clozapine's cue in rats with a 5.0-mg/kg training dose, there are differences in clozapine's cue with a low training dose and in pigeons and mice. With a low training dose, clozapine has consistently produced full or partial generalization to atypical but not to typical antipsychotics. Although not evaluated as extensively, the atypical antipsychotics quetiapine and ziprasidone also appear to generalize to atypical but not typical antipsychotics. This has not been the case for other antipsychotic drugs (olanzapine, chlorpromazine, haloperidol) used as training drugs.
  
  
  CONCLUSIONS
  There are important differences in discriminative stimulus properties both between and within atypical and typical antipsychotics and across species. While low-dose clozapine discrimination in rats appears to provide a more sensitive behavioral assay for distinguishing atypical from typical antipsychotics, the extent to which clozapine's discriminative stimulus properties are predictive of its antipsychotic effects remains to be determined.
authors.affiliation: Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, P.O. Box 842018, Richmond, VA, USA. jporter@vcu.edu
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Porter
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Prus
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D011600:Psychopharmacology / Q000379:methods*; D011950:Receptors, Cholinergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D011950:Receptors, Cholinergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D003024:Clozapine
references.citation: J Pharmacol Exp Ther. 1997 Apr;281(1):440-7
references.pmid: 9103528
references.citation: Br J Pharmacol. 1980 Mar;68(3):541-9
references.pmid: 7052344
references.citation: Pharmacol Biochem Behav. 1999 Oct;64(2):337-45
references.pmid: 10515310
references.citation: J Pharmacol Exp Ther. 1997 Nov;283(2):566-73
references.pmid: 9353371
references.citation: J Clin Psychopharmacol. 1987 Dec;7(6):377-84
references.pmid: 3323261
references.citation: J Psychopharmacol. 1997;11(3):195-9
references.pmid: 9305410
references.citation: Psychopharmacologia. 1962;3:132-8
references.pmid: 13917138
references.citation: Psychopharmacologia. 1976 Mar 16;46(2):169-77
references.pmid: 951454
references.citation: Int J Neuropsychopharmacol. 2005 Sep;8(3):457-72
references.pmid: 15784157
references.citation: Psychopharmacol Bull. 1989;25(1):57-62
references.pmid: 2772119
references.citation: Neuropsychopharmacology. 2005 Nov;30(11):1986-95
references.pmid: 15900318
references.citation: Schizophr Bull. 1999;25(2):233-55
references.pmid: 10416729
references.citation: Psychopharmacology (Berl). 2009 Apr;203(2):295-301
references.pmid: 18685832
references.citation: Brain Res. 1994 Apr 18;643(1-2):1-9
references.pmid: 8032906
references.citation: Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
references.pmid: 8935801
references.citation: Pharmacol Biochem Behav. 1997 Aug;57(4):707-19
references.pmid: 9258998
references.citation: Behav Pharmacol. 1990;1(6):469-490
references.pmid: 11175433
references.citation: Behav Pharmacol. 2008 Sep;19(5-6):530-42
references.pmid: 18690107
references.citation: J Pharmacol Exp Ther. 1993 Aug;266(2):684-91
references.pmid: 8102646
references.citation: Pharmacol Biochem Behav. 2004 Jan;77(1):163-73
references.pmid: 14724054
references.citation: Behav Pharmacol. 2005 Nov;16(7):511-20
references.pmid: 16170228
references.citation: Pharmacol Biochem Behav. 1992 Nov;43(3):961-5
references.pmid: 1448493
references.citation: Am J Health Syst Pharm. 2008 Mar 1;65(5):403-13
references.pmid: 18281731
references.citation: Psychopharmacology (Berl). 2009 Apr;203(2):303-15
references.pmid: 18989659
references.citation: Exp Clin Psychopharmacol. 2002 Nov;10(4):376-84
references.pmid: 12498334
references.citation: Neuropsychopharmacology. 1996 Feb;14(2):87-96
references.pmid: 8822531
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1101-11
references.pmid: 14642970
references.citation: J Psychopharmacol. 2007 Mar;21(2):179-90
references.pmid: 17329298
references.citation: Psychopharmacology (Berl). 1996 Nov;128(2):216-9
references.pmid: 8956383
references.citation: Psychopharmacology (Berl). 2004 Dec;177(1-2):207-16
references.pmid: 15258717
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):853-61
references.pmid: 11082417
references.citation: Psychopharmacology (Berl). 2005 Jun;180(1):49-56
references.pmid: 15696329
references.citation: J Clin Psychiatry. 2007;68 Suppl 14:20-6
references.pmid: 18284274
references.citation: J Pharmacol Exp Ther. 2000 Jan;292(1):54-66
references.pmid: 10604931
references.citation: Neuropharmacology. 2003 Apr;44(5):604-15
references.pmid: 12668046
references.citation: Mol Pharmacol. 1985 Jun;27(6):600-11
references.pmid: 2860558
references.citation: J Clin Psychopharmacol. 1984 Oct;4(5):286-7
references.pmid: 6149239
references.citation: Psychopharmacology (Berl). 1997 Aug;132(3):261-9
references.pmid: 9292626
references.citation: J Pharmacol Exp Ther. 1989 Oct;251(1):238-46
references.pmid: 2571717
references.citation: Psychopharmacology (Berl). 1998 Feb;135(4):392-400
references.pmid: 9539264
references.citation: Psychopharmacology (Berl). 2005 Feb;178(1):67-77
references.pmid: 15316715
references.citation: Br J Psychiatry. 2008 Mar;192(3):161-3
references.pmid: 18310570
references.citation: Eur J Pharmacol. 1997 Mar 5;321(3):349-54
references.pmid: 9085047
references.citation: Eur J Pharmacol. 1994 Oct 13;264(1):99-102
references.pmid: 7530204
references.citation: J Pharmacol Exp Ther. 1992 Aug;262(2):545-51
references.pmid: 1354253
references.citation: Psychopharmacologia. 1974 Feb 6;34(4):351-60
references.pmid: 4812658
references.citation: Behav Pharmacol. 2006 Mar;17(2):185-94
references.pmid: 16495726
references.citation: Pharmacol Biochem Behav. 1978 Mar;8(3):235-41
references.pmid: 652832
references.citation: J Pharmacol Exp Ther. 1998 Sep;286(3):1356-73
references.pmid: 9732399
references.citation: J Psychopharmacol. 1998;12(1):84-92
references.pmid: 9584972
references.citation: Behav Pharmacol. 1998 Dec;9(8):699-710
references.pmid: 9890260
references.citation: Pharmacol Biochem Behav. 2004 Feb;77(2):199-208
references.pmid: 14751446
references.citation: Psychopharmacology (Berl). 1988;94(1):115-8
references.pmid: 3126519
references.citation: J Pharmacol Exp Ther. 1992 Oct;263(1):276-84
references.pmid: 1403790
references.citation: Neuropsychopharmacology. 2003 Aug;28(8):1400-11
references.pmid: 12784105
references.citation: Psychopharmacology (Berl). 2000 Apr;149(2):189-93
references.pmid: 10805615
references.citation: Behav Pharmacol. 2001 Sep;12(5):303-15
references.pmid: 11710745
references.citation: Psychopharmacology (Berl). 2004 Jan;171(2):212-22
references.pmid: 14691616
references.citation: J Clin Psychiatry. 1999;60 Suppl 10:42-6
references.pmid: 10340686
references.citation: J Clin Psychiatry. 1999;60 Suppl 10:47-51
references.pmid: 10340687
references.citation: Exp Clin Psychopharmacol. 1997 Aug;5(3):216-34
references.pmid: 9260069
references.citation: Int J Neuropsychopharmacol. 2005 Sep;8(3):341-56
references.pmid: 15707540
references.citation: Pharmacol Biochem Behav. 1999 Oct;64(2):193-201
references.pmid: 10515292
references.citation: NIDA Res Monogr. 1991;(116):307-23
references.pmid: 1369675
references.citation: Psychopharmacology (Berl). 1989;99 Suppl:S47-53
references.pmid: 2682732
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1994 May;18(3):563-74
references.pmid: 8078990
references.citation: J Clin Psychiatry. 1999;60 Suppl 10:5-14
references.pmid: 10340682
references.citation: Psychopharmacology (Berl). 2000 Feb;148(3):224-33
references.pmid: 10755735
references.citation: Neuropsychopharmacology. 1998 Feb;18(2):63-101
references.pmid: 9430133
references.citation: Pharmacol Ther. 1993 Jan;57(1):1-78
references.pmid: 8099741
references.citation: Psychopharmacology (Berl). 1995 Aug;120(4):491-3
references.pmid: 8539332
references.citation: Psychopharmacologia. 1966;10(1):6-31
references.pmid: 5982984
references.citation: J Pharmacol Exp Ther. 1994 Mar;268(3):1403-10
references.pmid: 7908055
references.citation: Behav Pharmacol. 2007 May;18(3):185-90
references.pmid: 17426482
references.citation: J Pharmacol Exp Ther. 1992 Mar;260(3):1361-5
references.pmid: 1347569
references.citation: Expert Opin Pharmacother. 2007 Oct;8(14):2307-13
references.pmid: 17927485
references.citation: J Pharmacol Exp Ther. 1999 Apr;289(1):427-36
references.pmid: 10087034
references.citation: Psychopharmacology (Berl). 2005 Apr;178(4):451-60
references.pmid: 15765260
references.citation: J Pharmacol Exp Ther. 2003 May;305(2):625-31
references.pmid: 12606608
references.citation: Behav Pharmacol. 2007 Feb;18(1):9-17
references.pmid: 17218793
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1071-9
references.pmid: 14642967
references.citation: Arch Gen Psychiatry. 1988 Sep;45(9):789-96
references.pmid: 3046553
references.citation: Brain Res. 1994 May 30;647(1):167-71
references.pmid: 8069701
references.citation: Psychopharmacology (Berl). 1982;76(4):385-95
references.pmid: 6812113