Discriminative stimulus properties of atypical and typical antipsychotic drugs: a review of preclinical studies.
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.
Porter
Joseph H
JH
Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, P.O. Box 842018, Richmond, VA, USA. jporter@vcu.edu
Prus
Adam J
AJ
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
D014150:Antipsychotic Agents; D011950:Receptors, Cholinergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D003024:Clozapine
J Pharmacol Exp Ther. 1997 Apr;281(1):440-7
9103528
Br J Pharmacol. 1980 Mar;68(3):541-9
7052344
Pharmacol Biochem Behav. 1999 Oct;64(2):337-45
10515310
J Pharmacol Exp Ther. 1997 Nov;283(2):566-73
9353371
J Clin Psychopharmacol. 1987 Dec;7(6):377-84
3323261
J Psychopharmacol. 1997;11(3):195-9
9305410
Psychopharmacologia. 1962;3:132-8
13917138
Psychopharmacologia. 1976 Mar 16;46(2):169-77
951454
Int J Neuropsychopharmacol. 2005 Sep;8(3):457-72
15784157
Psychopharmacol Bull. 1989;25(1):57-62
2772119
Neuropsychopharmacology. 2005 Nov;30(11):1986-95
15900318
Schizophr Bull. 1999;25(2):233-55
10416729
Psychopharmacology (Berl). 2009 Apr;203(2):295-301
18685832
Brain Res. 1994 Apr 18;643(1-2):1-9
8032906
Psychopharmacology (Berl). 1996 Mar;124(1-2):57-73
8935801
Pharmacol Biochem Behav. 1997 Aug;57(4):707-19
9258998
Behav Pharmacol. 1990;1(6):469-490
11175433
Behav Pharmacol. 2008 Sep;19(5-6):530-42
18690107
J Pharmacol Exp Ther. 1993 Aug;266(2):684-91
8102646
Pharmacol Biochem Behav. 2004 Jan;77(1):163-73
14724054
Behav Pharmacol. 2005 Nov;16(7):511-20
16170228
Pharmacol Biochem Behav. 1992 Nov;43(3):961-5
1448493
Am J Health Syst Pharm. 2008 Mar 1;65(5):403-13
18281731
Psychopharmacology (Berl). 2009 Apr;203(2):303-15
18989659
Exp Clin Psychopharmacol. 2002 Nov;10(4):376-84
12498334
Neuropsychopharmacology. 1996 Feb;14(2):87-96
8822531
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1101-11
14642970
J Psychopharmacol. 2007 Mar;21(2):179-90
17329298
Psychopharmacology (Berl). 1996 Nov;128(2):216-9
8956383
Psychopharmacology (Berl). 2004 Dec;177(1-2):207-16
15258717
J Pharmacol Exp Ther. 2000 Dec;295(3):853-61
11082417
Psychopharmacology (Berl). 2005 Jun;180(1):49-56
15696329
J Clin Psychiatry. 2007;68 Suppl 14:20-6
18284274
J Pharmacol Exp Ther. 2000 Jan;292(1):54-66
10604931
Neuropharmacology. 2003 Apr;44(5):604-15
12668046
Mol Pharmacol. 1985 Jun;27(6):600-11
2860558
J Clin Psychopharmacol. 1984 Oct;4(5):286-7
6149239
Psychopharmacology (Berl). 1997 Aug;132(3):261-9
9292626
J Pharmacol Exp Ther. 1989 Oct;251(1):238-46
2571717
Psychopharmacology (Berl). 1998 Feb;135(4):392-400
9539264
Psychopharmacology (Berl). 2005 Feb;178(1):67-77
15316715
Br J Psychiatry. 2008 Mar;192(3):161-3
18310570
Eur J Pharmacol. 1997 Mar 5;321(3):349-54
9085047
Eur J Pharmacol. 1994 Oct 13;264(1):99-102
7530204
J Pharmacol Exp Ther. 1992 Aug;262(2):545-51
1354253
Psychopharmacologia. 1974 Feb 6;34(4):351-60
4812658
Behav Pharmacol. 2006 Mar;17(2):185-94
16495726
Pharmacol Biochem Behav. 1978 Mar;8(3):235-41
652832
J Pharmacol Exp Ther. 1998 Sep;286(3):1356-73
9732399
J Psychopharmacol. 1998;12(1):84-92
9584972
Behav Pharmacol. 1998 Dec;9(8):699-710
9890260
Pharmacol Biochem Behav. 2004 Feb;77(2):199-208
14751446
Psychopharmacology (Berl). 1988;94(1):115-8
3126519
J Pharmacol Exp Ther. 1992 Oct;263(1):276-84
1403790
Neuropsychopharmacology. 2003 Aug;28(8):1400-11
12784105
Psychopharmacology (Berl). 2000 Apr;149(2):189-93
10805615
Behav Pharmacol. 2001 Sep;12(5):303-15
11710745
Psychopharmacology (Berl). 2004 Jan;171(2):212-22
14691616
J Clin Psychiatry. 1999;60 Suppl 10:42-6
10340686
J Clin Psychiatry. 1999;60 Suppl 10:47-51
10340687
Exp Clin Psychopharmacol. 1997 Aug;5(3):216-34
9260069
Int J Neuropsychopharmacol. 2005 Sep;8(3):341-56
15707540
Pharmacol Biochem Behav. 1999 Oct;64(2):193-201
10515292
NIDA Res Monogr. 1991;(116):307-23
1369675
Psychopharmacology (Berl). 1989;99 Suppl:S47-53
2682732
Prog Neuropsychopharmacol Biol Psychiatry. 1994 May;18(3):563-74
8078990
J Clin Psychiatry. 1999;60 Suppl 10:5-14
10340682
Psychopharmacology (Berl). 2000 Feb;148(3):224-33
10755735
Neuropsychopharmacology. 1998 Feb;18(2):63-101
9430133
Pharmacol Ther. 1993 Jan;57(1):1-78
8099741
Psychopharmacology (Berl). 1995 Aug;120(4):491-3
8539332
Psychopharmacologia. 1966;10(1):6-31
5982984
J Pharmacol Exp Ther. 1994 Mar;268(3):1403-10
7908055
Behav Pharmacol. 2007 May;18(3):185-90
17426482
J Pharmacol Exp Ther. 1992 Mar;260(3):1361-5
1347569
Expert Opin Pharmacother. 2007 Oct;8(14):2307-13
17927485
J Pharmacol Exp Ther. 1999 Apr;289(1):427-36
10087034
Psychopharmacology (Berl). 2005 Apr;178(4):451-60
15765260
J Pharmacol Exp Ther. 2003 May;305(2):625-31
12606608
Behav Pharmacol. 2007 Feb;18(1):9-17
17218793
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1071-9
14642967
Arch Gen Psychiatry. 1988 Sep;45(9):789-96
3046553
Brain Res. 1994 May 30;647(1):167-71
8069701
Psychopharmacology (Berl). 1982;76(4):385-95
6812113