Neur05c1ence • 8106ehav10ra1 Rev1ew5, V01. 15. pp. 35-43. ~ Per9am0n Pre55 p1c. 1991. Pr1nted 1n the •U.5.A. 0149-7634/91 $3.00 + .00

An1ma1 M0de15 f0r A55e551n9 Dru95 0f A6u5e

J 0 5 E P H V. 8 R A D Y t

7he J0hn5 H0pk1n5 Un1ver51ty 5ch001 0f Med1c1ne, 8a1t1m0re, MD 21205

8RADY, J. V. An1ma1 m0de15f0r a55e551n9 dru95 0fa6u5e. NEUR05C1 8108EHAV REV 15(1) 35--43, 1991.--A maj0r t0x1c effect that ha5 11m1ted the c11n1ca1 u5efu1ne55 0f med1c1na1 dru95 ha5 6een the1r 5u5cept16111ty t0 n0nmed1ca1 u5e and a6u5e 6y 519n1f- 1cant 5e9ment5 0f the p0pu1at10n. Maj0r re5earch eff0rt5 have 6een d1rected t0ward the deve10pment 0f 5afer and m0re effect1ve therapeut1c a9ent5 that w0u1d n0t he 5u6ject t0 5uch m15u5e, and 1a60rat0ry an1ma1 a55e55ment m0de15 have c0ntr16uted 1mp0rtant1y t0 the eva1uat10n 0f 5uch c0mp0und5. 7here are n0w 5evera1 c0nver91n9 f1ne5 0f ev1dence that te5t1fy t0 the re11a6111ty and 6r0ad 9enera11ty 0f 065ervat10n5 c0ncern1n9 dru9 a6u5e 11a6111ty 1n human5 6a5ed up0n 5uch an1ma1 1a60rat0ry m0de15. 7he m05t 1mp0r- tant p01nt 0f c0ntact that character12e5 the 1nteract10n 6etween 5uch an1ma1 a55e55ment m0de15 and the human dru9 a6u5e arena 15 the dem0n5trated re1at10n5h1p 6etween the 610chem1ca1/pharmac01091ca1/t0x1c pr0pert1e5 0f dru95 0n the 0ne hand, and the1r env1- r0nmenta1/6ehav10ra1 5t1mu1u5 funct10n5 0n the 0ther. A5 a re5u1t 0f the5e deve10pment5 1n an1ma1 m0de1 re5earch techn0109Y and the c0n5e4uent advance5 1n kn0w1ed9e 0f dru9 act10n, an 0perat10na1 6a515 ha5 6een pr0v1ded f0r redef1n1n9 the 6ew11der1n9 ran9e 0f phen0mena and exper1ent1a1 p5eud0-phen0mena 1005e1y 1dent1fy w1th 5uch term5 a5 ••add1ct10n,•• ••dependence•• and ••a6u5e.••

Dru9 a6u5e An1ma1 m0de15 8ehav10ra1 t0x1c1ty

Phy5101091ca1 dependence Dru9 5e1f-adm1n15trat10n Dru9 d15cr1m1nat10n

A maj0r t0x1c effect that ha5 11m1ted the c11n1ca1 u5efu1ne55 0f med1c1na1 dru95 ha5 6een the1r 5u5cept16111ty t0 n0nmed1ca1 u5e and a6u5e 6y 519n1f1cant 5e9ment5 0f the p0pu1at10n. Maj0r re- 5earch eff0rt5 have 6een d1rected t0ward the deve10pment 0f 5afer and m0re effect1ve therapeut1c a9ent5 that w0u1d n0t 6e 5u6ject t0 5uch m15u5e, and 1a60rat0ry an1ma1 a55e55ment m0de15 have c0n- tr16uted 1mp0rtant1y t0 the eva1uat10n 0f 5uch c0mp0und5. 7he meth0d01091ca1 and 5u65tant1ve 1nteract10n5 6etween the 6ehav- 10ra1, pharmac01091ca1, and t0x1c01091ca1 5c1ence5 9enerated 6y the deve10pment 0f 5uch an1ma1 m0de15 have c0mp1emented tra- d1t10na1 610chem1ca1/phy5101091ca1 eva1uat10n5 0f 5tructure-ac- t1v1ty re1at10n5h1p5 and pr0v1ded a m0re c0mprehen51ve 6a515 f0r eva1uat1n9 a dru95 dependence p0tent1a1 and a6u5e 11a6111ty. 7he re5u1t1n9 advance5 1n kn0w1ed9e 0f dru9 act10n, and part1cu1ar1y 1n re5earch techn0109y, have made p055161e an 0perat10na1 ap- pr0ach t0 pharmac01091ca1 and t0x1c01091ca1 eva1uat10n 0f a6u5e dru95 and empha512ed the need f0r reappra15a1 0f trad1t10na1 c0n- cept5 and def1n1t10n5 1n the 6r0ad d0ma1n 0f 5u65tance u5e and m15u5e.

c0NcEP7uAL AND ME7H0D0L061cAL c0N51DERA710N5

Preva111n9 v1ew5 re9ard1n9 the 1ncrea51n91y u614u1t0u5 dru9 and a1c0h01 a6u5e pr0ce55 have 10n9 empha512ed 1t5 react1ve na- ture w1th attent10n f0cu5ed up0n antecedent c0nd1t10n5 a5 pr1mary determ1nant5--the c1a551ca1 W. C. F1e1d5 f0rmu1at10n that ••1t wa5 a w0man wh0 dr0ve me t0 dr1nk and 1 never 90t a chance t0

thank her••• 8u t the d15c0very that an1ma15 1mp1anted w1th 1ntra- ven0u5 catheter5 (F19. 1) w0u1d repeated1y 5e1f-1nject pharmac0- 1091ca1 5u65tance5 (20,78) wa5 re5p0n5161e f0r a dec151ve 5h1ft 1n f0cu5 t0 the m0re act1ve, c0n5e4uent1a1 c0ntr01 feature5 0f 5uch a6u51ve dru9 5e1f-adm1n15trat10n.

1ndeed, the re5earch 0cca510ned 6y th15 5em1na1 f1nd1n9 ha5 pr0v1ded c0nv1nc1n9 ev1dence 0f a remarka61e c0nc0rdance 6e- tween the ran9e 0f chem1ca1 5u65tance5 5e1f-adm1n15tered 1n the c0ntext 0f an1ma1 dru9 a55e55ment m0de15 and th05e a6u5ed 6y human5 (15, 29, 30, 49). M0re0ver, the var1a61e5 0f wh1ch 5uch dru9 5e1f-adm1n15trat10n are a funct10n (e.9., d05e, re5p0n5e c05t, 5chedu1e 0f ava11a6111ty, env1r0nmenta1 c0nd1t10n5, pa5t h15t0ry) have a11 6een f0und t0 exert the1r 1nf1uence 1n a 51m11ar fa5h10n 1ndependent1y 0f the type 0f 5u65tance ma1nta1n1n9 the perf0r- mance 0r the 5pec1e5 0f 0r9an15m 1nv01ved (30,51). 7he rec09n1- t10n 0f the5e cr055-5pec1e5 and cr055-5u65tance 9enera11t1e5 ha5 rad1ca11y chan9ed c0nceptua112at10n5 0f dru9 and a1c0h01 a6u5e fr0m a react1ve t0 a m0re act1ve pr0ce55 and ha5 enc0ura9ed the k1nd 0f funct10na1 ana1y515 0f dru9-5eek1n9 and dru9-tak1n9 1n an1ma1 m0de15 that ha5 pr0ven 50 u5efu1 and pr0duct1ve 1n 0ther 6106ehav10ra1 area5 (9).

7h15 empha515 up0n an1ma1 m0de15 and 5u65tance a6u5e c0m- m0na11t1e5 make5 c0ntact w1th an expand1n9 60dy 0f re5earch kn0w1ed9e 6a5ed up0n the ana1y515 0f 6ehav10ra1, pharmac01091- ca1, t0x1c01091ca1 1nteract10n5 and 15 advanta9ed 6y the 5tr0n9 emp1r1ca1 1nf1uence 0f the exper1menta1 1a60rat0ry. 7he m05t 1m- p0rtant p01nt 0f 1nteract1ve c0ntact that character12e5 5uch an1ma1

*Re4ue5t5 f0r repr1nt5 5h0u1d 6e addre55ed t0 J05eph V. 8rady, Ph.D., D1v1510n 0f 8ehav10ra1 810109y, 7ray10r 8u11d1n9, R00m 624, J0hn5 H0pk1n5 Un1ver51ty, 5ch001 0f Med1c1ne, 720 Rut1and Avenue, 8a1t1m0re, MD 21205.

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F16. 1. A draw1n9 0f a 6a600n wear1n9 a harne55/tether 5y5tem and h01d- 1n9 a 1ever, re5p0n5e5 up0n wh1ch pr0duce dru9 1nject10n5 6y 0perat1n9 a 5yr1n9e pump.

a55e55ment m0de15 15 the dem0n5trated re1at10n5h1p 6etWeen the 610C6em1Ca1/pharmaC01091Ca1/t0X1C01091Ca1 pr0pert1e5 0f dru95 0n the 0ne hand, and the1r enV1r0nmenta1/6ehaV10ra1 5t1mU1U5 func- t10n5 0n the 0ther. 7he a5pect 0f th15 re1at10n5h1p that d0m1nate5 1nve5t19at1ve attent10n ha5 c0nt1nued t0 f0cu5 0n the re1nf0rc1n9 funct10n5 0f dru95 and the c0nd1t10n5 under wh1ch dru9-5eek1n9 and dru9-tak1n9 6ehav10r5 are 1nf1uenced 6y the1r phy510-610chem- 1ca1 pr0pert1e5. A5 a re5u1t, exper1menta1 pr0cedure5 f0r the 9en- erat10n and ma1ntenance 0f dru9 5e1f-adm1n15trat10n perf0rmance5 have 6ec0me the ha11mark 0f a55e55ment m0de15 that have 900d pred1ct1ve va11d1ty f0r human dru9 a6u5e 11a6111ty (17).

7HE RE1NF0RC1N6 FUNC710N5 0F DRU65

7he pr0cedure5 u5ed m05t c0mm0n1y t0 a55e55 the re1nf0rc1n9 funct10n5 0f unkn0wn pharmac01091c a9ent5 1nv01ve e1ther d1rect acce55 t0 the te5t c0mp0und (v1a aut0mat1c 0ra1-dr1nk1n9 5y5tem5 0r 1n5trumenta1 1ever pre551n9 6y an1ma15 w1th 1ntraven0u5 and/0r 1ntra9a5tr1c catheter5) w1th0ut pr10r dru9 5e1f-adm1n15trat10n expe- r1ence (1, 24, 59) 0r 5u65t1tut10n 0f the te5t c0mp0und 0n a dru9 5e1f-adm1n15trat10n 6a5e11ne prev10u51y e5ta6115hed w1th 5tandard re1nf0rc1n9 a9ent5 (12,15). 0ne var1ant 0f the 1atter pr0cedure de5cr16ed 6y 6r1ff1th5 et a1. (38) f0r examp1e, ha5 6een u5ed t0 5y5temat1ca11y eva1uate the re1nf0rc1n9 eff1cacy and c0mpare a ran9e 0f d05e5 0f 50me 15 5t1mu1ant an0rect1c5 and m0re than 20 5edat1ve anx101yt1c5 5u65t1tuted after 5evera1 c0n5ecut1ve day5 0f mu1t1p1e c0ca1ne 1nject10n5 per day. Acce55 t0 each d05e 0f each 0f the te5t c0mp0und5 wa5 perm1tted f0r at 1ea5t 12 day5, and F195. 2 and 3 111u5trate the re5u1t1n9 c0mparat1ve ana1y515 0f re1n- f0rc1n9 eff1cacy 6a5ed up0n dru9 5e1f-adm1n15trat10n tr1a1 fre- 4uency w1th a 5er1e5 0f pr0t0typ1ca1 5t1mu1ant5 (F19, 2), and up0n

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F16.2. Avera9e num6er 0f 1nject10n5 per day w1th 14 pheny1ethy1am1ne5. 1ntraven0u5 1nject10n5 were de11vered up0n c0mp1et10n 0f 160 1ever pre55- e5: a 3-h0ur t1me-0ut f0110wed each 1nject10n perm1tt1n9 a max1mum 0f e19ht 1nject10n5 per day. (C) 1nd1cate5 mean 0f a11 the 3-day per10d5 w1th c0ca1ne wh1ch 1mmed1ate1y preceded every 5u65t1tut10n 0f a pheny1ethy1- am1ne 0r 5a11ne. (5) 1nd1cate5 mean 0f day 8-12 after 5u65t1tut10n 0f 5a- f1ne (tw0 5a11ne 5u65t1tut10n5 1n each 0f 15 an1ma15). 8racket5 1nd1cate ran9e5 0f 1nd1v1dua1 an1ma1•5 mean5. Dru9 data p01nt5 1nd1cate mean 0f day5 8-12 after 5u65t1tut10n 0f a dru9 f0r 1nd1v1dua1 an1ma15. L1ne5 c0n- nect mean5 at 1nd1cated d05e5 0f dru9.

1ever-pre551n9 re5p0n5e rate w1th a 5er1e5 0f pr0t0typ1ca1 5edat1ve5 (F19. 3), 60th a5 a funct10n 0f d05e.

C0mpar150n5 6etween 5e1f-adm1n15tered dru95 w1th re5pect t0 the1r re1nf0rc1n9 funct10n5 h0wever, have c0nt1nued t0 pre5ent meth0d01091ca1 cha11en9e5 t0 the extent that effect5 up0n re5p0n5e t0p09raphy (e.9., d15rupt10n 0f m0t0r c0ntr01) may c0mpr0m15e 1n5trumenta1 perf0rmance mea5ure5 (e.9., 1ever pre551n9), per 5e. A ran9e 0f 1nve5t19at1ve appr0ache5 t0 the 501ut10n 0f th15 pr06- 1em ha5 6een rep0rted 1nc1ud1n9 the u5e 0f c0ncurrent 5chedu1e pr0cedure5 (47), ch01ce pr0cedure5 (38,50), re5p0n5e rate ana1y- 515 (7,37), and pr09re551ve rat10 pr0cedure5 (12, 15, 81). 7he m05t exten51ve1y d0cumented re5u1t5 have 1nv01ved the u5e 0f pr09re551ve rat10 meth0d5 f0r mea5ur1n9 the re1at1ve re1nf0rc1n9 5tren9th 0f a dru9 6y determ1n1n9 the max1mum am0unt 0f re- 5p0nd1n9 (1.e., w0rk) that can 6e ma1nta1ned 6y the c0mp0und (14). 7he re5p0n5e re4u1rement 15 5y5temat1ca11y 1ncrea5ed unt11

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F16. 3. Mean re5p0n5e rate5 ma1nta1ned 6y dru9. Y-ax15:re5p0n5e5 per 5ec0nd, 109 5ca1e. X-ax15: d05e (m9/k9/1nject10n). 109 5ca1e. F0r each an1ma1 exp05ed t0 a dru9 d05e 0r veh1c1e (V), the 0vera11 re5p0n5e rate wa5 ca1cu1ated f0r the 1a5t 5 day5 0f the c0nd1t10n 6y d1v1d- 1n9 the t0ta1 re5p0n5e5 (exc1ud1n9 th05e em1tted dur1n9 t1me-0ut) 6y the t0ta:1 t1me 1n 5ec0nd5 (exc1ud1n9 t1me-0ut per10d5). 7he mean and ran9e 0f the5e 0vera11 re5p0n5e rate5 are pre5ented. C0ntr01 c0ca1ne data (C) were ca1cu1ated 1dent1ca11y fr0m the 3-day c0ntr01 per10d5 wh1ch 1mmed1ate1y preceded 5u65t1tut10n 0f veh1c1e 0r the dru9 d05e5.

the num6er 0f c0mp1eted 1nject10n tr1a15 fa115 6e10w a cr1ter10n 1eve1. 5uch "•6reak1n9 p01nt•• determ1nat10n5, f0r examp1e, have 6een made 0ver a ran9e 0f d05e5 w1th fenf1uram1ne, ch10rphen- term1ne, d1ethy1pr0p10n and c0ca1ne (34). W1th1n-an1ma1 c0mpar- 150n 0f the max1mum 6reak1n9 p01nt5 ma1nta1ned 6y the d1fferent dru95 are 111u5trated 1n F19.4 wh1ch 5h0w5 that c0ca1ne 9enera11y ma1nta1ned the h19he5t 6reak1n9 p01nt5, f0110wed 1n 0rder 6y d1- ethy1pr0p10n, ch10rphenterm1ne and fenf1uram1ne.

A u5efu1 pr0cedure f0r rank1n9 the a6u5e 11a6111ty 0f an0rect1c dru95 ha5 a150 6een de5cr16ed (35) 6a5ed up0n an 0rder1n9 0f c0mp0und5 1n term5 0f a rat10 6etween tw0 d05e5: a d05e that pr0duced a 5pec1f1ed an0rect1c effect and a d05e that pr0duced a 5pec1f1ed re1nf0rc1n9 effect. C1ear1y, the m05t de51ra61e an0rect1c dru9 w0u1d have p0tent an0rect1c pr0pert1e5 6ut m1n1ma1 re1nf0rc- 1n9 funct10n5. An unde51ra61e an0rect1c w0u1d 6e a weak appet1te 5uppre55ant 6ut a p0tent re1nf0rcer. A num6er 0f 5u65t1tuted phen- y1ethy1am1ne5 and c0ca1ne have 6een eva1uated u51n9 th15 an0rec- t1c/re1nf0rcement rat10 (ak1n t0 the ••therapeut1c rat10,•• f0r examp1e) and F19. 5 111u5trate5 the re5u1t5 0f 5uch c0mpar150n5 and c0n- f1rm5 the c0nc0rdance 6etween an1ma1 and human f1nd1n95 6a5ed up0n an0rect1c dru9 d05e determ1nat10n5.

519n1f1cant1y. the 9enera11ty 0f the5e re5u1t5 rep0rted w1th an- 1ma1 5e1f-1nject10n m0de15 0f a6u5e 11a6111ty ha5 6een we11 d0cu- mented 1n c0ntr011ed 1a60rat0ry dru9 5e1f-adm1n15trat10n 5tud1e5 w1th human v01unteer5. A 6r0ad ran9e 0f pharmac01091c a9ent5 1nc1ud1n9 her01n (62), methad0ne (58,76), ethan01 (31,61), pen- t06ar61ta1 (32), d1a2epam (33), c0ca1ne (28), amphetam1ne (52,53), n1c0t1ne (36), and mar1juana (63), am0n9 0ther5 (19), ha5 6een 5h0wn t0 ma1nta1n dru9 5e1f-adm1n15trat10n 6y human5 1ndepen- dent1y 0f whether the part1c1pant v01unteer5 were 0cca510na1 0r ca5ua1 dru9 u5er5 (52), had 5u65tant1a1 and var1ed dru9 u5e h15t0- r1e5 (25), 0r were phy51ca11y dependent 0n dru95 (62,76).

1n 0ther re5pect5 a5 we11, the human data fr0m dru9 5e1f-ad- m1n15trat10n 5tud1e5 1n exper1menta1 5ett1n95 tend t0 c0nf1rm the funct10na1 re1at10n5 de5cr16ed 1n 1a60rat0ry an1ma1 1nve5t19at10n5 (8). When ••re5p0n5e c05t•• wa5 man1pu1ated, f0r examp1e, w1th human 1npat1ent v01unteer5 5e1f-adm1n15ter1n9 the1r ma1ntenance d05e 0f methad0ne c0nt1n9ent up0n an 0perant perf0rmance, 1n-

tr0duct10n 0f a pr09re551ve rat10 re4u1rement f0r methad0ne de- crea5ed re5p0n5e rate5 and 1ncrea5ed the 11ke11h00d that the 5u6ject5 w0u1d det0x1fy (58). 51m11ar1y, re5p0n5e c05t 5tud1e5 w1th hu- man5 have 5h0wn that a1c0h01 c0n5umpt10n 1eve15 var1ed 1nver5e1y w1th the am0unt 0f w0rk re4u1red t0 ma1nta1n dru9 acce55 (60). And the rep0rted data fr0m exper1ment5 u51n9 ch01ce pr0cedure5 w1th human v01unteer5 t0 a55e55 the re1at1ve re1nf0rc1n9 5tren9th 0f dru95 ha5 6een 9enera11y c0n515tent w1th the an1ma1 1a60rat0ry f1nd1n95:pent06ar61ta1 15 preferred t0 d1a2epam (30); h19h d05e5 0f c0ca1ne are ch05en 0ver 10wer d05e5 (27); and c0ca1ne 15 pre- ferred t0 pr0ca1ne (26).

7 H E D 1 5 C R 1 M 1 N A 7 1 V E F U N C 7 1 0 N 5 0 F D R U 6 5

Wh11e re1nf0rc1n9 funct10n5 a5 ref1ected 6y 5e1f-adm1n15trat10n have pr0v1ded a d0m1nant f0cu5 f0r an1ma1 m0de15 and pr0ce- dura1 appr0ache5 t0 the a55e55ment 0f a6u5e 11a6111ty, recent re- f1nement5 1n the ana1y515 0f d15cr1m1nat1ve funct10n5 have pr0v1ded a m0re c0mprehen51ve 6a515 f0r character121n9 a dru9•5 5pectrum 0f act10n and eva1uat1n9 1t5 a6u5e 11a6111ty (11, 17, 80). 7here 15 n0w a6undant ev1dence that 60th 1a60rat0ry an1ma15 and human5 can 6e tra1ned t0 re5p0nd d1fferent1a11y 1n the pre5ence 0f d1ffer- ent 5t1mu1u5 c0nd1t10n5, whether the 5t1mu11 are pre5ented exter0- cept1ve1y (e.9., v1510n, aud1t10n) 0r 1nter0cept1ve1y, a5 1n the ca5e 0f dru95 (21,22). 1n the typ1ca1 dru9 d15cr1m1nat10n exper1ment, f0r examp1e, d1fferent1a1 re1nf0rcement pr0cedure5 are u5ed t0 5tren9then 0ne re5p0n5e (e.9., pre551n9 the 1eft 1ever) after a cer- ta1n dru9 d05e 15 adm1n15tered and a d1fferent re5p0n5e (e.9., pre551n9 the r19ht 1ever) after n0 dru9, the dru9 veh1c1e a10ne, 0r a dru9 0f a d1fferent c1a55 15 adm1n15tered. 7he pre5ence 0r a6- 5ence 0f the tra1n1n9 dru9 c0me5 t0 5et the 0cca510n f0r mak1n9 0ne 0f tw0 (0r m0re) re5p0n5e5, 0n1y 0ne 0f wh1ch w111 6e re1n- f0rced 1n any 91ven tra1n1n9 5e5510n (48, 67, 70, 79). 7h15 pr0ce- dure perm1t5 5tudy n0t 0n1y 0f the d15cr1m1na6111ty 0f 1nd1v1dua1 dru95 (66), 6ut a150 0f the ran9e 0f dru95 that w111 0cca510n the 5ame re5p0n5e a5 the tra1n1n9 dru9 1n te5t5 0f dru9 5t1mu1u5 9en- era112at10n. Dru95 that are pharmac01091ca11y 51m11ar t0 the tra1n- 1n9 dru9 9enera11y 0cca510n re5p0nd1n9 51m11ar t0 that under the

38 8RADY

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F16. 4. 8reak1n9 p01nt va1ue5 f0r d05e5 0f fenf1uram1ne, ch10rphenter- m1ne, d1ethy1pr0p10n, and c0ca1ne 1n f1ve 6a600n5. 0rd1nate5:8reak1n9 p01nt5; A65c155ae: D05e (m9/k9/1nject10n). Each p01nt repre5ent5 a 51n91e 6reak1n9 p01nt 065ervat10n. L1ne5 c0nnect the mean5 0f the 6reak1n9 p01nt 065ervat10n5 at d1fferent d05e5 0f dru9. F111ed c1rc1e5 1nd1cate data 06- ta1ned dur1n9 the f1r5t exp05ure t0 a dru9 d05e, Unf111ed c1rc1e5 1nd1cate data 06ta1ned dur1n9 a 5ec0nd exp05ure t0 a dru9 d05e.

tra1n1n9 dru9 c0nd1t10n wh11e dru95 fr0m d1fferent c1a55e5 d0 n0t (67). 5uch cr055-dru9 te5t pr0cedure5 may 6e 0perat10na11y ana1- 090u5 t0 the a55e55ment 0f 5e1f-rep0rted c0mpar150n 0f dru9 ef- fect5 1n exper1enced human dru9 u5er5 (39,46).

Dru9 d15cr1m1nat10n pr0cedure5 1n 6a600n5 have 6een u5ed 1n a 5er1e5 0f 5tud1e5 0f 5edat1ve/anx101yt1c5 1nc1ud1n9 recent1y de- ve10ped n0ve1 c0mp0und5 purp0rted t0 6e c11n1ca11y u5efu1 a5 anx101yt1c5 (2--6). 8a600n5 were tra1ned t0 d15cr1m1nate the 6en- 20d1a2ep1ne 10ra2epam under c0nd1t10n5 where f00d de11very de- pended 0n a f1xed num6er 0f c0n5ecut1ve re5p0n5e5 0n 0ne 1ever when the 5e5510n wa5 preceded 6y 10ra2epam 0r 0n the 0ther 1e- ver under n0-dru9 0r veh1c1e c0nd1t10n5. C0mpar150n5 6etween a ran9e 0f 0ther 6en20d1a2ep1ne5 (1.e., a1pra201am, 6r0ma2epam, ch10rd1a2ep0x1de, d1a2epam, tema2epam and tr1a201am) w1th re- 5pect t0 the 1nduct10n 0f dru9-1ever re5p0nd1n9 1n an1ma15 tra1ned t0 d15cr1m1nate 10ra2epam revea1ed d05e-dependent 9enera112at10n 9enera11y character121n9 the re1at1ve p0tency 0r eff1cacy 0f the5e dru95 t0 pr0duce 6en20d1a2ep1ne-11ke anx101yt1c effect5. 1mp0r- tant1y, the5e 10ra2epam-tra1ned 6a600n5 were 065erved t0 9ener- a112e (1.e., made the dru9-1ever re5p0n5e) when 0ther 6en20d1a2ep1ne5 were adm1n15tered 6ut n0t when 0ther 5edat1ve/ anx101yt1c5 n0t 61nd1n9 t0 the 6en20d1a2ep1ne recept0r were ad- m1n15tered (16).

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F16. 5. An0rect1c-Re1nf0rcement Rat105 f0r c0ca1ne and e19ht an0rect1c dru95. F111ed 6ar5 5h0w data der1ved ent1re1y fr0m 6a600n exper1ment5. 5tr1ped 6ar5 5h0w data der1ved fr0m 60th human c11n1ca1 1nf0rmat10n and 6a600n exper1ment5. C0mp0und5 w1th h19h rat10 va1ue5 are m0re p0tent re1nf0rcer5 (re1at1ve t0 the1r an0rect1c p0tency) than c0mp0und5 w1th 10wer rat10 va1ue5.

7he5e f1nd1n95 h19h119ht 0ne 0f the m0re pr0m151n9 a5pect5 0f the re1at10n5h1p 6etween an1ma1 m0de15 and the deve10pment 0f 1ncrea51n91Y m0re effect1ve med1c1na1 dru95 9enerated 6y the ex- p1051ve advance5 1n new kn0w1ed9e 0f neur0tran5m1tter and re- cept0r dynam1c5. 7he deve10pment 0f c0mp0und5 that appear t0 have 5pec1f1c act10n5 at the 6en20d1a2ep1ne/6A8A ch10r1de 10n0- ph0re c0mp1ex, f0r examp1e, 5u99e5t5 a 6a515 f0r de519n1n9 5tud- 1e5 t0 exam1ne the 6ehav10ra1 c0rre1ate5 0f th15 recept0r act1v1ty, and the 5pec1f1c1ty 0f an1ma1 dru9 d15cr1m1nat10n m0de15 pr0v1de5 a p0werfu1 parad19m f0r c0nduct1n9 5uch an exam1nat10n. 7he kn0wn 5pec1f1c1ty 0f act10n w1th re5pect t0 neur0tran5m1tter 5y5- tem5 and the 900d c0rre5p0ndence w1th 9enera112at10n pr0f11e5 1n an1ma1 dru9 d15cr1m1nat10n m0de15 can pr0v1de a m0re prec15e 6ehav10ra1 ref1ect10n 0f neur0chem1ca1 mechan15m5.

7 H E E L 1 C 1 7 1 N 6 F U N C 7 1 0 N 5 0 F D R U 6 5

1n add1t10n t0 eva1uat1n9 a pharmac01091c a9ent•5 re1nf0rc1n9 and d15cr1m1nat1ve funct10n5, an1ma1 m0de15 f0r the a55e55ment 0f a6u5e 11a6111ty and dependence p0tent1a1 have c0ntr16uted 1mp0r- tant1y t0 an ana1y515 0f the phy5101091ca1 and 6ehav10ra1 chan9e5, 60th acute and chr0n1c, that are e11c1ted f0110w1n9 dru9 adm1n15- trat10n. 5u65tance5 w1th 0n1y m1n1ma1, 1f any, d15rupt1ve phy510- 1091ca1/6ehav10ra1 effect5 are n0t 9enera11y re9arded a5 hav1n9 519n1f1cant dependence p0tent1a1 0r a6u5e 11a6111ty even th0u9h the1r u5e may 6e w1de5pread (e.9., caffe1ne 1n tea 0r c0ffee). 1n c0ntra5t, c0mp0und5 5e1f-adm1n15tered even 5par1n91y that are a5- 50c1ated w1th d15rupt1ve phy5101091ca1/6ehav10ra1 chan9e5 are c0n- 51dered t0 have h19h a6u5e 11a6111ty (e.9., 1y5er91c ac1d d1ethy1am1de, L5D). Dru95 may fa11 anywhere 0n the c0nt1nua def1ned 6y the5e a55e55ment parameter5 and an1ma1 eva1uat10n m0de15 0f dru9 de- pendence p0tent1a1 and/0r a6u5e 11a6111ty have 9reat1y enhanced 1nteract1ve ana1y515 0f re1nf0rc1n9, d15cr1m1nat1ve, and e11c1t1n9 funct10n5.

7he meth0d5 u5ed f0r an1ma1 a55e55ment m0de15 0f phy510- 1091ca1 dependence have 6een exten51ve1y de5cr16ed, and the1r effect1vene55 a5 pred1ct0r5 0f dependence p0tent1a1 1n human5 ha5 6een we11 d0cumented (23, 71, 72, 77). 5u65t1tut10n te5t5 are 0f- ten c0nducted f1r5t t0 a55e55 the 5uppre5510n 0f w1thdrawa1 519n5 1n 0p1ate-dependent an1ma15 den1ed the1r u5ua1 dru9 d05e. 1f 5uch

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F16. 6. Mean chan9e5 1n aud1t0ry react10n t1me5 (t0p pane1) and v15ua1 thre5h01d5 (60tt0m pane1) a5 a funct10n 0f dru9 d05e f0r 51x c0mp0und5. Each p01nt repre5ent5 the mean chan9e 5c0re f0r at 1ea5t three 6a600n5.

pr0cedure5 1nd1cate 0n1y e4u1v0ca1 dependence p0tent1a1, pr1mary (0r d1rect) dependence and prec1p1tated w1thdrawa1 te5t5 are car- f1ed 0ut 1n wh1ch an1ma15 are treated chr0n1ca11y w1th dru9 and 065erved f0r w1thdrawa1 519n5 after dru9 adm1n15trat10n 15 5t0pped 0r after adm1n15trat10n 0f a pharmac01091ca1 anta90n15t (e.9., na10x0ne). 519n1f1cant1y, the f1nd1n95 fr0m an1ma1 m0de1 5tud1e5 0f phy5101091ca1 dependence 0n 5edat1ve-hypn0t1c5 (e.9., 6ar61tu- rate5) and anx101yt1c5, part1cu1ar1y the 6en20d1a2ep1ne5 (e.9., d1- a2epam) are 1n 900d a9reement w1th what ha5 6een rep0rted a60ut the dependence p0tent1a1 0f the5e c0mp0und5 1n human5 (54,55).

Pr0cedure5 f0r a55e551n9 the 6ehav10ra1 t0x1c1ty 0f a ran9e 0f a6u5ed dru95 1n term5 0f the1r effect5 0n 5en50ry and m0t0r func- t10n have 6een prev10u51y de5cr16ed 1n deta11 (42-44). 7he 6a51c meth0d0109y f0cu5e5 0n a react10n t1me techn14ue that ha5 6een u5ed exten51ve1y w1th pr1mate5 a5 an 1ndex 0f 5en50ry funct10n (65, 68, 69, 74). An1ma15 are tra1ned t0 perf0rm 60th an aud1t0ry and a v15ua1 react10n t1me pr0cedure. 80th are 5e1f-paced pr0ce- dure5 1n wh1ch an an1ma1 1n1t1ate5 each 0f a 5er1e5 0f d15crete re- act10n t1me tr1a15 6y pre551n9 and h01d1n9 d0wn a 1ever when a "•ready•• 519na1 (e.9., a f1a5h1n9 red cue 119ht) 15 pre5ented, and re1ea51n9 the 1ever when a ••react10n t1me•• 5t1mu1u5 0ccur5 at a rand0m t1me 1ater. Dur1n9 aud1t0ry te5t1n9 the ••react10n t1me•• 5t1mu1u5 wa5 the 0ccurrence 0f a 16.0 kH2 t0ne 6ur5t 1a5t1n9 1.5 5; dur1n9 v15ua1 te5t1n9 the 5t1mu1u5 wa5 the 0ccurrance 0f wh1te 119ht 0n a c1rcu1ar 5t1mu1u5 patch f0r 1.5 5. A re1ea5e 0f the 1ever w1th1n the 1.5-5 5t1mu1u5 durat10n wa5 c0n51dered a c0rrect detec- t10n 0f the 5t1mu1u5.

7he 1nten51ty 0f the react10n t1me 5t1mu11 were 5y5temat1ca11y var1ed fr0m tr1a1 t0 tr1a1 and the fre4uency 0f c0rrect and 1nc0r- rect re5p0n5e5 t0 each react10n t1me 5t1mu1u5 were rec0rded. Fr0m the5e data, p5ych0metr1c funct10n5 were 9enerated re1at1n9 the

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F16. 7. Re1at10n5h1p 6etween cr1ter10n 5en50ry and m0t0r t0x1c1ty d05e5 and cr1ter10n 5e1f-adm1n15trat10n d05e5 f0r three 6ar61turate5, tw0 6en20- d1a2ep1ne5, tw0 d1550c1at1ve ane5thet1c5, and a 5t1mu1ant. 7he 6r0ken d1- a90na1 11ne repre5ent5 e4ua11ty 6etween re1nf0rc1n9 and t0x1c d05e5.

percenta9e 0f c0rrect detect10n5 t0 5t1mu1u5 1nten51ty. 5t1mu1u5 detect10n thre5h01d5, def1ned a5 the 5t1mu1u5 1nten51ty detected 50% 0f the t1me, were a150 determ1ned, a5 were react10n t1me funct10n5 re1at1n9 re5p0n5e 1atency t0 5t1mu1u5 1nten51ty. Fa15e a1arm rate5 were mea5ured 6y pre5ent1n9 ••catch,•• 0r n0-5t1mu1u5 tr1a15 0n 20% 0f the tr1a15. Aud1t0ry and v15ua1 react10n t1me 5e5- 510n5 were c0nducted 5eparate1y, w1th dru9 effect5 5tud1ed under 0ne m0da11ty, and then the 0ther. 0 n th15 p5ych0phy51ca1 perf0r- mance 6a5e11ne, dru95 were adm1n15tered e1ther 1ntramu5cu1ar1y 0r 0ra11y at the 6e91nn1n9 0f a 5e5510n, f0110wed 6y a 30-m1n de- 1ay f0r dark adaptat10n and warm-up 6ef0re f0rrna1 thre5h01d de- term1nat10n5 were 6e9un. Veh1c1e c0ntr01 5e5510n5 were c0nducted 0n n0ndru9 day5, w1th 6a5e11ne perf0rmance5 rec0vered pr10r t0 further dru9 adm1n15trat10n.

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ta1n 6a5e11ne data 0n 6a600n thre5h01d funct10n5, and mea5ured pure t0ne thre5h01d5 at 12 fre4uenc1e5 ran91n9 fr0m 62 H2 t0 40.0 kH2. 7he5e thre5h01d funct10n5 c105e1y matched th05e 0f 0ther 01d W0r1d m0nkey5, and 0f man 1n the 10wer fre4uency ran9e5. 7he c105e c0rre5p0ndence am0n9 the thre5h01d funct10n5 06ta1ned w1th the react10n-t1me pr0cedure and w1th 0ther an1ma1 p5ych0- phy51ca1 pr0cedure5 1nd1cate5 th15 pr0cedure t0 6e a re11a61e and 5en51t1ve t001 f0r mea5ur1n9 hear1n9 thre5h01d5 1n 6a600n5.

7he effect5 0f 5edat1ve/hypn0t1c5 and 0ther CN5 depre55ant5 0n the5e p5ych0phy51ca1 perf0rmance 6a5e11ne5 have 6een prev1- 0u51y de5cr16ed 1n 5evera1 pu6115hed rep0rt5 (40, 43, 56, 57) and are 5ummar12ed 1n F19. 6. Under n0ndru9 c0nd1t10n5, react10n t1me5 typ1ca11y decrea5e 1n 1en9th and 1n var1a6111ty a5 5t1mu1u5 1nten51ty 15 1ncrea5ed. Dru95 5uch a5 pent06ar61ta1, d1a2epam and ketam1ne have 6een 5h0wn t0 1en9then react10n t1me5 6y pr0duc- 1n9 r0u9h1y para11e1 5h1ft5 1n the5e 1atency-1nten51ty funct10n5 t0 10n9er 1atenc1e5 at a11 1nten51t1e5. 1n 9enera1, the5e dru95 pr0- duced d05e-re1ated 1ncrea5e5 1n v15ua1 thre5h01d5 and 1n v15ua1 and aud1t0ry react10n t1me5 (5ee F19. 6). 5ma11 e1evat10n5 1n au- d1t0ry thre5h01d5 were 065erved 0n1y f0r d1a2epam and ketam1ne at the h19her dru9 d05e5. 5uch 5h1ft5 1n thre5h01d funct10n5 were n0t nece55ar11y due t0 c0nc0m1tant 5h1ft5 1n the 1atency-1nten51ty funct10n5 51nce pent06ar61ta1 pr0duced the 1ar9e5t aud1t0ry reac- t10n t1me 1ncrea5e w1th0ut e1evat1n9 aud1t0ry thre5h01d5.

CN5 depre55ant5 are n0t the 0n1y c0mp0und5 that may affect 5en50ry and m0t0r funct10n, d-Methamphetam1ne, f0r examp1e, ha5 6een 5h0wn t0 pr0duce chan9e5 1n v15ua1 5t1mu1u5 519na1 de- tecta6111ty (1.e., c1ear, c0n515tent 5h1ft5 t0 the r19ht 1n v15ua1 p5y- ch0metr1c funct10n5), 1nd1cat1ve 0f a decrea5e 1n 5en51t1v1ty t0 wh1te 119ht 5t1mu11 (44). 7he 5hape5 0f the5e funct10n5, h0wever, were the 5ame a5 th05e 06ta1ned dur1n9 5a11ne 5e5510n5, 1nd1cat- 1n9 that the dru9 d1d n0t 51mp1y reduce percent c0rrect 5c0re5 at a11 5t1mu1u5 1nten51t1e5. N0 5uch 5h1ft5 were 065erved dur1n9 au- d1t0ry thre5h01d te5t1n9, d-Methamphetam1ne a150 decrea5ed reac- t10n t1me5 at a11 5t1mu1u5 1nten51t1e5 (70p 5ect10n, F19. 6), w1th the5e fa5ter react10n t1me5 6e1n9 r0u9h1y e4u1va1ent acr055 5t1mu- 1u5 1nten51ty.

N0ta61e d1fference5 0ccurred 1n the t1me c0ur5e 0f d-metham- phetam1ne•5 effect5 0n v15ua1 thre5h01d5 and v15ua1 react10n t1me5. 7hre5h01d5 were e1evated w1th1n the f1r5t 40 m1n f0110w1n9 dru9 adm1n15trat10n 1n the a65ence 0f 519n1f1cant chan9e5 1n react10n t1me5. React10n t1me5, 0n the 0ther hand, pr09re551ve1y 5h0rtened dur1n9 the per10d fr0m 60 t0 100 m1n after dru9 adm1n15trat10n wherea5 thre5h01d e1evat10n5 were n0 10n9er apparent 6y 100-m1n p05tdru9, when the 9reate5t 5h0rten1n9 1n react10n t1me5 wa5 06- 5erved.

50me dru95 may have effect5 that are 5t1mu1u5-5pec1f1c. Wherea5 phencyc11d1ne 5e1ect1ve1y e1evate5 aud1t0ry react10n t1me5 w1th0ut affect1n9 aud1t0ry thre5h01d5, ketam1ne e1evate5 aud1t0ry thre5h- 01d5 6ut chan9e5 aud1t0ry react10n t1me5 0n1y at the h19he5t keta- m1ne d05e (56). 7he ketam1ne-1nduced 5h1ft5 1n aud1t0ry thre5h01d funct10n5 were fre4uency-dependent, w1th 1ncrea5e5 0ccur1n9 at fre4uenc1e5 0f 4 kH2 and a60ve, and n0t at 1 kH2 0r 500 H2. A 51n91e mechan15m 0f 51mp1e m0t0r 1mpa1rment, theref0re, cann0t acc0unt f0r the fre4uency-5pec1f1c effect5 0f the dru9 1n e1evat1n9 aud1t0ry thre5h01d5. 7he fre4uency-5pec1f1c effect5 0f ketam1ne are a150 rem1n15cent 0f am1n091yc051de ant1610t1c 0t0t0x1c1ty wh1ch affect5 h19h-fre4uency hear1n9 f1r5t 6y pr09re551ve1y de5tr0y1n9 ha1r ce115 5tart1n9 at the 6a5a1 end 0f the c0ch1ea (75).

7he5e p5ych0phy51ca1 techn14ue5 may 6e emp10yed n0t 0n1y t0 exam1ne effect5 0f acute adm1n15trat10n 0f dru95, 6ut a150 t0 track dru9-1nduced chan9e5 dur1n9 repeated da11y d051n9. 7he c0n5e4uence5 0f 5uch 10n9-term dru9 adm1n15trat10n 0n v15ua1 thre5h01d5 and v15ua1 react10n t1me5 were exam1ned 0ver 21-day per10d5 0f da11y 1M adm1n15trat10n 0f 0.32, 1.0, and 3.2 m9/k9 d1a2epam (13). C0n515tent 1ncrea5e5 1n react10n t1me5 were 5een

at the 10we5t dru9 d05e, w1th t01erance t0 the dru9•5 effect5 0n react10n t1me5 deve10p1n9 9radua11y. When d1a2epam wa5 w1th- he1d, w1th1n-5e5510n var1a6111ty 1n react10n t1me5 1ncrea5ed mark- ed1y. 7he5e chan9e51n react10n t1me5, the deve10pment 0f t01erance, and the 1ncrea5ed var1a6111ty 1n react10n t1me5 dur1n9 w1thdrawa1, were amp11f1ed when the da11y d05e wa5 1ncrea5ed t0 1.0 m9/k9, and then t0 3.2 m9/k9.

An ana1y515 0f the 1nteract10n5 6etween dru95 0f a6u5e 0n 5en- 50ry and m0t0r funct10n ha5 a150 6een undertaken 1n a 5er1e5 0f 5tud1e5 exam1n1n9 the effect5 0f acute d05e5 0f ethan01 (0.1-1.3 9/k9 91ven 0ra11y) c0m61ned w1th A-9-7HC (0.1-3.2 m9/k9 91ven 0ra11y). 51n91e ethan01 d05e5 adver5e1y affect aud1t0ry and v15ua1 thre5h01d5 and react10n t1me5; 51n91e A-9-7HC d05e5, 0n the 0ther hand, appear t0 have 11tt1e decrementa1 effect 0n e1ther aud1t0ry 0r v15ua1 thre5h01d5, and 0n1y m1n1ma1 effect5 0n react10n t1me5 at the h19he5t A-9-7HC d05e5. 7he m0de5t v15ua1 thre5h01d e1e- vat10n5 065erved w1th ethan01 a10ne, h0wever, were amp11f1ed further when 5ucce551ve1y h19her d05e5 0f A-9-7HC were c0m- 61ned w1th 1.0 m9/k9 0f ethan01.7he ethan01 d05e ran9e f0r th15 1nteract10n effect appear5 t0 6e fa1r1y re5tr1cted, n0t 0ccurr1n9 at 0.32 m9/k9 0r 10wer d05e5, n0r at the h19he5t ethan01 d05e te5ted 0f 1.3 9/k9. 51m11ar1y, 0ne exten51ve1y te5ted 5u6ject 5h0wed n0 chan9e5 1n aud1t0ry react10n t1me5 f0110w1n9 51n91e d05e5 0f A-9- 7HC 0f 0.32 and 1.0 m9/k9. C0m61n1n9 the5e 5ame 7HC d05e5 w1th ethan01 (e1ther 1 0r 1.3 9/k9), h0wever, pr0duced react10n t1me e1evat10n5 tw1ce a5 9reat a5 th05e 5een w1th ethan01 a10ne.

7he u5e 0f 5uch pr0cedure5 15 n0t re5tr1cted t0 the ana1y515 0f 51mp1e d15cr1m1nat10n5, 6ut may 6e extended t0 the d15cr1m1nat10n 0f human 5peech 50und5 a5 we11. Adu1t ma1e 6a600n5 have 6een tra1ned, f0r examp1e, t0 d15cr1m1nate am0n9 f1ve 5ynthet1c, 5teady- 5tate v0we1 50und5 (/a/. /ae/, /e/, /U/, and/au/) (41,42). A pu15ed tra1n 0f 0ne v0we1 c0mpr15ed the reference 5t1mu1u5 dur1n9 a 5e5- 510n. An1ma15 were tra1ned t0 pre55 and h01d a 1ever, re1ea51n9 1t 0n1y when the reference v0we1 50und chan9ed t0 0ne 0f the c0m- par150n v0we15. 7he 6a600n5 read11y d15cr1m1nated am0n9 d1ffer- ent 1501ated v0we15, and made 5uch d15cr1m1nat10n5 a5 human5 d0, 0n the 6a515 0f 5pectra1 d1fference5 am0n9 the v0we15. When the an1ma15 were 91ven d1a2epam, c0n515tent d05e-re1ated decre- ment5 1n v0we1 d15cr1m1na6111ty were f0und that were 9reater at the h19her d1a2epam d05e5.7he v0we1 d15cr1m1nat10n effect5 were a150 5t1mu1u5-dependent 1n that the decrement5 were 1ar9er f0r th05e c0mpar150n v0we15 w1th 5ma11er f0rmant d1fference5 fr0m the reference v0we1. 51nce d1a2epam a150 ha5 decrementa1 effect5 0n 60th aud1t0ry thre5h01d5 (57) and aud1t0ry-ev0ked p0tent1a15 (73), centra1 med1at10n 0f d1a2epam•5 effect 0n v0we1 d15cr1m1na- t10n5 15 5u99e5ted. 51nce d1a2epam affected the v0we1 d15cr1m1na- t10n5 6y pr0duc1n9 decrea5e5 pr0p0rt10na1 t0 the re1at1ve 5pectra1 d1fference5 am0n9 the v0we15, h0wever, the dru9 may 6e affect- 1n9 the fre4uency-re501v1n9 a6111t1e5 0f the aud1t0ry 5y5tem 1t5e1f. 1n c0ntra5t t0 the d05e-re1ated effect5 0f d1a2epam 0n v0we1 d15- cr1m1na6111ty, we have f0und A-9-7HC t0 have 11tt1e 0r n0 decre- menta1 effect 0n v0we1 d15cr1m1nat10n5.

A pr0cedure ha5 6een deve10ped f0r an 1nteract1ve ana1y515 0f the d15rupt1ve e11c1t1n9 effect5 0f a6u5ed dru95 up0n 5en50ry/m0- t0r funct10n5 0n the 0ne hand, and the1r re1nf0rc1n9 effect5 1n ma1nta1n1n9 5e1f-adm1n15trat10n, 0n the 0ther. 7he re1nf0rcement/ t0x1c10, rat10 (18) c0mpare5 the re1at1ve p0tency 0f a dru9 a5 a re1nf0rcer w1th 1t5 re1at1ve p0tency 1n e11c1t1n9 d15rupt1ve 5en50ry/ m0t0r effect5. A dru9 w1th p0tent-re1nf0rc1n9 funct10n5 (1.e., ma1nta1n5 5e1f-1nject10n at re1at1ve1y 10w d05e5) 6ut wh1ch pr0- duce5 d15rupt1ve effect5 0n1y at re1at1ve1y h19h d05e5 w0u1d have a 10w re1nf0rcement/t0x1c1ty rat10, wherea5 a dru9 that ma1nta1n5 5e1f-1nject10n 0n1y at re1at1ve1y h19h d05e5 6ut pr0duce5 d15rupt1ve 5en50ry/m0t0r effect5 at re1at1ve1y 10w d05e5 w0u1d have a h19h re1nf0rcemenUt0x1c1ty rat10.

7he re1nf0rc1n9 funct10n5 0f a 5er1e5 0f 6ar61turate5, 6en20d1-

A55E551N6 DRU65 0 F A8U5E 41

a2ep1ne5, 5t1mu1ant5 and d1550c1at1ve ane5thet1c5 were eva1uated w1th 1a60rat0ry 6a600n5 t0 determ1ne the d05e 0f each c0mp0und that ma1nta1ned cr1ter10n 5e1f-adm1n15trat10n. 7he pr0cedure f0r determ1n1n9 re1nf0rc1n9 funct10n5 ha5 6een prev10u51y de5cr16ed 1n deta11 (37,38) and 1nv01ved the 1n1t1a1 e5ta6115hment 0f dru9 5e1f-adm1n15trat10n w1th c0ca1ne f0110wed 6y 5u65t1tut10n 0f 5a11ne 0r an0ther dru9 f0r c0ca1ne a5 de5cr16ed a60ve. When 5a11ne 0r 10w d05e5 0f dru95 were 5u65t1tuted, the num6er 0f 1nject10n5 taken decrea5ed 0ver 5ucce551ve day5. When h19her d05e5 0f the dru95 were 5u65t1tuted f0r c0ca1ne, h0wever, the 5e1f-1nject10n rate wa5 re11a61y ma1nta1ned a60ve 5a11ne c0ntr01 1eve15. A11 dru95 were a150 eva1uated t0 determ1ne the cr1ter10n d05e wh1ch pr0- duced a 50% chan9e 1n aud1t0ry and/0r v15ua1 thre5h01d5, and/0r a 10% chan9e 1n m0t0r react10n t1me. 7he pr0cedure f0r deter- m1n1n9 5uch 5en50ry/m0t0r t0x1c1ty have 6een prev10u51y de- 5cr16ed 1n deta11 (10, 40, 43) and 1nv01ved tra1n1n9 6a600n5 t0 perf0rm the react10n t1me pr0cedure de5cr16ed a60ve.

F19ure 7 5ummar12e5 the re1at10n5h1p5 revea1ed 6y the re1n- f0rcement/t0x1c1ty rat105 f0r am06ar61ta1, pent06ar61ta1, 5ec06ar- h1ta1, d-methy1amphetam1ne, tr1a201am, d1a2epam, phencyc11d1ne (PCP) and ketam1ne. A rat10 va1ue 0f 1.0 repre5ent5 e4ua11ty 6e- tween re1nf0rc1n9 and t0x1c dru9 d05e5. A11 three 6ar61turate5, d- methamphetam1ne, and the 5h0rt-act1n9 6en20d1a2ep1ne tr1a201am, are character12ed 6y 60th 5en50ry and m0t0r rat10 va1ue5 6e10w 1.0, 1nd1cat1n9 that the d15rupt1ve 5en50ry/m0t0r chan9e5 0ccurred at d05e5 we11 a60ve the cr1ter10n re1nf0rc1n9 d05e. A c0n515tent re1at10n5h1p 6etween the 5en50ry and m0t0r effect5 0f the5e c0m- p0und5 15 a150 apparent 1n that the m0t0r effect5 appear at 10wer d05e5 than the 5en50ry effect5 (1.e., m0t0r rat105 h19her than 5en- 50ry rat105). A 51m11ar re1at10n5h1p 6etween m0t0r and 5en50ry effect5 a150 character12e5 the 10n9-act1n9 6en20d1a2ep1ne d1a2epam, hut d15rupt1ve m0t0r effect5 appeared at d05e5 we11 6e10w th05e re4u1red t0 ma1nta1n 5e1f-adm1n15trat10n (1.e., m0t0r rat10 9reater than 1.0). 1n the ca5e 0f the d1550c1at1ve ane5thet1c5, PCP and ketam1ne are read11y d1fferent1ated fr0m the 0ther c0mp0und5 6y a rever5a1 0f the re1at10n5h1p 6etween 5en50ry and m0t0r effect5 5een w1th the 0ther c0mp0und5. F0r PCP and ketam1ne, 5en50ry chan9e5 appeared at d05e5 6e10w th05e wh1ch pr0duced m0t0r effect5 (1.e., 5en50ry rat105 h19her than m0t0r rat105). And PCP appear5 un14ue am0n9 the c0mp0und5 thu5 far 5tud1ed 1n that 60th 5en50ry and m0t0r rat10 va1ue5 were 9reater than 1.0, 1nd1- cat1n9 that the cr1ter10n 5e1f-adm1n15trat10n d05e wa5 h19her than the d05e5 wh1ch pr0duce 519n1f1cant 6ehav10ra1 t0x1c1ty.

7h15 re11a61e and 5en51t1ve an1ma1 p5ych0phy51ca1 m0de1 0f dru9-1nduced chan9e5 1n aud1t0ry and v15ua1 thre5h01d5, aud1t0ry and v15ua1 react10n t1me5, and 5peech 50und d15cr1m1nat10n5 can thu5 pr0v1de an ana1y515 0f t1me and d05e dependenc1e5, a5 we11 a5 a 4uant1tat1ve 6a515 f0r de5cr161n9 the re1at10n5h1p 6etween the re1nf0rc1n9 funct10n5 0f dru95 and the1r t0x1c effect5 up0n 5en- 50r1m0t0r funct10n5. 5uch 1nteract1ve mea5ure5 can 6e 0f p0ten- t1a1 ut111ty 1n the prec11n1ca1 a55e55ment 0f the extent t0 wh1ch 5e1f-adm1n15trat10n 0f a c0mp0und may d15rupt 6a51c p5ych0phy5- 1ca1 pr0ce55e5 1n human5.

5UMMARY AND C0NCLU510N5

7here are n0w 5evera1 c0nver91n9 11ne5 0f ev1dence that te5- t1fy t0 the re11a6111ty and 6r0ad 9enera11ty 0f 065ervat10n5 c0n- cern1n9 dru9 a6u5e 11a6111ty 1n human5 6a5ed up0n an1ma1 1a60rat0ry m0de15. 7he 0rder11ne55 0f the data re1at1n9 the5e an1ma1 1a60ra- t0ry-der1ved funct10n5 t0 1ndependent1y der1ved mea5ure5 0f phar- mac01091ca1 act1v1ty (e.9., the an0rect1c/re1nf0rcement rat10, the re1nf0rcement/t0x1c1ty rat10) a150 5peak5 d1rect1y t0 the 155ue 0f c0n5truct va11d1ty 1n eva1uat1n9 the c0ntr16ut10n 0f an1ma1 1a60ra- t0ry meth0d5 f0r the a55e55ment 0f human dru9 a6u5e 11a6111ty and dependence p0tent1a1.5uch an1ma1 1a60rat0ry m0de15 n0t 0n1y

te11 u5 that there are c0nd1t10n5 under wh1ch dru95 can 6e 5e1f- adm1n15tered (1.e., have re1nf0rc1n9 funct10n5), 6ut they can a5 we11 def1ne the ran9e 0f the5e c0nd1t10n5 t0 a 519n1f1cant extent (1.e., 5pec1e5, d05e and t1me dependence) and the 1nf1uence 0f c1rcum5tance5 (1.e., env1r0nmenta1 c0nt1n9enc1e5) 1n p0tent1at1n9 0r attenuat1n9 5uch 5t1mu1u5 funct10n5. A5 a re5u1t 0f the5e deve1- 0pment5 1n an1ma1 m0de1 re5earch techn0109Y and the c0n5e4uent advance5 1n kn0w1ed9e 0f dru9 act10n, an 0perat10na1 6a515 ha5 6een pr0v1ded f0r redef1n1n9 the 6ew11der1n9 ran9e 0f phen0mena and exper1ent1a1 p5eud0-phen0mena 1005e1y 1dent1fy w1th 5uch term5 a5 ••add1ct10n,•• ••dependence•• and ••a6u5e.••

At 1ea5t 50me def1n1t10na1 c1ar1ty ha5 6een atta1ned a5 a c0n- 5e4uence 0f 5uch an1ma1 m0de1 ana1y5e5 d1v1d1n9 the va5t array 0f event5 that character12e th15 d0ma1n 1nt0 tw0 rea50na61y exc1u- 51ve cate90r1e5 6a5ed up0n exp11c1t1y 0perat10na1 cr1ter1a. 5uch a d1v1510n, f0r examp1e, d15t1n9u15he5 6etween event5 that 0ccur 6ef0re and event5 that 0ccur after actua1 5u65tance 1ntake (F19. 8). A5 a f1r5t appr0x1mat10n, the def1n1n9 0perat10n5 0f the "•6ef0re•• c1a55, 0n the 0ne hand, w0u1d 1nc1ude (6ut are n0t nec- e55ar11y 11m1ted t0) pr0act1ve dru9-5eek1n9 and dru9-d15cr1m1na- t10n 6ehav10r5. 7he def1n1n9 0perat10n5 0f the ••after•• c1a55, 0n the 0ther hand, w0u1d f0cu5 up0n the react1ve 610chem1ca1, phy5- 101091ca1, and 6ehav10ra1 chan9e5 a550c1ated w1th t01erance and an a65t1nence 5yndr0me when dru9 15 w1thdrawn.

7he temp0ra1 0rder1n9 0f 610chem1ca1, phy5101091ca1 and 6e- hav10ra1 chan9e5 1n re1at10n5h1p t0 the dru9 1ntake event revea1ed 6y an1ma1 m0de1 5tud1e5 ha5 thu5 pr0v1ded an 0perat10na1 6a515 f0r character121n9 the ran9e 0f a pharrnac01091c a9ent5 funct10na1 pr0pert1e5 and f0r 1dent1fy1n9 d15t1n9u15ha61e feature5 0f 1t5 5pec- trum 0f act10n. 7he re1evance and 1mp0rtance 0f th15 d15t1nct10n 6etween pr0act1ve "•a6u5e 11a6111ty•• and react1ve ••phy5101091ca1 dependence p0tent1a1•• re51de5 1n the fact that, fr0m the per5pec- t1ve 0f an1ma1 dru9 a55e55ment m0de15, the1r def1n1n9 pr0pert1e5 are n0t c0exten51ve, they d0 n0t 1nvar1a61y 0ccur t09ether, and the meth0d5 6y wh1ch they are eva1uated d1ffer. Pr0act1ve dru9- 5eek1n9 and dru9 5e1f-adm1n15trat10n perf0rmance5 a5 card1na1 519n5 1n the an1ma1 m0de1 a55e55ment 0f a6u5e 11a6111ty f0r exam- p1e, can 6e ma1nta1ned 1n 5tren9th 6y u5e pattern5 and d05e5 0f c0mp0und5 (e.9., c0ca1ne) that pr0duce n0 519n1f1cant t01erance 0r w1thdrawa1--the react1ve chan9e5 trad1t10na11y a550c1ated w1th phy5101091ca1 dependence. 0n the 0ther hand, there are t01erance and a65t1nence-pr0duc1n9 c0mp0und5 (e.9., pr0pran0101) that ne1- ther 9enerate n0r ma1nta1n dru9 5e1f-adm1n15trat10n.

1nteract10n5 6etween the5e pr0act1ve and react1ve feature5 0f the dru9 and a1c0h01 5cene are 0f c0ur5e, c0mm0np1ace. Chan9e5 1n dru9-5eek1n9 and dru9-tak1n9 0ften 0ccur a5 5e4ue1ae t0 60th the acute effect5 0f a pharmac01091c a9ent and t0 the t01erance and w1thdrawa1 effect5 that f0110w m0re chr0n1c dru9 exp05ure. C0nver5e1y, the chem1ca1 and 6101091ca1 chan9e5 that def1ne phy5- 101091ca1 dependence can a5 we11 6e 5e4ue1ae t0 the repeated 5e1f0 adm1n15trat10n 0f a6u5ed dru95. 8ut the re1at1ve c0ntr16ut10n5 0f the5e d15t1n9u15ha61e pr0ce55e5 t0 dru9- and a1c0h01-re1ated pr06- 1em5 can vary w1de1y w1th d1fferent pharmac01091c a9ent5 a5 a funct10n 0f d05e, env1r0nmenta1 c1rcum5tance5, and prev10u5 dru9 h15t0ry (64).

De5p1te the5e 1nteract1ve feature5 h0wever, 1t 15 1mp0rtant t0 rec09n12e that the meth0d5 u5ed 1n 60th 1a60rat0ry an1ma15 and human5 t0 a55e55 the5e d15t1n9u15ha61e pharmac01091ca1 pr0per- t1e5 are 4u1te d1fferent. N0t 5urpr151n91y, the pred1ct1ve va11d1ty 0f 5e1f-adm1n15trat10n (1.e., re1nf0rc1n9 funct10n5) a5 an an1ma1 dru9 eva1uat10n m0de1 may 6e 4u1te p00r 1f the 06ject1ve 15 t0 a55e55 a c0mp0und•5 phy5101091ca1 dependence p0tent1a1 (1.e., e11c1t1n9 5t1mu1u5 funct10n). 8ut 1f a c0mprehen51ve eva1uat10n 0f a c0m- p0und•5 dependence p0tent1a1 and a6u5e 11a6111ty 15 the 06ject1ve, an an1ma1 m0de1 a55e55ment 0f 1t5 mu1t1p1e 5t1mu1u5 funct10n5 ha5 pr0ven t0 6e a 900d pred1ct0r 0f 5uch t0x1c effect5 1n human5.

42 8 R A D Y

ACKN0WLED6EMEN75 7h15 manu5cr1pt wa5 5upp0rted 6y N1DA Re5earch 5c1ent15t Award

DA00018 and N1DA 6rant5 DA01147, DA04133, DA02490 and DA04731 and 6y N1DA C0ntract 271-86-8113. 5pec1a1 thank5 t0 Mr5.5u5an 5m1th f0r a5515tance w1th manu5cr1pt preparat10n.

R E F E R E N C E 5

1. A1t5hu1er, H.; Weaver, 5.; Ph1111p5, P. 1ntra9a5tr1c 5e1f-adm1n15tra- t10n 0f p5ych0act1ve dru95 6y the rhe5u5 m0nkey. L1fe 5c1. 17:883; 1975.

2. At0r, N. A.; 6r1ff1th5, R. R. L0ra2epam and pent06ar61ta1 dru9 d15- cr1m1nat10n 1n 6a600n5:Cr055-dru9 9enera112at10n te5t5 and 1nterac- t10n w1th R0 15-1788. J. Pharmac01. Exp. 7her. 226:776-782; 1983.

3. At0r, N. A.; 6r1ff1th5, R. R. L0ra2epam and pent06ar61ta1 d15cr1m1- nat10n: 1nteract10n5 w1th C65 8216 and caffe1ne. Eur. J. Pharmac01. 107:169-181; 1985.

4. At0r, N. A.; 6r1ff1th5, R. R. D15cr1m1nat1ve 5t1mu1u5 effect5 0f atyp- 1ca1 anx101yt1c5 1n 6a600n5 and rat5. J. Pharmac01. Exp. 7her. 237: 93---403; 1986.

5. At0r, N. A.; 6r1ff1th5, R. R. A5ymmetr1ca1 cr055-9enera112at10n w1th 10ra2epam and pent06ar61ta1 tra1n1n9 c0nd1t10n5. Dru9 Dev. Re5. 16: 355-364; 1989.

6. At0r, N. A.; 6r1ff1th5, R. R. D1fferent1a1 9enera112at10n t0 pent06ar- 61ta1 1n rat5 tra1ned t0 d15cr1m1nate 10ra2epam, ch10rd1a2ep0x1de, d1- a2epam 0r tf1a201am. P5ych0pharmac0109y (8er11n) 98:20--30; 1989.

7. 8a15ter, R. L.; 5chu5ter, C. R. F1xed-1nterva1 5chedu1e 0f c0ca1ne re1nf0rcement: Effect 0f d05e and 1nfu510n durat10n. J. Exp. Ana1. 8ehav. 20:119; 1973.

8. 819e10w, 6.; 6r1ff1th5, R. R.; L1e650n, 1. Exper1menta1 human dru9 5e1f-adm1n15trat10n: Meth0d0109y and app11cat10n t0 the 5tudy 0f 5ed- at1ve a6u5e. Pharmac01. Rev. 27:523-531; 1976.

9. 8rady, J. V. C0mm0n mechan15m5 1n 5u65tance a6u5e. 1n: 7h0mp- 50n, 7.; J0han50n, C. E., ed5. 8ehav10ra1 pharmac0109y 0f human dru9 dependence. Nat1. 1n5t. Dru9 A6u5e Re5. M0n0.5er1e5 N0.37, DHH5 Pu611cat10n N0. (ADM)81-1137. Wa5h1n9t0n, DC: U5 60v- ernment Pr1nt1n9 0ff1ce; 1981 : 11-20.

10. 8rady, J. V.; 8radf0rd, D. L.; H1en2, R. D. 8ehav10ra1 a55e55ment 0f r15k-tak1n9 and p5ych0phy51ca1 funct10n 1n the 6a600n. Neur06e- hav. 70x1c01. 1(5upp1. 1):73-84; 1979.

11. 8rady, J. V.; F15chman, M. W. A55e55ment 0f dru95 f0r dependence p0tent1a1 and a6u5e 11a6111ty: An 0verv1ew. 1n: 5e1den, L. 5.; 8a15ter, R. L., ed5.8ehav10ra1 pharmac0109y: 7he current 5tatu5. New Y0rk: A1an R. L155, 1nc.; 1985:361-382.

12. 8rady, J. V.; 6r1ff1th5, R. R. 8ehav10ra1 pr0cedure5 f0r eva1uat1n9 the re1at1ve a6u5e p0tent1a1 0f CN5 dru95 1n pr1mate5. Fed. Pr0c. 35: 2245; 1976.

13. 8rady, J. V.; 6r1ff1th5, R. R.; H1en2, R. D.; At0r, N. A.; Luka5, 5. E.; Lam6, R. J. A55e551n9 dru95 f0r a6u5e 11a6111ty and dependence p0tent1a1 1n 1a60rat0ry pr1mate5. 1n: 802arth, M. A., ed. Meth0d5 0f a55e551n9 the re1nf0rc1n9 pr0pert1e5 0f a6u5ed dru95. New Y0rk: 5pr1n9er-Ver1a9; 1987:45-85.

14. 8rady, J. V.; 6r1ff1th5, R. R.; H1en2, R. D.; Luka5, 5. E. Ana1y515 0f dru9 a6u5e 11a6111ty and 6ehav10ra1 t0x1c1ty 1n a 1a60rat0ry pr1mate m0de1. 1n: 5p1e9e15te1n, M. Y.; Levy, A., ed5. 8ehav10ra1 m0de15 and the ana1y515 0f dru9 act10n. Am5terdam: E15ev1er 5c1ent1f1c Pu6- 115h1n9 C0mpany; 1982:241-276.

15. 8rady, J. V.; 6r1ff1th5, R. R.; W1n9er, 6. Dru9-ma1nta1ned perf0r- mance pr0cedure5 and the eva1uat10n 0f 5edat1ve hypn0t1c dependence p0tent1a1. 1n: Ka9an, F.; Harw00d, 7.; R1cke15; Rud21k, H. 50rer, H., ed5. Hypn0t1c5:Meth0d5 0f deve10pment and eva1uat10n. New Y0rk: 5pectrum; 1975:221-235.

16. 8rady, J. V.; H1en2, R. D.; At0r, N. A. 5t1mu1u5 funct10n5 0f dru95 and the a55e55ment 0f a6u5e 11a6111ty. Dru9 Dev. Re5. 20:231-290; 1990.

17. 8rady, J. V.; Luka5, 5. E. 7e5t1n9 dru95 f0r phy51ca1 dependence p0tent1a1 and a6u5e 11a6111ty. Nat1. 1n5t. Dru9 A6u5e Re5. M0n0. 5e- r1e5 N0. 52, DHH5 Pu611cat10n N0. (ADM)84-1332. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0ff1ce; 1984.

18. 8rady, J. V.; Luka5, 5. E.; H1en2, R. D. Re1at10n5h1p 6etween re1n- f0rc1n9 pr0pert1e5 and 5en50ry/m0t0r t0x1c1ty 0f CN5 depre55ant5: 1mp11cat10n5 f0r the a55e55ment 0f a6u5e 11a6111ty. 1n: Harr15, L. 5., ed. Pr061em5 0f dru9 dependence 1982. Nat1. 1n5t. Dru9 A6u5e Re5.

M0n0.5er1e5 N0.43, DHH5 Pu611cat10n N0. (ADM)83-1264. Wa5h- 1n9t0n, DC: U.5. 60vernment Pr1nt1n9 0ff1ce; 1983:196-202.

19. Cha1t, L.; Uh1enhuth, E. H.; J0han50n, C. E. Dru9 preference and m00d: ma21nd01 and pheny1pr0pan01am1ne. Nat1. 1n5t. Dru9 A6u5e Re5. M0n0. 5er1e5 N0. 49, DHH5 Pu611cat10n N0. (ADM)84-1316. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0ff1ce; 1984.

20. C1ark, R.; 5chu5ter, C. R.; 8rady, J. V. 1n5trumenta1 c0nd1t10n1n9 0f ju9u1ar 5e1f-1nfu510n 1n the rhe5u5 m0nkey. 5c1ence 133:1829; 1961.

21. C01paert, F. C.; R05ecran5, J. A., ed5. 5t1mu1u5 pr0pert1e5 0f dru95: 7en year5 0f pr09re55. Am5terdam: E15ev1er; 1978.

22. C01paert, F. C.; 51an9en, J. L., ed5.: Dru9 d15cr1m1nat10n: App11ca- t10n5 1n CN5 pharmac0109y. Am5terdam: E15ev1er; 1982.

23. Deneau, 6. A. An ana1y515 0f fact0r5 1nf1uenc1n9 the deve10pment 0f phy51ca1 dependence t0 narc0t1c ana19e51c5 1n the rhe5u5 m0nkey w1th meth0d5 f0r pred1ct1n9 phy51ca1 dependence 11a6111ty 1n man. D0c- t0ra1 D155ertat10n, Un1ver51ty 0f M1ch19an; 1956.

24. Deneau, 6 . A.; Yana91ta, 7.; 5eever5. M. H. 5e1f-adm1n15trat10n 0f p5ych0act1ve 5u65tance5 6y the m0nkey--A mea5ure 0f p5ych01091- ca1 dependence. P5ych0pharmac01091a 16:30--48; 1969.

25. F15chman, M. W. Eva1uat1n9 the a6u5e p0tent1a1 0f p5ych0tr0p1c dru95 1n man. 1n: 7h0mp50n, 7.; Unna, K., ed5. Pred1ct1n9 depen- dence 11a6111ty 0f 5t1mu1ant and depre55ant dru95. 8a1t1m0re: Un1ver- 51ty Park Pre55; 1976:261.

26. F15chman, M. W. A55e551n9 the a6u5e p0tent1a1 0f 10ca1 ane5thet1c5. Pre5ented at the 44th Annua1 5c1ent1f1c Meet1n9, the C0mm1ttee 0n Pr061em5 0f Dru9 Dependence, 70r0nt0, Canada; 1982.

27. F15chman, M. W.; 5chu5ter, C. R. Exper1menta1 1nve5t19at10n5 0f the act10n5 0f c0ca1ne 1n human5.1nteramer1can 5em1nar a60ut C0ca and C0ca1ne--Med1ca1 and 50c101091ca1 A5pect5. L1ma, Peru; 1979: 62.

28. F15chman, M. W.; 5chu5ter, C. R. C0ca1ne 5e1f-adm1n15trat10n 1n human5. Fed. Pr0c. 41:241-246; 1982.

29. 6r1ff1th5, R. R.; 8a15ter, R. L. 0p101d5: 51m11ar1ty 6etween eva1ua- t10n5 0f 5u6ject1ve effect5 and an1ma1 5e1f-adm1n15trat10n re5u1t5. C11n. Pharmac01. 7her. 25:611-617; 1979.

30. 6r1ff1th5, R. R.; 819e10w, 6. E.; Henn1n9f1e1d, J. E. 51m11ar1t1e5 1n an1ma1 and human dru9-tak1n9 6ehav10r. 1n: Me110, N. K., ed., Ad- vance5 1n 5u65tance a6u5e, v01. 1.6reenw1ch: JA1 Pre55; 1980:1-90.

31. 6r1ff1th5, R. R.; 819e10w, 6. E.; L1e650n, 1. A55e55ment 0f effect5 0f ethan01 5e1f-adm1n15trat10n 0n 50c1a1 1nteract10n5 1n a1c0h011c5. P5ych0pharmac0109y (8er11n) 38:105-110; 1974.

32. 6r1ff1th5, R. R.; 819e10w, 6. ; L1e650n, 1. Human dru9 5e1f-adm1n15- trat10n: D0u61e-611nd c0mpar150n 0f pent06ar61ta1, d1a2epam, ch10r- pr0ma21ne and p1ace60. J. Pharmac01. Exp. 7her. 210:301-310; 1979.

33. 6r1ff1th5• R. R.; 819e10w, 6. E.; L1e650n, 1. D1fferent1a1 effect5 0f d1a2epam and pent06ar61ta1 0n m00d and 6ehav10r. Arch. 6en. P5y- ch1atry 40:865-873; 1983.

34. 6r1ff1th5, R. R.; 8rady, J. V.; 5ne11, J. D. Pr09re551ve-rat10 perf0r- mance ma1nta1ned 6y dru9 1nfu510n5: C0mpar150n 0f c0ca1ne, d1eth- y1pr0p10n, ch10rphenterm1ne and fenf1uram1ne. P5ych0pharmac0109y (8er11n) 56:5-13; 1978.

35. 6r1ff1th5, R. R.; 8rady, J. V.; 5ne11, J. D. Re1at10n5h1p 6etween an- 0rect1c and re1nf0rc1n9 pr0pert1e5 0f appet1te 5uppre55ant dru95: 1m- p11cat10n5 f0r a55e55ment 0f a6u5e 11a6111ty. 8101. P5ych1atry 13:283- 290; 1978.

36. 6r1ff1th5, R. R.; Henn1n9f1e1d, J. E.; 819e10w, 6 . E. Human c19a- rette 5m0k1n9; Man1pu1at10n 0f num6er 0f puff5 per 60ut, 1nter60ut 1nterva1, and n1c0t1ne d05e. J. Pharmac01. Exp. 7her. 220:256-265; 1982.

37. 6r1ff1th5, R. R.; Luka5, 5. E.; 8radf0rd, L. D.; 8rady, J. V.; 5ne11, J. D. 5e1f-1nject10n 0f 6ar61turate5 and 6en20d1a2ep1ne5 1n 6a600n5. P5ych0pharmac0109y (8er11n) 75:101-109; 1981.

38. 6r1ff1th5, R. R.; W1n9er, 6 . ; 8rady, J. V.; 5ne11, J. D. C0mpar150n 0f 6ehav10r ma1nta1ned 6y 1nfu510n5 0f e19ht pheny1ethy1am1ne5 1n

A55E551N6 DRU65 0 F A8U5E 43

6a600n5. P5ych0pharmac0109y (8er11n) 50:251-258; 1976. 39. Haert2en, C.; H1ckey, J. Add1ct10n Re5earch Center 1nvent0ry

(ARC1): Mea5urement 0f euph0r1a and 0ther dru9 effect5.1n: 802arth, M. A., ed. Meth0d5 0f a55e551n9 the re1nf0rc1n9 pr0pert1e5 0f a6u5ed dru95. New Y0rk: 5pr1n9er-Ver1a9; 1987:489-524.

40. H1en2, R. D.; 8rady, J. V. P5ych0phy51ca1 pr0f11e5 d1fferent1ate dru95 0f a6u5e. 1n: Harr15, L. 5., ed. Pr061em5 0f dru9 dependence. 1980: 226-231. Nat1.1n5t. Dru9 A6u5e Re5. M0n0.5er1e5 N0. 34, DHH5 Pu611cat10n N0. (ADM)81-1058. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0ff1ce; 1981.

41. H1en2, R. D.; 8rady, J. V. Effect5 0f d1a2epam and de1ta-9-7HC 0n the d15cr1m1nat10n 0f 5peech 50und5 1n the 6a600n. 1n: Harr15, L. 5., ed. Pr061em5 0f dru9 dependence. 1986:226--232. Nat1. 1n5t. Dru9 A6u5e Re5. M0n0. 5er1e5 N0. 76, DHH5 Pu611cat10n N0. (ADM) 87-1508. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0ff1ce; 1987.

42. H1en2, R. D.; 8rady, J. V. 7he ac4u151t10n 0f v0we1 d15cr1m1nat10n5 1n n0nhuman pr1mate5. J. Ac0u5t. 50c. Am. 84:186-194; 1988.

43. H1en2, R. D.; Luka5, 5. E.; 8rady, J. V. 7he effect5 0f pent06ar- 61ta1 up0n aud1t0ry and v15ua1 thre5h01d5 1n the 6a600n. Pharmac01. 810chem. 8ehav. 15:799-805; 1981.

44. H1en2, R. D.; Luka5, 5. E.; 8rady, J. V. Effect5 0f d-methamphet- am1ne 0n aud1t0ry and v15ua1 react10n t1me5 and detect10n thre5h01d5 1n the 6a600n. P5ych0pharmac0109y (8er11n) 85:476--482; 1985.

45. H1en2, R. D.; 7urkkan, J. 5.; Harr15, A. H. Pure t0ne thre5h01d5 1n the ye110w 6a600n (Pap10 cyn0cepha1u5). Hear. Re5. 8:71-75; 1982.

46. H111, H. E.; Haert2en, C. A.; W016ach, A. 8., Jr.; M1ner, E. J. Ad- d1ct10n Re5earch Center 1nvent0ry (ARC1): 5tandard12at10n 0f 5ca1e5 wh1ch eva1uate 5u6ject1ve effect5 0f m0rph1ne, amphetam1ne, pent0- 6ar61ta1, a1c0h01, L5D-25, pyrahexy1 and ch10rpr0ma21ne. P5ych0- pharmac01091a 4:167-183; 1963.

47. 191auer, D.; L1ewe11yn, M. E.; W00d5, J. 6. C0ncurrent 5cheudu1e5 0f c0ca1ne 1nject10n 1n rhe5u5 m0nkey5: D05e var1at10n5 under 1nde- pendent and n0n1ndependent var1a61e-1nterva1 pr0cedure5. Pharma- c01. Rev. 27:367; 1975.

48. Jar6e, 7. U. C. Dru9 d15cr1m1nat10n 1earn1n9 Cue pr0pert1e5 0f dru95. 1n: 6reen5haw, J.; D0ur15h, C. 7., ed5. Exper1menta1 p5ych0pharma- c0109y: C0ncept5 and meth0d5. New Jer5ey: Humana Pre55; 1987: 433-479.

49. J0han50n, C. E.; 8a15ter, R. L. A 5ummary 0f the re5u1t5 0f a dru9 5e1f-adm1n15trat10n 5tudy u51n9 5u65t1tut10n pr0cedure5 1n rhe5u5 m0n- key5. 8u11. Narc. 30:43-54•, 1978.

50. J0han50n, C. E.; 5chu5ter, C. R. A c0mpar150n 0f c0ca1ne and d1- ethy1pr0p10n under tw0 d1fferent 5chedu1e5 0f dru9 pre5entat10n. 1n: E111nw00d, E.; K116y, M., ed5. C0ca1ne and 0ther 5t1mu1ant5. New Y0rk: P1enum Pre55; 1977:545.

51. J0han50n, C. E.; 5chu5ter, C. R. A c0mpar150n 0f the 6ehav10ra1 ef- fect5 0f 1- and d-cath1n0ne and d-amphetam1ne. J. Pharmac01. Exp. 7her. 219:355; 1981.

52. J0han50n, C. E.; Uh1enhuth, E. H. Dru9 preference and m00d 1n human5: D1a2epam. P5ych0pharmac0109y (8er11n) 71:269; 1980.

53. J0han50n, C. E.; Uh1enhuth, E. H. Dru9 preference and m00d 1n human5: d-Amphetam1ne. P5ych0pharmac0109y (8er11n) 71:274; 1980.

54. Luka5, 5. E.; 6r1ff1th5, R. R. Prec1p1tated d1a2epam w1thdrawa1 1n 6a600n5:Effect5 0f d05e and durat10n 0f d1a2epam exp05ure. Eur. J. Pharmac01. 100:163-171; 1984.

55. Luka5, 5. E.; 6r1ff1th5, R. R.; 8radf0rd, L. D.; 8rady, J. V.; Da1ey, L. A tether1n9 5y5tem f0r 1ntraven0u5 and 1ntra9a5tr1c dru9 adm1n15- 1xat10n 1n the 6a600n. Pharmac01. 810chem. 8ehav. 17:823-829; 1982.

56. Luka5, 5. E.; H1en2, R. D.; 8rady, J. V. 7he effect5 0f phencyc11- d1ne and ketam1ne 0n 5en50ry thre5h01d5 and react10n t1me5 1n the 6a600n. Pharmac01. 810chem. 8ehav. 23:743-747; 1985.

57. Luka5, 5. E.; H1en2, R. D.; 8rady, J. V. Effect5 0f d1a2epam and tr1a201am 0n aud1t0ry and v15ua1 thre5h01d5 and react10n t1me5 1n the 6a600n. P5ych0pharmac0109y (8er11n) 87:167-172; 1985.

58. McLe0d, D. R.; 819e10w, 6. E.; L1e650n, 1. A. 5e1f-re9u1ated 0p1- 01d det0x1f1cat10n 6y human5:Effect5 0f methad0ne pretreatment. 1n: Harr15, L. D., ed. Pr061em5 0f dru9 dependence 1981:232. Nat1. 1n5t. Dru9 A6u5e Re5. M0n0. 5er1e5 N0.41, DHH5 Pu611cat10n N0. (ADM)82-600540. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0f- r1ce; 1982.

59. Me15ch, R. A.; Henn1n9f1e1d, J. E. Dr1nk1n9 0f ethan01 6y rhe5u5 m0nkey5:Exper1menta1 5trate91e5 f0r e5ta6115h1n9 ethan01 a5 a re1n-

f0rcer. 1n: 6r055, M. M., ed. A1c0h01 1nt0x1cat10n and w1thdrawa1. New Y0rk: P1enum Pre55; 1977:443.

60. MeU0, N. K.; McNamee, H. 8.; Mende150n, J. H. Dr1nk1n9 pattern5 0f chr0n1c a1c0h011c5:6am611n9 and m0t1vat10n f0r a1c0h01.1n: C01e, J. 0. , ed. C11n1ca1 re5earch 1n a1c0h0115m. P5ych1atr1c Re5earch Re- p0rt N0. 24, Wa5h1n9t0n, DC: Amer1can P5ych1atr1c A550c1at10n; 1968:83.

61. Me110, N. K.; Mende150n, J. H. Dr1nk1n9 pattern5 dur1n9 w0rk c0n- t1n9ent and n0n-c0nt1n9ent a1c0h01 ac4u151t10n. 1n: Me110, N.; Men- de150n, J., ed5. Recent advance51n 5tud1e5 0f a1c0h0115m. Wa5h1n9t0n, DC: U5 60vernment Pr1nt1n9 0ff1ce; 1971:647.

62. Me110, N. K.; Mende150n, J. H.; Kuehn1e, J. C.; 5e11er5, M. 5. 0p- erant ana1y515 0f human her01n 5e1f-adm1n15trat10n and the effect5 0f na1trex0ne. J. Pharmac01. Exp. 7her. 216:45; 1981.

63. Mende150n, J. H.; Kuehn1e, J. C.; 6reen6er9, 1.; Me110, N. K. 0p- erant ac4u151t10n 0f mar1huana 1n man. J. Pharmac01. Exp. 7her. 198:42; 1976.

64. Mende150n, J. H.; Me110, N. K. C0mm0n1y a6u5ed dru95.1n: Harr1- 50n•5 pr1nc1p1e5 0f 1nterna1 med1c1ne. Chap. 241. New Y0rk: Mc- 6raw H111 800k C0; 1982.

65. M00dy, D. 8. React10n t1me a5 an 1ndex 0f 5en50ry funct10n. 1n: 5te661n5, W. C., ed. An1ma1 p5ych0phy51c5, the de519n and c0nduct 0f 5en50ry exper1ment5. New Y0rk: App1et0n; 1970.

66. 0vert0n, D. A. C0mpar150n 0f the de9ree 0f d15cr1m1na6111ty 0f var- 10u5 dru95 u51n9 the 7-Ma2e dru9 d15cr1m1nat10n parad19m. P5ych0- pharmac0109y (8er11n) 76:385-395; 1982.

67. 0vert0n, D. A. 5tate dependent 1earn1n9 and dru9 d15cr1m1nat10n5. 1n: 1ver5en, L. L.; 1ver5en, 5. D.; 5nyder, 5. H. Hand600k 0f p5y- ch0pharmac0109Y, v01. 18. New Y0rk: P1enum Pre55; 1984:59-127.

68. Pf1n95t, 8. E.; H1en2, R.; K1mm, J.; M111er, J. React10n-t1me pr0ce- dure f0r mea5urement 0f hear1n9. 1. 5uprathre5h01d funct10n5. J. Ac0u5t. 50c. Am. 57:421--430; 1975.

69. Pf1n95t, 8. E.; H1en2, R.; M111er, J. React10n-t1me pr0cedure f0r mea5urement 0f hear1n9. 11. 7hre5h01d funct10n5. J. Ac0u5t. 50c. Am. 57:431--436; 1975.

70. 5chu5ter, C. R.; 8a15ter, R. L. 7he d15cr1m1nat1ve 5t1mu1u5 pr0per- t1e5 0f dru95. 1n: 7h0mp50n, 7.; Dew5, P. 8., ed5. Advance5 1n 6e- hav10ra1 pharmac0109y, v01. 1. New Y0rk: Academ1c Pre55; 1977: 85-138.

71. 5eever5, M. H. 0p1ate add1ct10n 1n the m0nkey. 1. Meth0d5 0f 5tudy. J. Pharmac01. Exp. 7her. 56:147; 1936.

72. 5eever5, M. H.; Deneau, 6. A. Phy5101091ca1 a5pect5 0f t01erance and phy51ca1 dependence. 1n: R00t, W. 5., H0fman, F. D., ed5. Phy5101091ca1 pharmac0109y, v01. 1. New Y0rk: Academ1c Pre55; 1963.

73. 5pren9, M. Artefact rec09n1t10n and d1a2epam 1n e1ectr1c re5p0n5e aud10metry. Aud10109y 12:137-149; 1973.

74. 5te661n5, W. C. Aud1t0ry react10n t1me and the der1vat10n 0f e4ua1 10udne55 c0nt0ur5 f0r the m0nkey. J. Exp. Ana1. 8ehav. 9:135-142; 1966-

75. 5te661n5, W. C. 5tud1e5 0f hear1n9 and hear1n9 1055 1n the m0nkey. 1n: 5te661n5, W. C., ed. An1ma1 p5ych0phy51c5, the de519n and c0n- duct 0f 5en50ry exper1ment5. New Y0rk: App1et0n; 1970.

76. 5t1t2er, M. L.; McCau1, M. E.; 819e10w, 6. E.; L1e650n, 1. A. 0ra1 methad0ne 5e1f-adm1n15trat10n: Effect5 0f d05e and a1ternat1ve re1n- f0rcer5. C11n. Pharmac01.7her. 34:29; 1983.

77. V111arrea1, J. E. 7he effect5 0f m0rph1ne a90n15t5 and anta90n15t5 0n m0rph1ne-dependent rhe5u5 m0nkey. 1n: K05ter11t2, H. W.; C0111er, H. 0. J.; V111arrea1, J. E., ed5. A90n15t and anta90n15t act10n5 0f narc0t1c ana19e51c dru95. 8a1t1m0re: Un1ver51ty Park Pre55; 1973:73- 93.

78. Week5, J. R. Exper1menta1 m0rph1ne add1ct10n: Meth0d f0r aut0- mat1c 1ntraven0u5 1nject10n5 1n unre5tra1ned rat5. 5c1ence 138:143; 1962.

79. W1nter, J. C. Dru9-1nduced 5t1mu1u5 c0ntr01. 1n: 81ackman, D. E.; 5an9er, D. J., ed5. C0ntemp0rary re5earch 1n 6ehav10ra1 pharmac01- 09Y. New Y0rk: P1enum Pre55; 1978:209-237.

80. W00d5, J. H.; Y0un9, A. M.; Her11n9, 5. C1a551f1cat10n 0f narc0t1c5 0n the 6a515 0f the1r re1nf0rc1n9, d15cr1m1nat1ve, and anta90n15t ef- fect5 1n rhe5u5 m0nkey5. Fed. Pr0c. 41:221-227; 1982.

81. Yana91ta, 7. An exper1menta1 framew0rk f0r eva1uat10n 0f depen- dence 11a6111ty 0f var10u5 type5 0f dru95 1n m0nkey5.8u11. Narc. 24: 57--64; 1973.