Neur05c1ence• 8106ehav10ra1Rev1ew5,V01. 15. pp. 35-43. ~ Per9am0n Pre55p1c. 1991. Pr1nted1n the •U.5.A.
0149-7634/91 $3.00 + .00
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8RADY, J. V. An1ma1m0de15f0r a55e551n9dru95 0fa6u5e. NEUR05C1 8108EHAV REV 15(1) 35--43, 1991.--A maj0r t0x1c effect that ha5 11m1tedthe c11n1ca1u5efu1ne550f med1c1na1 dru95 ha5 6een the1r 5u5cept16111tyt0 n0nmed1ca1 u5e and a6u5e 6y 519n1f1cant 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 re11a6111tyand 6r0ad 9enera11ty 0f 065ervat10n5 c0ncern1n9 dru9 a6u5e 11a6111ty1n human5 6a5ed up0n 5uch an1ma1 1a60rat0ry m0de15. 7he m05t 1mp0rtant 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/t0x1cpr0pert1e5 0f dru95 0n the 0ne hand, and the1r env1r0nmenta1/6ehav10ra1 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 An1ma1m0de15 8ehav10ra1 t0x1c1ty
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thank her••• 8 u t the d15c0very that an1ma15 1mp1anted w1th 1ntraven0u5 catheter5 (F19. 1) w0u1d repeated1y 5e1f-1nject pharmac01091ca1 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 6etween 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 perf0rmance 0r the 5pec1e5 0f 0r9an15m 1nv01ved (30,51). 7he rec09n1t10n 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 c0mm0na11t1e5 make5 c0ntact w1th an expand1n9 60dy 0f re5earch kn0w1ed9e 6a5ed up0n the ana1y515 0f 6ehav10ra1, pharmac01091ca1, t0x1c01091ca1 1nteract10n5 and 15 advanta9ed 6y the 5tr0n9 emp1r1ca1 1nf1uence 0f the exper1menta1 1a60rat0ry. 7he m05t 1mp0rtant p01nt 0f 1nteract1ve c0ntact that character12e5 5uch an1ma1
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 re5earch 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 c0ntr16uted 1mp0rtant1y t0 the eva1uat10n 0f 5uch c0mp0und5. 7he meth0d01091ca1 and 5u65tant1ve 1nteract10n5 6etween the 6ehav10ra1, pharmac01091ca1, and t0x1c01091ca1 5c1ence5 9enerated 6y the deve10pment 0f 5uch an1ma1 m0de15 have c0mp1emented trad1t10na1 610chem1ca1/phy5101091ca1 eva1uat10n5 0f 5tructure-act1v1ty 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 appr0ach t0 pharmac01091ca1 and t0x1c01091ca1 eva1uat10n 0f a6u5e dru95 and empha512ed the need f0r reappra15a1 0f trad1t10na1 c0ncept5 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 nature 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
*Re4ue5t5 f0r repr1nt5 5h0u1d 6e addre55ed t0 J05eph V. 8rady, Ph.D., D1v1510n0f 8ehav10ra1 810109y, 7ray10r 8u11d1n9, R00m 624, J0hn5 H0pk1n5 Un1ver51ty, 5ch001 0f Med1c1ne, 720 Rut1and Avenue, 8a1t1m0re, MD 21205.
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F16.2. Avera9e num6er 0f 1nject10n5 per day w1th 14 pheny1ethy1am1ne5. 1ntraven0u5 1nject10n5 were de11vered up0n c0mp1et10n 0f 160 1ever pre55e5: 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 pheny1ethy1am1ne 0r 5a11ne. (5) 1nd1cate5 mean 0f day 8-12 after 5u65t1tut10n 0f 5af1ne (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 c0nnect mean5 at 1nd1cated d05e5 0f dru9.
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 exper1ence (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 re1nf0rc1n9 eff1cacy 6a5ed up0n dru9 5e1f-adm1n15trat10n tr1a1 fre4uency w1th a 5er1e5 0f pr0t0typ1ca1 5t1mu1ant5 (F19, 2), and up0n
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 pr061em ha5 6een rep0rted 1nc1ud1n9 the u5e 0f c0ncurrent 5chedu1e pr0cedure5 (47), ch01ce pr0cedure5 (38,50), re5p0n5e rate ana1y515 (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 re5p0nd1n9 (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 d1v1d1n9 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, ch10rphenterm1ne, d1ethy1pr0p10n and c0ca1ne (34). W1th1n-an1ma1 c0mpar150n 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 d1ethy1pr0p10n, 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 re1nf0rc1n9 funct10n5. An unde51ra61e an0rect1c w0u1d 6e a weak appet1te 5uppre55ant 6ut a p0tent re1nf0rcer. A num6er 0f 5u65t1tuted pheny1ethy1am1ne5 and c0ca1ne have 6een eva1uated u51n9 th15 an0rect1c/re1nf0rcement rat10 (ak1n t0 the ••therapeut1c rat10,•• f0r examp1e) and F19. 5 111u5trate5 the re5u1t5 0f 5uch c0mpar150n5 and c0nf1rm5 the c0nc0rdance 6etween an1ma1 and human f1nd1n95 6a5ed up0n an0rect1c dru9 d05e determ1nat10n5. 519n1f1cant1y. the 9enera11ty 0f the5e re5u1t5 rep0rted w1th an1ma1 5e1f-1nject10n m0de15 0f a6u5e 11a6111ty ha5 6een we11 d0cumented 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), pent06ar61ta1 (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 1ndependent1y 0f whether the part1c1pant v01unteer5 were 0cca510na1 0r ca5ua1 dru9 u5er5 (52), had 5u65tant1a1 and var1ed dru9 u5e h15t0r1e5 (25), 0r were phy51ca11y dependent 0n dru95 (62,76). 1n 0ther re5pect5 a5 we11, the human data fr0m dru9 5e1f-adm1n15trat10n 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 decrea5ed re5p0n5e rate5 and 1ncrea5ed the 11ke11h00d that the 5u6ject5 w0u1d det0x1fy (58). 51m11ar1y, re5p0n5e c05t 5tud1e5 w1th human5 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 preferred t0 pr0ca1ne (26). 7HE
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Wh11e re1nf0rc1n9 funct10n5 a5 ref1ected 6y 5e1f-adm1n15trat10n have pr0v1ded a d0m1nant f0cu5 f0r an1ma1 m0de15 and pr0cedura1 appr0ache5 t0 the a55e55ment 0f a6u5e 11a6111ty, recent ref1nement5 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 d1fferent 5t1mu1u5 c0nd1t10n5, whether the 5t1mu11 are pre5ented exter0cept1ve1y (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 certa1n 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 a65ence 0f the tra1n1n9 dru9 c0me5 t0 5et the 0cca510n f0r mak1n9 0ne 0f tw0 (0r m0re) re5p0n5e5, 0n1y 0ne 0f wh1ch w111 6e re1nf0rced 1n any 91ven tra1n1n9 5e5510n (48, 67, 70, 79). 7h15 pr0cedure 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 9enera112at10n. Dru95 that are pharmac01091ca11y 51m11ar t0 the tra1n1n9 dru9 9enera11y 0cca510n re5p0nd1n9 51m11ar t0 that under the
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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 c11n1ca11nf0rmat10n and 6a600n exper1ment5. C0mp0und5 w1th h19h rat10 va1ue5 are m0re p0tent re1nf0rcer5 (re1at1ve t0 the1r an0rect1c p0tency) than c0mp0und5 w1th 10wer rat10 va1ue5.
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8RADY, J. V. An1ma1m0de15f0r a55e551n9dru95 0fa6u5e. NEUR05C1 8108EHAV REV 15(1) 35--43, 1991.--A maj0r t0x1c effect that ha5 11m1tedthe c11n1ca1u5efu1ne550f med1c1na1 dru95 ha5 6een the1r 5u5cept16111tyt0 n0nmed1ca1 u5e and a6u5e 6y 519n1f1cant 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 re11a6111tyand 6r0ad 9enera11ty 0f 065ervat10n5 c0ncern1n9 dru9 a6u5e 11a6111ty1n human5 6a5ed up0n 5uch an1ma1 1a60rat0ry m0de15. 7he m05t 1mp0rtant 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/t0x1cpr0pert1e5 0f dru95 0n the 0ne hand, and the1r env1r0nmenta1/6ehav10ra1 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 An1ma1m0de15 8ehav10ra1 t0x1c1ty
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thank her••• 8 u t the d15c0very that an1ma15 1mp1anted w1th 1ntraven0u5 catheter5 (F19. 1) w0u1d repeated1y 5e1f-1nject pharmac01091ca1 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 6etween 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 perf0rmance 0r the 5pec1e5 0f 0r9an15m 1nv01ved (30,51). 7he rec09n1t10n 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 c0mm0na11t1e5 make5 c0ntact w1th an expand1n9 60dy 0f re5earch kn0w1ed9e 6a5ed up0n the ana1y515 0f 6ehav10ra1, pharmac01091ca1, t0x1c01091ca1 1nteract10n5 and 15 advanta9ed 6y the 5tr0n9 emp1r1ca1 1nf1uence 0f the exper1menta1 1a60rat0ry. 7he m05t 1mp0rtant p01nt 0f 1nteract1ve c0ntact that character12e5 5uch an1ma1
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 re5earch 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 c0ntr16uted 1mp0rtant1y t0 the eva1uat10n 0f 5uch c0mp0und5. 7he meth0d01091ca1 and 5u65tant1ve 1nteract10n5 6etween the 6ehav10ra1, pharmac01091ca1, and t0x1c01091ca1 5c1ence5 9enerated 6y the deve10pment 0f 5uch an1ma1 m0de15 have c0mp1emented trad1t10na1 610chem1ca1/phy5101091ca1 eva1uat10n5 0f 5tructure-act1v1ty 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 appr0ach t0 pharmac01091ca1 and t0x1c01091ca1 eva1uat10n 0f a6u5e dru95 and empha512ed the need f0r reappra15a1 0f trad1t10na1 c0ncept5 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 nature 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
*Re4ue5t5 f0r repr1nt5 5h0u1d 6e addre55ed t0 J05eph V. 8rady, Ph.D., D1v1510n0f 8ehav10ra1 810109y, 7ray10r 8u11d1n9, R00m 624, J0hn5 H0pk1n5 Un1ver51ty, 5ch001 0f Med1c1ne, 720 Rut1and Avenue, 8a1t1m0re, MD 21205.
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a55e55ment m0de15 15 the dem0n5trated re1at10n5h1p 6etWeen the 610C6em1Ca1/pharmaC01091Ca1/t0X1C01091Ca1 pr0pert1e5 0f dru95 0n the 0ne hand, and the1r enV1r0nmenta1/6ehaV10ra1 5t1mU1U5 funct10n5 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 phy510-610chem1ca1 pr0pert1e5. A5 a re5u1t, exper1menta1 pr0cedure5 f0r the 9enerat10n 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).
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F16.2. Avera9e num6er 0f 1nject10n5 per day w1th 14 pheny1ethy1am1ne5. 1ntraven0u5 1nject10n5 were de11vered up0n c0mp1et10n 0f 160 1ever pre55e5: 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 pheny1ethy1am1ne 0r 5a11ne. (5) 1nd1cate5 mean 0f day 8-12 after 5u65t1tut10n 0f 5af1ne (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 c0nnect mean5 at 1nd1cated d05e5 0f dru9.
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 exper1ence (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 re1nf0rc1n9 eff1cacy 6a5ed up0n dru9 5e1f-adm1n15trat10n tr1a1 fre4uency w1th a 5er1e5 0f pr0t0typ1ca1 5t1mu1ant5 (F19, 2), and up0n
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 pr061em ha5 6een rep0rted 1nc1ud1n9 the u5e 0f c0ncurrent 5chedu1e pr0cedure5 (47), ch01ce pr0cedure5 (38,50), re5p0n5e rate ana1y515 (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 re5p0nd1n9 (1.e., w0rk) that can 6e ma1nta1ned 6y the c0mp0und (14). 7he re5p0n5e re4u1rement 15 5y5temat1ca11y 1ncrea5ed unt11
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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, ch10rphenterm1ne, d1ethy1pr0p10n and c0ca1ne (34). W1th1n-an1ma1 c0mpar150n 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 d1ethy1pr0p10n, 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 re1nf0rc1n9 funct10n5. An unde51ra61e an0rect1c w0u1d 6e a weak appet1te 5uppre55ant 6ut a p0tent re1nf0rcer. A num6er 0f 5u65t1tuted pheny1ethy1am1ne5 and c0ca1ne have 6een eva1uated u51n9 th15 an0rect1c/re1nf0rcement rat10 (ak1n t0 the ••therapeut1c rat10,•• f0r examp1e) and F19. 5 111u5trate5 the re5u1t5 0f 5uch c0mpar150n5 and c0nf1rm5 the c0nc0rdance 6etween an1ma1 and human f1nd1n95 6a5ed up0n an0rect1c dru9 d05e determ1nat10n5. 519n1f1cant1y. the 9enera11ty 0f the5e re5u1t5 rep0rted w1th an1ma1 5e1f-1nject10n m0de15 0f a6u5e 11a6111ty ha5 6een we11 d0cumented 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), pent06ar61ta1 (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 1ndependent1y 0f whether the part1c1pant v01unteer5 were 0cca510na1 0r ca5ua1 dru9 u5er5 (52), had 5u65tant1a1 and var1ed dru9 u5e h15t0r1e5 (25), 0r were phy51ca11y dependent 0n dru95 (62,76). 1n 0ther re5pect5 a5 we11, the human data fr0m dru9 5e1f-adm1n15trat10n 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 decrea5ed re5p0n5e rate5 and 1ncrea5ed the 11ke11h00d that the 5u6ject5 w0u1d det0x1fy (58). 51m11ar1y, re5p0n5e c05t 5tud1e5 w1th human5 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 preferred t0 pr0ca1ne (26). 7HE
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