Doc 0000151876

. •. ·.4 Use ot a Dilute Aqueous Solution (5 QCg/m!) ot a Benzim1dn:o1c Derlvat.lve wl t.h Pot~nt Morph!ne-Ltite Actions Orally as a Relnforclng Agent. ln Cond! t1on1ng Pre~ur.lpt.l•J>e ~r Drug-Seeklng Behavior tn the Rat Wtklcr, u.D. Ahr~~aQ c. Phillip O~cen D. Smlth Herb~rt 8.&"1d Frank T. P~seor From tha National Inst1 tute of r.. t ental Health Addiction ~eseareh Cente~ u. s. Public Health Service Lexington, i~entucky ........... ____________________ _ ot Use or a Dilute Aqueous Solution (5 mcg/ml) a Ben~lmldazole Dcrtvat1vc with Potent Actions Orally as a ~~rph1ne•L1~e Presu.'npt1ve-nc1n!orc1ng Agent 1n Conditioning ot Drug-Seeltlng Behavior ln. tho Rat. Durlng the past 12 years, one ot us has repeatedly called or attention to certain aspects the behavior ot addicts which strongly suggest (a) that relapss utter fteure" cay represent, · at least ln part, a condltioncd response to stlmull that have ,regularly been associated w1th the per1od1c relle! o£ such distress as develops between doses ot during abs~1nence opiate~ previous episodes of addlctlon (1,2.3 4)J and (b) that the 1 or probab111ty such wcondlt!oncdu relapse ls d1rectly related to the "attort" ("hustling") expended by tha addlct ln his or drug•seektng behavSor durlng previous episodes addiction ($). ?or heurlstlc these concepts·have been expressed p~rposes1 formally 1n t~rms·or both •etasslcal8 (Pavlovian) and "tnstru• or mentalw models cond1t1on1ng {1,6,7,8), (ln~ludlng "~perant") or the former emphaslzlna tho ro1a that. condlt lon!ng the syndrome may play ln rclapse and the latter, the .ahs~l~ence 1 role ot the manlpulatlve activity •. org~ism•s • Il-l! J -- . . ~ . More recently, a tav lnvestloatQt~, operatinG on hypotheses ai~ lar ln a·~me r'i$pocta t.·l tl1os.a dl ~euss"'a ·att-JV!cl, have r~port.oc1 avi~encc obtalneQ in studies on animals ~nd!cating beth that t.ha 01-~lat~ ~b$Lln,~r.c~ ~;yn<!r~.-:1c ca.r •. b\:ec~e :-:~n-:iitior:~d .. lCJ) end. tt1at. "pTC.i'6frtncet• for morpl"line, f~l"SiSt.ing !or 1)ef'it.IC:S bcyontl the e).p..er:t.\!..! uuH.;t.1c·r. o! tJ: ..~ ali~t l;l~nc\1! $}1%h.'t'Ovie,. C.+.;ft b\• dev~lope~ .by 1nstruw"-nt.a1 eOJlci1t.1c,n1r.g tluri:lQ addlct!~n (10,11). ln our lal):..ratol·les, r-~p.Hl.teu. a.tt..:tt:~t.s to cc.ndlt.!cn 'lither rats in ~&ich the an1~ls a~llv~r~d doses oi ~orphin~ to them• ope1-ant. tecl·~n1Gue, onr.:.e'- r.asas\.r~usly aft.ur a. !cw "A'Ut:JI.s, h'iCAU$~ the lnt.t·apt;rf t.:!lnaal u~~uinS"; t)! t.he pol~·eU~yt~ns cnU~~ter t·~caa-.e eccl~.!!~c.· by t. thleh ~~r:.t·ran~. Not. to be d~lerrea "wy $UCh tri!l~s, \.'U tegar. to cunstdur t~t'tcn:.~ly the prt;arat.S on of nnl;;.~ls wl til chron1 cnlly 1t;plant~tl lntruv~nous rations lntacL tor several months ware net trlght. .8-!7~ I ... ·~ • .... The image displays a stylized graphic on the left, featuring an open vault door with intricate mechanical workings and a bluish glow. The right side of the image contains text on a black background. The text, in white and yellow, explains that the document was obtained from "The Black Vault," an online database of declassified government documents, specifically the MKULTRA/Mind Control Collection. It states that the entire collection is available for free download at a provided URL. There are no photographs, handwritten annotations, official stamps, filled-in forms, diagrams, tables, or redacted content visible in this image. The page is a title page for a scientific paper. It contains a handwritten number "156" circled in the upper right quadrant and a handwritten identifier "B-19" in the bottom right quadrant. The text includes the title of the paper, the authors' names and affiliations, and the date. There are no photographs, stamps, forms, diagrams, or redations; however, there are several small dark dots scattered across the page that may be from the printing process or age of the document. lnt.t·apt;rf t.:!lnaal u~~uinS"; t)! t.he pol~·eU~yt~ns cnU~~ter t·~caa-.e eccl~.!!~c.· by t. thleh ~~r:.t·ran~. Not. to be d~lerrea "wy $UCh tri!l~s, \.'U tegar. to cunstdur t~t'tcn:.~ly the prt;arat.S on of nnl;;.~ls wl til chron1 cnlly 1t;plant~tl lntruv~nous rations lntacL tor several months ware net trlght. .8-!7~ I ... ·~ • .... , Pa ~ w .... - Meanwhile. however, our attention was directed to tha or a new drug, l•(Seta-d1athylam1noethyl)·2-(p• propertl~s ethoxyben:vl)·S-n!troben:1m1dnzole methane sultonate (NIH-76o7). was then under stucy for its addlctlon 11ab111ty on the -~Jch or rcseare."l wards thls Cent.er. Thl s drt:g, which will be reterre~ to by its ~qc number, 1-G-2, 1n thls report, had been synth~slzed or by chemists the C1ba Pharmaccuttcal Company ln Basel• Switzerland, and was found by their pharcacologists (12,13) and others subsequently to typical morphine-like actions ln c~ert animals ln extremely small Thus, I·G-2 ls 1 000 times do~es. 1 more potent than morph1ne_as en analgesic 1n rats (13), and 1 SOO t1mes ln the mouse (14); 1n eddlcted monkeys, 1-G·2 ts 1 1.5oo times as as morphine 1n suppressing signs ot pot~1t abstinence trom.morphlna (1$). In post-addicts. 1sbe11 arid Fraser. (16} round that I-G-2 ls 80-120 more powartul than ti~es morphine as a 1n slngle oral doses, and l.mg ot eup~orlant or 1.0·2 ls as e!'!ect1ve orally as 60 mg morphine subcutaneously, ln suppressing abstinence from morphine. Tolerance to repeated doses or 1-G·2 dovelops raplaly ln the rat (13) and ln oan (16), or and ln the latter. the degree "physical dependence" developed Is comparable ln intensity with that produced by equivalent doses ot morphtna (16). or Such evidence the morphine-like ot 1-o-2, p~opert1es and of Its very much greater potency, suggested to us the poss1blllty that rats eight· not be averse to dr1nklng an a~ucous solution or th!s drug, ln concentrations would produce tha~ of morphlnc•l!ke etteets aftGr cons~~pt10A scall quantities. A n~1nglc•b11nd~ t3ste-d1scr1m1natlon test perform~d by one ot the authors on another, yielded a threshold concentration of 4•5 meg ot I-G-2 per ml ot water. Jiop!ng that the dlscrlm!nn• t!ve capacity of the rat 1s somewhere !n thls vleinity 1 calibrated dr1rut1ng tubes tilled with 3. S or 10 mcg/ml aqueous solution of l-G•2 were ottered to rats deprived of water tor hours. The rats drank all the solutions avidly, and wlthtn ~ tour to seven minutes arter beglnnlng to (or atter dr1~ consumption of 66·144 mcg~tg ot I-G-2) they calibrated dr1rut1ng tubes tilled with 3. S or 10 mcg/ml aqueous solution of l-G•2 were ottered to rats deprived of water tor hours. The rats drank all the solutions avidly, and wlthtn ~ tour to seven minutes arter beglnnlng to (or atter dr1~ consumption of 66·144 mcg~tg ot I-G-2) they exh1b1ted morphine lUte ettects •• exophthalmos. tail rigidity, stup.or (snout. #O=et!mes talllng.tnto the well of the'drlnkfng tube) ~d/or or hyperact1v1ty (qu!ck, Jerky movements head. darting about. floor we~plortng," chewJng on ot the cage). One rat, after consuming about 3JO meg/kg ot 1•0•2, lay prostrate on lts side with outstretched hindteet, breathing lrregularly. a Wl~~ln tcw cinutes after InJection or 10 mg/kg of nalor subcutan~ous phine, however, 1t recovered, the upright poa!tlon, ass~~!ng and responding to prodding. Addicted r3ts (oa1ntained on -· 200 me/kg or_morph1nc by subcutaneous lnjectlon once dally for several months), 11kewise showed no apparent aversion to the 1-G-2 co1ut1on (5-oc~/~1) ~en water-deprived. These an1mals were test&d just prior to their dally dose or regula~ morphine~ . whan t..'le acute effects of the previous day's dose (tall rlg!dl ty, hyperactlv! ty) were no longer apparent, ~"ld when th•Jy were exh1blt1ng slgns ot morphlne•abstlnence. notably, repented discrete twl tches of t.he sl·dn of the back, rese:'lblt·ng t.he rn~!d orr sk!n•shaklng ot a ~t dog, or ot a horse shaking. a tly (see bolow). As ln the non-addicted rats, typical morphlne•llke effect: appeared wlth!n tour to seven minutes after beginning to drink, ~Ad.Concomitantly, ~~0 °wet.dog~ tWitCh8S Ceased, SUggeS• ·t1ng rel!et ot wh1eh persisted until the time !or abs~inencc, the re2Ular aa.11y dose ot morphine a taw bours later. The only dlttersnca observed 1A the etrccta or 1-0-2 111 the addicted rats was that the usedatlven et!ecta much shorter 1n.duratlon, ~rc or predominating withln an hour attar hyperac~iv!ty 1nge~t1on the drug. - prellmlnary 1nd1cated that a dlluto Th~so ob~ervatlona solution ot 1-G-2 might well be substituted for morphine as a rclntorc1ng agent by oral route, and enable us to th~ ther~by the d1ft1cult!ss that attended our ear11er et!orts clrcum~nt lJ-;9; .to lnduce rats to drink solutions ot morphine or other opiates, or or to welcome subcutaneous lnJectlons these materials. The n present eor.munleatlon Is· ln the.nature ot "progress report" on two studlcs that have been with thls purpose ln ln1tlate~ m!nd. METHODS ln Study A• 6 ttexp·erl:nent.al" rats, gradually brought. up to a dnlly dose level ovar a.perlod ot slx to ten The document page displays typed text with a title and several paragraphs discussing drug-seeking behavior in rats and relapse in addicts. There are no photographs, diagrams, or tables. The only visual elements besides the text are a few scattered black dots, likely from the printing process, and a handwritten annotation in the bottom right corner reading "B-195" in black ink. No stamps, seals, or redactions are visible on this page. The page contains typed text that appears to be part of a scientific or research document. There are no photographs, diagrams, forms, tables, or official stamps visible. However, there is a handwritten annotation in the bottom right corner, reading "B-194". Additionally, there are a few small dark circular markings and some faint dots scattered across the page, which might be remnants of a hole punch or other damage. There is also a faint horizontal line near the top right. or to welcome subcutaneous lnJectlons these materials. The n present eor.munleatlon Is· ln the.nature ot "progress report" on two studlcs that have been with thls purpose ln ln1tlate~ m!nd. METHODS ln Study A• 6 ttexp·erl:nent.al" rats, gradually brought. up to a dnlly dose level ovar a.perlod ot slx to ten weeks. eonst~~t or , are maintained on once•da11y subcuta.,eous InJections 200 mg/l<g ot morphine, given about 2 p.m., while 6 "control" rats reeelve volumetrically equivalent subcutaneous Injections ot phys1olog- 1ca1 solution on the same All rats are alloW9d aal~ne a~hedule. tood ad llbitum. but they are dQprlvsd ot water tor 22 hours each day. atter the training and experiment• 1n the morning. te~tlng The study ls des.i gned to proceed ln three phases. In Phase 1, all rats are given access each morning to a wire cage 24 x 17.S x 17.5 em• divtded Into· two ·~~al compartments by a transparent vertical part1t1on from the central entrance to which they ean or see two drlnklng tubes placed vertically at the tar end 1 each compartment. The r:t can enter either compartment, drink tro= the tube therein, and also go· back around the partltlon • to the other compartment to drink from the tuba there. On succeas!vs days both contaln but on ths thre~ tube~ ~ater, 8-!?t rourth day, one or th0 tubes conta1n3 a S mcs/ml solution or I-G-2, the eo~part~ent ln whlch this tube is placed bclng alternated ln successive tour-day blocks (total ot 17 blocks, or 68 days). st1mu11 (bl!nklng metal D1ser1~1nat1vo l!ghts~ strips wlth black and white stripes on drinking a1tarn~t1ng tube floor). for use ln Phase 11, are also provlced, ~~d lat~r but !n l,hase I, the sides ot the compart:::u'fnt ln .\Vhlch they are. placed arc randomized. -Each day, the rats arc allo\'lt.!d to drinit tor 15 records are made ot the volumes consumed ~lnutes, ~,~ '!rom each tube every day, during successive perlocs. three-~lnu~a Alter each 1Som!nute trial. the rats are returned to their home cagQs, where are allowed to drink water ad th~; 11bltu~ from a metnl eup !or two hours, after which all water ls remo~ed or until the naxt morning. Tho purposes Phase 1 aro to de~ermine whether or not, wlthottt dtscrlm!natlve either tha tr~ln!ng. cr the "contro1° pre£aronee for, or Wexpcrlmental~ ratS·~Xhlblt aversion to !-G-2 ·1n tha concentration used on the basts ot taste, and whsther o~ riot the dlscr!~lnatlve The document is a typed page, denoted as "Page 3", with some handwritten annotations. In the bottom right corner, there is a handwritten mark "B-193". There are no photographs, stamps, forms, diagrams, tables, or redactions visible on this page. The content consists entirely of text, discussing the properties of a new drug, I-G-2, and its effects in comparison to morphine. all water ls remo~ed or until the naxt morning. Tho purposes Phase 1 aro to de~ermine whether or not, wlthottt dtscrlm!natlve either tha tr~ln!ng. cr the "contro1° pre£aronee for, or Wexpcrlmental~ ratS·~Xhlblt aversion to !-G-2 ·1n tha concentration used on the basts ot taste, and whsther o~ riot the dlscr!~lnatlve st1~11 have I appet1t1ve or aversive propertieD independent ot 1-G-2. Since ths grossly vl~lble effects ~t 1-0-2 begtn ns early a3 !our minutes after eer.n:u:ru:emen.t. at erinldng~ t.ho cr1 t.1cal measures or tor taste d1scr!m!nat1on arc tho relatlve quant1t!es 1.0·2 solution and tap water drurut trom a gtven tube (right or left) during the t!rst three minutes. Slm11arly- the erltlcal or mea:urcs ror tho re1nforc1ng the dlscr!minattve prop~rt!es st1cu11 per sa are the relative amounts ot water (only) consumed when these are in tho right or.lcft compartment. ln at1~~11 Phase 1, the.. 1-0-2 solution ls presented only every fourth ~ay • or to mln1m1ze cond1tlcn1ng by e£reet ana the development tolerance. In Phase 11, all the rats, maintained on morphine or Stl11ne and on food-and•water schedules as be:!oro, are given access to a cage similar to that. already described but const.ruct.t::d or or plastic and larger dimensions (40 x 26 x 3S em) with an opaque partition. However, the daily schedule 1s designed to or permit learn!ng ot a dlser1~1natlon the 1•0•2 solution by effect, using successive six-day block trials follows. On a~ or the tlrst tour days each blcclt, only 'Orie tube !s presented, · eonta!nlng either tap water the tlrst and·second days, or the on 1.0-2 solution the thJrd and tourth days, the order belno reversed tor each succcs:Jtve block. Thq compart::sent In which the l·G-2 solution 1a· placed ls always equipped wlth the discrtmlnative previously and remains st1~ul1 ~entioned, th~ !or a glvcn rat throughout all blocks, though s~a th~ ln1t1ally, the_rats are assigned one or the other 1-0-2 t~ compartoent (right or lett) 1n alternation. Al5o, after /J-Ilt or to dr1nk on each the four days, egress .trom the ·co~encing compartment ls prevented by closing a ~~ar ~ate, to ensure that. whatever re1ritorc1.ng eftects tha water or· 1.0-2 solution may have, will be associated with that ecmpart=ent lts ~a d1 ser1m1nat.1ve st1mu11 ( lt a.a•y) only. On the !1 !t.h c;ay, the water tube ls Invariably presented in lt.s usual compartment, and eoress is on the previous tour days. On the pr~ented_ns slxth day or each or· 1.0-2 solution may have, will be associated with that ecmpart=ent lts ~a d1 ser1m1nat.1ve st1mu11 ( lt a.a•y) only. On the !1 !t.h c;ay, the water tube ls Invariably presented in lt.s usual compartment, and eoress is on the previous tour days. On the pr~ented_ns slxth day or each block, both W3ter and 1.0•2 tuhes (the lattc~ with the d1scr1m1nat1ve stlrnnll) are presented !n thelr respec• t!ve eo=partments the egress gates remain open, and the rats 1 arc permitted to rrom either tube at any time within the dr1~~ 15-mlnute period testing. The critical measure 1n Phase II o~ or lu the relative amounts 1-G-2 solutlon and water consumed ln tlrst three by the and 8 control8 L~c m!nut~s "experimental~ rats on each ot the slxth•day test trials, arter cotrcetlon tor . whatever appetitive or aversive effects the discr1rn1natlve may have been f()und. to exert n,er !.!!. in Pha:le 1. stllr~ll In Pha:e 111, all rats w111 be testsd tor nre1aps~" several after abrupt withdrawal ot under cond1t1ona of ~eks ~orphine, water ftat1atlon and water-deprivation, by the technic described tor t.he sixth day or each block ln Phase 11. '\ 10 ?a~-e ln St.udy B, "e.xperir.lent.al" and neontro1" ra.t.s are·prepared I end on morphine or sallne injections ~a1nta!ned re~pectlvoly as ln Study A. Each morning (about 16 hours alter the previous daily uose at morphine, 200 co/kg), they are placed in an operant conditioning apparatus equipped with a lever whlch, when depressed, act.lvatcs a mechanism t.hnt uncovers a dipper or contalning 0.25 ol of tluid, set on the floor cnge about 6 em to the rear of the lever. No trials run on Saturday ~a or Sunc~ (41though, the dally oorphine or saline tnjectlons arc continued), !rt.1t. on the other tlve days ot each week, the rats are given access to the under tour conditions which leve~ nra ra1,domized and balanced over a period or =saven weeks: 22 hours water depr!vatlon, 22 hours water v~ter rein!orc~cnt; dcprlvat!on, 1-G-2 solution (5 mcg/.~1) rsintorecment; water satiation, water water I-G·2 re1n ~einforccment; ~atlat1on1 Each 1n the operant condit1on!ng apparatus foree~ent. tr1~1 .proceeda tor l.S s!nutea, o.!ter whlch water is supplied ad 11bltum in the home cage3 tor two hour3 on days preceding the uwator deprivation" runs, and throughout the cay and night before the sntlation" runs, food be1ng available at. all n~~t~r tlmes throughout. Diser1m1nat1vG ln tha operant st1~11 cond1t1oning apparstua consist The document contains typed text, likely a research report, with a handwritten annotation in the bottom right corner reading "B-192". There are also several small black dots, possibly ink smudges or artifacts from the printing process. No images, stamps, or forms are present. The content appears to describe an experiment involving rats and a substance identified as "I-G-2," detailing their reactions to consumption and injection. The document is a typed page, likely from a report or research paper, with the header "Page 5". It contains a handwritten annotation in the bottom right corner, "B-191". There are also several small black dots, possibly ink blots or remnants of a binding, scattered across the page. The text describes observations related to morphine and a solution labeled "1-G-2" in experiments with animals, including details on their behavior and reactions such as "rigidity, hyperactivity" and "wet dog" twitches. There are no photographs, stamps, forms, diagrams, tables, or other visual elements besides the typed text and the handwritten annotation. tor l.S s!nutea, o.!ter whlch water is supplied ad 11bltum in the home cage3 tor two hour3 on days preceding the uwator deprivation" runs, and throughout the cay and night before the sntlation" runs, food be1ng available at. all n~~t~r tlmes throughout. Diser1m1nat1vG ln tha operant st1~11 cond1t1oning apparstua consist ot rough (h3rdwnre cloth). aurtaces for tha floor end on days wtth water 1~~er trl~l _fJ-;r6 11 Pa:~ and s=ooth surfaces with 1·0·2 relntorea~ent. (pla~t!c) ln addition, on days with 1·0·2 re!ntorc~cnt. reintorce~snt, each lever presa actuates a clicker placed lnsldc the Skinner Dox, to serve as a "sacondary reinforcer• (rcpresen;1ng the trn41t1onal "bad associata" or narcotic acdlcts' 1orc). The crlt!cal measures ln th1s study arc thP. comparative rates of bar-pressing the lS•minute trlal periods ~~rou~hcut wtth!n each group (•exper!mentaln end ucontrol") tor watar or versus 1.0·2 reinforcement, and ccmparattvc rates bar pressing hctw?.en the two grov.ps or 1.0-2 re!ntorce to~ ~tcr msnt, both measures to water-satlatlon days. In rcter~~ng addlt.lon, stallnr eo::sparlsons are made ot unreinforeed bnr• pressing rates on water satiation since both ftcxper1mcntal" da}~• and engase in such actlvlty (possibly because ~control" ~~mals a or uncontrolled secondary reinforcers) as wall. ts Stu~y . also scheduled to.proc:ccd ln three the t1rnt·ot which pha~es~ has already been described. In the second phase, bar•pres31ng rates for water and I.0-2 will be relnforc~ments eo~pared within between both groups ot ot er~ animal~ un~er condition~ water snt!at.lon during the acute morphine withdrawal p(!ricd, and lntor, ln tho thlrd phase, tests for "relapsen will be or made ln both groups, under conditions water dcpr!vntlon and W\\ter sat.!a.t.lon, e.nd the dlscr!m1nat1va sti=uli and (eont.rollcd) secondary reinforcer nlready d~scribed. - If poeltlva results are obtained sf't.er c:o:npletlon ot .study D~ !t 1s planned to conduct a sl~ilBrly designed 1nves• tlgat1on, wlth a number ot schedules ot relntorc~cnt, to analyze the 1nt1uencc of various pnra~cters ot "cttort~ or "hust:.llng" on Uua probah111t.y ot "relapse." RJ£Sl.ILTS At the present t!me. only the tlrst phnses or both stud1~~ have been COQpleted. The data fo~ thls phase of Study A have ,been ~~alyzed only wlth ragard to the question ot the capacity ot tho an!Qals to d1scr1m1nate bct~een water and the l·G-2 solution by ta3te. As show.n tn Tabla 1, the overall dltterences obtnlned se~ to 1n41catc that, without d!scrfminnttve training, tha "cxper1~enta1" rata e~;1blt a s11ght "prererence" and the "controln r~ts a s11~~t "aversion~ ~o the 1•0•2 solution, The visually sparse page contains typed text and a handwritten annotation. At the top, there are two dark circular ink blots, possibly from a photocopier or scanner malfunction. To the right, "Page 6" is typed. The main body of the page consists of typed text detailing experimental procedures involving rats and morphine. In the lower right corner, "B-190" is handwritten in blue ink. There are no photographs, diagrams, stamps, or forms present. ot the capacity ot tho an!Qals to d1scr1m1nate bct~een water and the l·G-2 solution by ta3te. As show.n tn Tabla 1, the overall dltterences obtnlned se~ to 1n41catc that, without d!scrfminnttve training, tha "cxper1~enta1" rata e~;1blt a s11ght "prererence" and the "controln r~ts a s11~~t "aversion~ ~o the 1•0•2 solution, but. these d1fterence~ are not stat1stlca11Y si;n1t1cant by the chl square test. were Several analyses. made ot the data obtcln~d ln the tlr$t phase ot Study .e. In Table 2 are shown intergroup .eon:po..r!sons of "wet dogrt responses per 1.5-m!nutc trial 1n expcrl~entnl and control an!r.aa.ls on ~epa.rate days, undGr tho tour conditions ot the experiment. lt !a not¢WOrthy that on water satiation da~, the number ot "wet doo" responses ;. ::t~ ...... t ~ • &. ~ ·.• • -· exhtblted by.the experlsent.al antr:\als was greatar than those or the control animals to highly s1gn1t1cant degrees by the U test tor 1nteroroup comparisons (17), except ~~nn-Whltncy tor one t.rlal c!ay although., even then• .t ha trend. in the wa~ d1reet1on ot S.20 for the experimental, a~n d 2.60 fer sa~g (me~~ control animals). ln contrast, no s1gn1ticant differences th~ or were ob9erved on watQr days regardless whether · ~cprivat1on the tv.as water or the 1-0-2 solution. rein!ore~~ent us~d 1 The analyses prc!:e.'lt.ed 1n Table 3 reveal that on water depr1vat1on days., the rolntorccd bar-pre3s1ng rates o! experi or mental rat4 those control regardless ot exce~ded r~ts, whether water or I-G·2 was used as t.ho ralntoreer.tent. On water satiation davs, howevers the reinforced rates of bar•prcsnin~ or animals generally exceeded those control expcrl~cntal a~lm3!3 only when relntorcemv.nt was·provided by 1-G-2. Addlng or perhnps to the th~oretical s1gnlf1cance these results ara the comparisons (Table 3) reinforced and non-reinforced bet~en bar-pressing rates or cxpertccntal and an1Qa1s on water e~ntrol satiation d.ays. \!.'hen rein£oreed 1..0-2, the reinforced bar-• b~t pressing rate3 are s1gn1!1cantly di!!ercnt for the groups t~~ of anloa1s, but not the rates; reintorced non-relnfo~eed ~en by watar.rs1thar the raln!orecd nor the non-relntorced rctes arc generally d1!rcrent to c1on1fleant deg~ees. On the other ,• 1 . hand, th.e intragroup compcrlsons, ~hown tn Tabla 4 1ndlcate that on wate~ sotlat1on days, neither the experimentnl nor the control groups· showed sl anlflcant d1fterences between bar• . . pressing rates with water and I·G•2 re1ntoreements~ while on water depr!vnt!on days bot.h groups exhl'bltcd slgnlfleant.ly greate~ rates wlth water than with I-G-2 reinforcement. - DISCUSS10N or. The document is a single page of typed text, numbered "Page 7" in the upper right corner. The text describes an experiment involving rats and a solution labeled "I-G-2," detailing drinking periods, stimuli, and control measures. There is a handwritten annotation in the lower right corner, appearing to be an alphanumeric code "B-189," and a horizontal line drawn beneath it. There is another horizontal line located near the top right, with possible faint markings that are difficult to discern. The page also features a single, dark circular mark near the top center, and several smaller dots throughout the text, possibly representing original document imperfections or printer errors. Tabla 4 1ndlcate that on wate~ sotlat1on days, neither the experimentnl nor the control groups· showed sl anlflcant d1fterences between bar• . . pressing rates with water and I·G•2 re1ntoreements~ while on water depr!vnt!on days bot.h groups exhl'bltcd slgnlfleant.ly greate~ rates wlth water than with I-G-2 reinforcement. - DISCUSS10N or. The data tor t.he 1"1 rat. ·phase St.udy A 1nd1.cnt.c that, wtthout dlscr!mtnatlve training, nelther expertc~1tal nor control anloals 41splay either pre~erence ror or aversion to a S-rncg/~1 solution or I-G-2. Thls flnding is of basic l~portance·ror ~~e subsequ~nt phases or both studies, s1nca the hypotheses to be tested predlet tha ~evelopment ot a nprererenee" to~ I-G-2 by the e~perlaental. but not the control animals. The tlndlngs·so tar obtained ln Study Sere or interest ln several respects. The much greater 1nc1~ence ot "~t dog" or respon:;es 1n tho experimental ratsi observed at. 18 hours ab~t!nenee arA up to the time or the regular dally dose of morphine, aa well as t.he virtual dlsappeo.ranca ot these responses atter lnJcctlon ot morphine or lnnestlon of 1-G-2, suogc~t that they may be rollablc tndlcators or the morphine ~b$tln~nce 8-!h ·~ syndrooc ln this species. Earlier observnt!ons !n thls or a more sort. that nwct dogging" !abor~tory ea~~al ln~lcnte contlnuca at a hlgh tor two or three daY$ after abrupt r~te ot acrph!na and then grndually subsides to lnc!dQnees with~ra~~~ e~lblt~c by nonadd1ctcd rats ever a per1~d ot about two to three weeks. However. mere stud1cs ere needed to ~~nnt!tat!v• establish the re11cb111ty of this mcnsul"tt, and to correlate lt other phenomena tn these animals. Also, the ~1~h ab~t1nence curtou1 flndlng that water deprivation the incidence recu~s ot dogA responses ln acutcly·abst1nant rats to those o! ~~t control requires elucidation. an1~als1 or The generally h! gher b:.r•presslng rntcs exp.er!:nenta.l control in S may be to taetors other th~ 2n1~ats Stu~y ~ue than that postula.t.ed theorett.eally - that. "physical ~ely, or provides a "crlveu state through rcauctton d~p«r.dQncan whtch, drug behavlor "aucce$a!~l" seek!~g beco~cs relnforc~d. operation ot such other ls See~!ngly, th~ !actor~ su~sest~d .. by the data obtained on deprivation days, the ~ate~ wh~n bar-pressing rates wi t.h wnter re!nroreenu~nt exeeeaed those wlth 1·0·2 relntore~~ent1 not enty ln th~ control but al~o tn the e~~orl~cntal anl~als. This. however, may b~ due to th~ tact thct en days, both group$ ot ~ter d~prlvatlon ~~lmals _ .... . ::- • ~:. . . ~. . . bar-pressing rates wi t.h wnter re!nroreenu~nt exeeeaed those wlth 1·0·2 relntore~~ent1 not enty ln th~ control but al~o tn the e~~orl~cntal anl~als. This. however, may b~ due to th~ tact thct en days, both group$ ot ~ter d~prlvatlon ~~lmals _ .... . ::- • ~:. . . ~. . . . .. . . • · ,. : • l · eonsumc enough of tho 1-tl-2 aotu t.!on to produce v1 sl~l o morphine like effects wlthln four to seven minutes, after ~1ch thclr rates ot bar pressing dcclln~s sharply. en water 9at1atlon days, bar-pressing rates were much lower tn both groups, ~~d generally, ~ neither group eons~~cd enough 1·0·2 to affect the rates of ~ar or pressing. Under sueh clr~~stanccs, certain the evidence (Table 3) lndlcates that the I-G-2 Golut1on was re1n!ore1ng tor ths experimental grou;> only, but. evidence for a neat diserlm!natton between water and l·G-2 reinforcement eondltlons or by these anl~als was not obtained in thls ph~se the study (Table h.). As not.ed ear11cr, both of these studies are st111 In progress and lt ts hoped that more eonclusiv~ r~su1ts, either consonant or not consonant with the hypothesis, wlll be torthcol'lling ln the ncar tuture. SlJMZJAs1Y 1. £v1dence ln the literature 1s revtawed aupport!ng the at concept that~ in part lea~t, relapse 1s due to eond1t1on1ng factors, both ot the Aelass1eal" and "instrumental'• varlety operating durtng previous episodes ot addlct!on to narcotic drugs. !J--;;o . ' -- or 2. The :r.orphine•l1ke properties a new benzimidazole derivative (NIH-76G7 .- ~vqc 1-0-2) aro dE:scrJ.bcd ancl evidence ls presented that neither morphine add1~ted nor control rats dlsplny either preference for or aversion to a 5•meg/c1 aqueous or solution the drug, without dincrio!nntlva training. 3· T'~ studies ln progress are described, in which this concentration. ot 1-0-2 is being used as a re~n1'orc1ng agent in attempts to condition crug•seeking buhavtor in rats • ... ~ 1. W1k1er. A.: Recent Procress in Research on the Neurophysiological~ aasis ot Addiction. J. Psych!at., ~orph1ne A~. 105: 329•338, 1945. 2. Wlkler, A Study o! a Patient During ~~: Psyehodyn~~ic S~l.f•re.o ulated Readdtct.1on to ~!orphlne. The ?sychiat. Ouart., 26: 270-29J, 1952. 3. Wlltler, A.: Opiate Acdiction: Psychological and ,Neurophys!olo91cal Aspects 1n Relat!on t~ Cl1n1eal ?roble=s. c. c. Springtlcld, 1111nois. Thomas, 1953. 4• W1k1er A. Rasor, n. w.: Psyeh1atr1c A