Lisa H. Gold et al- Neurochemical Mechanisms Involved in Behavioral Effects of Amphetamines and Related Designer Drugs

8/3/2019 Lisa H. Gold et al- Neurochemical Mechanisms Involved in Behavioral Effects of Amphetamines and Related Designer Drugs

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ACKNOWLEDGMENTSThis review and research were supported in part by U.S. Public HealthService research grant DA 02632 and AA 05122. Mr. I.T. Sopko providedexport assistance in preparing the illustrations, the computerizedbibliographic data base, as well as in conducting the experimental work.a r.OS Neurochemical MechanismsYJausA.iczck,h.D. Involved in Behavioral Effects ofJennifer W. Tidey, B.S. A .,_L& _. and RelatedT fts.ive.ty mpnetam,nesford,MA02155 Designer Drugs

Lisa H. Gold, Mark A. Geyer, and George F. KoobINTRODUCTIONT he p sy cho activ e dru g 3 .4-m eth ylened io xym eth am ph etam in e (M DM A) h as

' become increasingly popular as an abused substance (Beck and Morgan1986; Peroutka 1987). Biochemically, MDMA is thought to releasesewtonin and to a lesser extent dopamine (Johnson et al. 1986; Nicholset al. 1982; Schmidt et al. 1987), while structurally, MDMA resembles bothmescaline and amphetamine (Nichols et al. 1986; Shulgin 1978). MDMA isthe N-methylated form of 3,4-methylenedioxyamphetamine (MDA), anothersubstituted phenylethylamine with psychotropic properties that may havecontributed to its popular name, "the love drug." MDA is considered to befrankly hallucinogenic and has been found to be highly toxic to serotonergicneurons (Ricaur te et al. 1985). Recently, long-term depletions of sero-tonergic markers have also been observed following single and multipleinjections of MDMA in experimental animals, indicat ing a neurotoxicpotential similar to that associated with MDA (Molder et al. 1987; Schmidt1987 ; Sto ne et a l. 1 986).Interestingly, some psychotherapists have been using MDMA to enhance thepsychotherapeutic process and to promote easy emotional communication intheir patients (Grinspoon and Bakalar 1986). MI)MA is characterized asevoking an altered state of consciousness with emotional and sensualovertones (Shulgin and Nichols 1978). This state is described as a pleasantstate of introspection, a highly controllable experience that invitesintensification of feelings (Grinspoon and Bakalar 1986) and greatlyfacilitates interpersonal communication (Nichols et al. 1986). Encouragedby these properties, the advocates of MDMA-assisted therapy argue thatMI)MA is a useful therapeutic tool. Unfortunately, sympathomimetic sideeffects are occasionally mentioned (Barnes 1988; Grinspoon and Bakalar1986; Shulgin and Nichols 1978), and concern over a potential to inducearrhythmias in individuals with underlying cardiac disease has been

100 expressed (Dowling et al. 1987).101


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has been hypothesized to result from release of dopamine from theTo better understand the behavioral effects of MDMA, this drug and various mesolimbic dopamine terminals in the region of the nucleus accumbens, butanalogs have been tested in several behavioral procedures in animals, other drugs with locomotor-activating properties may interact with otherSignificant abuse potential for MDMA was demonsuated by animal self- parts of the limbic-nucleus accumbens-ventral pallidal circuitry known to beadministration of MDMA (Beardsley et al. 1986; Lamb and Gri ffiths 1987) important for psychostimulant activation (Swerdlow et al. 1984; Swerdlowand a lowering of serf-stimulation thresholds by MDMA (Hubner et al. 1986).et al. 1988). MDMA has also been reported to generalize to amphetaminein drug discrimination studies, indicating that MDMA may have subjective Neural Substrates of Psychostimulant Reinforcementeffects similar to those of amphetamine (Evans and Johanson 1986; Kamienet al. 1986; Oberlender and Nichols 1988). A more complex mechanism of The locomotor-activating properties of psychomotor s timulants have beenaction has been suggested by one report of generalization to the serotonin hypothesized to be one aspect of thei r reinforcing properties (Muchaagonist fenfluramine (Schechter 1986) and another report that describeddrug-like responding following MDMA in rats trained on mescaline ........... _ ........

(Callahan and Appel 1987). Indeed, several authors have concluded that _._. ,o._ __... _' _f :_" _.

MDMA may produce discriminative stimulus effects that are different from _f" '_"_ !1" _'_ it_

bothstimulantsandhallucinogensGlennont al.1988;Oberlendernd [ '"' [Si ho, 'OCOMOTORACTIVITYANDPSYCHOSTIMULANTFFECTS .... Y_'-' -__Locomotor activity has histor ically been used as an index of psycho..........s timulant effects . Simple assessment of amount of locomotor activity can ................. _j__provide the basis for anatomical as well as pharmacological analysis of the .o[:r.. :r,.neural substrates that mediate the behavioral expression of stimulant action. : tMore sophisticated behavioral measurement systems can record multiple __f _j_.______.._ ! t __::::E;;_m ea su re s o f a ctiv ity an d d esc rib e sp atia l an d tem po ra l p attern in g o f lo co mo -tion. In such systems, qualitative aspects of behavioral activation can be __ _ -evaluated by examining the entire activity pro/de. A comparison of the '[ ' _ ' _ ;'-_ - _' ,_ _ '_ ,.._,.,_ _ _ .... ,....e ffec ts o f n ov el d ru gs w ith th ose p ro du ced by w ell-ch arac te rize d su bsta nc esm ay lead to a better u nd ers tan din g o f th eir m ech an ism s o f actio n an dsubjective properties. FIGURE 1. Effects of amphetamine, scopolamine, caffeine', and saline onlocomotor activity in rats with 6-OHDA lesions of theNeural Subs trates of Psychostimulant Locomotion nucleus accumbens or sham-operated controls(n=8 rats lgroup)The neural substrates of locomotor activation produced by psychomotorst imulants have been linked for some time to dopamine function in the *R_f_ toa dgniflc_tgroupefTe_nucleus accumbens. An early finding reported that direct injection of **Refer*to a significant difference between the groups at 10 minutes postinjeetion, simple main effects.dopamine into the nucleus accumbens produced enhanced locomotor activity ICE: Valuez in upper right corner of each panel represent mean + SEM for t he total activityin rats (Pijnenburg and Van Rossum 1973), and the unconditioned motor overthe2-hourrug teat.activ atio n pro duced by am phetam in e w as show n to be blocked by dop am inereceptor antagonists (Pijnenburg et al. 1975). Destruction of dopamine sotmc_: JoyceandKoob,1981.Copyright 1981. Springer-Vedas.terminals within the nucleus accumbens with 6-hydroxydopamine (6-OHDA)was found to attenuate the locomotion produced by indirect sympathomi-met ics (Joyce and Koob 1981; Kelly et al. 1975; Kelly and Iversen 1976) et al. 1982; Spyraki et al. 1982; Swerdlow and Koob 1984). Animals willbut not to dis rupt the locomotor-activating properties of caffeine, scopola- learn to prefer an environment previous ly associated with drags that producemine (Joyce and Koob 1981) (figure 1), corticotropin-releasing factor (CRF) hyperactivity, and pharmacological or surgical manipulations that block the(Swerdlow and Koob 1985), or heroin (Vaccarino et al. 1986) (figure 2) in locomotor-activating properties of psychomotor stimulants block this placerats. Thus, the loconiotor stimulation produced by psychostimulant drugs preference. The nucleus accumbens, which has been demonslxated to be

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LOCOMOTORESPONSE involved in a variety of the behavioral actions of stimulants and opiates,[ TO 0.5 mg/ko HEROIN(se} may act as a bridge betweenthe limbic systemand the extrapyramidal_ , o $ff motor system, integrating limbic influences and motor activity (Mogenson, 80HDA 2ooo[ and Nielson 1984; Swerdlow et al.o 2001-

1986).!f The reinforcing properties of psychomotor stimulants have also been linkedoeo to the activation of central dopamine neurons and their postsynaptic recep-

c_ __' __L!__ tors. When the synthesis of catecholamines is inhibited by administering

alpha-methyl-para-tyrosine, an attenuation of the subjective effects of100 euphoria associated with psychomotor stimulants occurs in man (Jonsson2a. et al. 1971), and a blockade of the reinforcing effects of methamphetamineoccurs in animals (Pickens et al. 1968). Furthermore, low doses of dopa-mine antagonists will increase response rates for intravenous injections ofd-amphetamine (Risner and Jones 1976; Yokel and Wise 1975; Yokel and

-5 Wise1976).20 40 80 80 100 120 140 160 180 Noradrenergic antagonists such as phenoxybenzamine, phentolamine, and

p ro pra no lo l h ad n o e ffe ct o n s tim ul an t (a mp he ta mi ne ) s el f-a dm in is tra ti onLOCOMOTORRESPONSETO 0.25 mo/kg d-AMPHETAMINE (DeWit and Wise 1977; Rimer and Jones 1976; Yokel and Wise 1976).'g _ o $H {sc) Wise and coworkers hypothesized that a partial blockade of dopamine

,-- \ J receptors produced a partial blockade of the reinforcing effects ofo 80/-/DA 2ooo d-amphetamine. Thus, animals were thought to compensate for decreases in\, 200 the magnitude of the reinforcer by increasing their self-administrationo _% WOO_l_ behavior. Similar resul ts have been observed with alpha-flupenthixol

(Ettenberg et al. 1982) and many other dopamine receptor antagonists,'_ including haloperidol, chlorpromazine, metoclopramide, thioridazine, ando -- sulpiride (Roberts and Vickers 1984). RecenQy, the selective D-1 antagonista. 1O0 __SX_ASH 60HDA SCH 23390 was shown to increase cocaine self-administration at doses that

I I ' I_

= did not impair motor function (Koob et al. 1987a), whereas spiperone, aD-2 selective compound, produced only small increases in responding at:_ doses close to those that produced motor dysfunction. These results suggestthat dopamine receptor blockade, particularly D-1 receptor blockade, may beinvolved in the reinforcing effects of psychomotor st imulants in rats. It20 ' '---':--_-- _t_40 60 80 100 120 140 160 180 should be noted, however, that the SCH 23390 compound failed to produceTime{rain) this action consistently when administered intravenously to rhesus monkeyss el f- adm in is te ri ng c oc ai ne (Woo lv er to n 1 98 6) .FIGURE 2. Effects of 6-OHDA lesions of the nucleus accumbens on the

locomotor response after SC injection of heroin (0.5 rog/kg) The role of dopamine in the reinforcing properties of psychomotor stimu-or amphetamine (0.25 mo/kg) lants was extended by the observations that 6-OHDA lesions of the nucleusaccumbens produce extinct ion-like responding and a significant and long-sJsain_ay auTe_teomsh_ grcop,p


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1982). Subsequent studies have shown that 6-OHDA lesions of the frontalcortex (Martin-Iverson et al. 1986) and corpus striatum (Koob et al. 1987b) AVERAGERESPONDINGdo not significantly alter cocaine self-administration. Interestingly, lesions 3 DAYSPOST-LESIONof specific subsets of the dopamine forebrain projections have been

associated with facilitated acquisition of amphetamine self-administration ._g'--:.5f :_3,_ __' 40

(Deminiere et al. 1984; Deminiere et al. 1988), suggesting that some _, ,__ - _ c _ 3 0specific neuropathology within the dopamine system could sensitize _ +_individuals to the reinforcing actions of psychostimulants, o = 20'.,_,These results, showing facilitated acquisition of psychostimulant self- ._ l0administration with lesions of subsets of the dopamine projections, empha- ShamCaudateN.Acc.size the need for other measures of reinforcement besides a continuousrein fo rce me nt sch ed ule. T o th is en d, rats th at h ad bee n tra ine d to se lf-administer cocaine intravenously were subjected to a progressive-ratio DOSERESPONSEprocedure following 6-OHDA lesion to the nucleus accumbens or corpus _ _ 100[striatum. The rats with a lesion of the nucleus accumbens showed a signi- '_ _ st _... 'rfibant decrease in the highest ratio for which they would respond to obtaincocaine (figure 3)(Koob et al. 1987b). Complementary results have been _ ::I_ __1 ..__llbtained using a similar progressive-ratio procedure in which rats with6-OHDA nucleus accumbens lesions increased significantly the highest ratios [._ 20 .........---;__or which they would self-administer apomorphine (Roberts and Vickers1988). This motivational probe thus avoids many of the problems associ- H.M.L. H.M.L. H.M.L.

ia ted wi th measuring local rates of responding. For example, the rats wi th Sham Caudate N. Acc.6-OHDA lesions showed a decrease in cocaine self-adminislxation while ona continuous reinforcement schedule that superficially could be interpretedas either a decrease or increase in the reinforcing value of cocaine. The PROGRESSIVEATIOresults in the progressive-ratio test suggest that this decrease in local rates .o _. aceof responding, previously observed with lesions to the region of the nucleus

accumbens, does in fact represent a motivational deficit. ___.6 30_-_-_'::'_;_i[] _ * u" "; 150

, ...L.-,c6+, 20 _ ._ 100_rz_..._jil Both amphetamine and cocaine have also been repor ted to support intra- .o_=_ lO '=_=_50]-[*'::_iil _sscranial self-administration in the mesolimbic/mesocortical dopaminergic 'E'_ ShamCaudateN.Acc _ ShamCaudateN.Accsystem. Rats will self-administer cocaine into the medial prefrontal cortex(Goeders and Smith 1983), while amphetamine is self-administered into the FIGURE 3. Effects of 6.0HDA lesions to the nucleus accumbens andorbitofrontal cortex of rhesus monkeys (Phil lips and Rol ls 1981) and the corpus striatum on respondingfor rats self-administeringnucleus accumbens of rats (Hoebel et al. 1983; Monaco et al. 1981). These cocainedata indicate that the mesolimbic/mesocortical dopaminergic system isinvolved in the initiation of stimulant reinforcement processes, and this work *Significantly differentromshamgroup,p


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(MDE) have been characterized and, the effects of these drugs compared Concomitant with this total increase in horizontal locomotion, MDMA (1.25with those of classic stimulants and hallucinogens (Gold et al. 1988). to 10.0 mg/kg) caused alterations in measures of investigatory behavior.Exploratory activity was monitored in eight setnu'ate behavioral pattern MDMA had a profound effect on the distribution of investigatory holepokesmonitor (BPM) chambers, each consisting of a 30.5 by 61 cm black Plexi- over time. Whereas the conlrol animals exhibited a decrease in the numberglas holeboard with three floor holes, seven wal l holes, and a steel of investigatory holepokes as they habituated to the chambers during thetouchplate 15 cm above the floor that detected rearings against the wall session, the MDMA-treated rats demonstrated an initial decrease in the(figure 4) (Geyer et al. 1986). The frequency of photobeam breaks was number of holepokes, followed by the tendency to increase investigatoryused as a general measure of motor activity, and the number and duration holepoking over time (figure 5B). Similarly, MDMA (1.25 to 10.0 rog/kg)of holepokes and rearings were cumulated, dramatically reduced the amount of rearing behavior measured. The amountand duration of this suppression of rearing was related to the dose of

f_l_ I MDMA studied (figure 5C). Rearing in rats treated with MDMA wasmarkedly reduced compared to control rat s during the fa'st 30 minutes.

-- _ More descriptive measures of the animals ' behavior were provided by

I [- _ o : cumulating entries into and time spent in each of nine unequally sizedL reg io ns, w hich inclu ded th e cen ter an d th e fo ur co rn er regio ns (Gey eret al. 1986). Accompanying these changes in the amount of rearing andI' _ o investigatory holepoking was an observable avoidance of the center of the_ [ l experimental chamber. Thus, a significant decrease in average duration ofenter entries for the first 30 minutes was obtained fol lowing MDMA doses

: of 1.25 to 10.0 mg/kg.__ _-__O__.i-]i~__Ii_I' _ _ I I O MDE, the N-ethyl derivative of MDA, produced a behavioral profile similaro that described for MDMA. MDE increased the number of crossoversmeasured during a 1-hour experimental session (figure 5A). A transienta. PHOTOBEANS b. SECTORS c. REGIONS decrease in the number of crossovers during the f irst 10 minutes in thechambers (0:549.1, 1.0:645.7, 3.0:313.1, 10.0:284.4) was noted for MDE at

FIGURE 4. Diagrammatic representation of the behavioral pattern monitor doses of 3.0 and 10.0 mg/kg. As with MDMA, the two highest doses ofchamber. The positions of the seven wall and threejToor MDE tested (3.0 and 10.0 mg/kg) significantly decreased the total numberholes are shown in each diagram of holepokes for the fi rst 30 minutes. Rearing was also suppressed bythese doses of MDE over a similar timecourso (figures 5B and 5C). At theKEY: a. lnfi'ared photobeams are a r ra nged ina C artesian Coordinatesystem on 7.6-cm centers 10 mg/kg dose of MDE, avoidance of the center was again observed as and are sampled five times per second.

b. Sector s are equal 15-cra squares and are used to define crossovers, a measure of significant decrease in the average duration of center entries.orizontal locomotion.c. Regions are unequa l in s ize and are used primarily to deme entriesin to thecenter For spatial pattern analyses, the data were reduced to sequences of X,Yregion and for the CV9analysis of spatial patterns of locomotion, posit ions as described elsewhere (Geyer et al. 1986). These sequences were

souRcE: Oeyer et al. 1987. Copyright 1987. Pergamon Press. used to produce video displays of the animal's position, rearings, andholepokes, which could be viewed from 1 to 20 t imes real-t ime speed. Thetransition frequency between any of five areas (two ends, center, and twoMDMA significantly altered the behavioral activity profile of rats. long wall areas) was calculated, as was the coefficient of variation (CV) forFigure 5A illustrates the timecourse of the effects of MDMA on crossovers the relative transition frequencies (Geyer 1982). A related but slightlyresolved into 30-minute blocks across the 2-hour test session. Doses of different procedure evaluated the sequence of position changes by calculat-1.25, 2.5, 5.0, and 10.0 mg/kg produced significant increases in crossovers, ing the number of occurrences of each of the 40 transitions among any of 9which remained elevated at the end of the session at the two highest doses specified regions. As an animal preferentially repeats certain transitions, thestudied. Interestingly, dur ing the first 10 minutes in the chamber (10 to 20 CV increases, while a more random pat tern produces a lower CV. The CVminutes postinjection), doses of 2.5 to 10 mg/kg did not significantly thus reflects the extent to which the animal establishes a preferred patternincrease crossovers, of locomotor activity over time.

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Both MDMA and MDE caused some obvious qualitative changes in the lo-comotor patterns of rats. At moderate to high doses of MDMA, a definiteMDMArog&g) MDEm_O) avoidance of the center of the experimental chamber was frequently seen,n0 D02o001.* _25 to and circling around the perimeter was the dominant behavior. This thigmo-2ooo s.o taxis is similar to that previously observed with apomorphine or scopola-

. / / ** [] s.o j lo.o ' ii,,00 ila - ,,00 imine (Geyer et al. 1986). Although most rats had a predominant directioni/LLA OO*OOnonmo__ revolutions. The impression of a disruption in locomotor patterns describedo2,_ above was corroborated by a significant change in the spatial CV measure.Both MDMA and MDE increased the spatial CV, which suggests a more500q i _ _ perseverative nature of locomotor patterns (table 1). In contrast, doses ofamphetamine (AMPH) that produced similar increases of horizontallocomotion tended to induce highly varied patterns of directional changes,3o so go _2o 3o 60 which were reflected in a reduced spatial CV (Geyer et al. 1986)._s'lj _so, Neural Substrates for the Psychostimulant Actions of MDMA. 0_ The neurochemical mechanisms for the stimulant properties of MDMA were

__i ***_* ' _00.. _ examined in a photocell cage apparatus following pharmacological and '

mo"':_ _ neurochemical manipulations. Locomotor activity was measured in a bank_x of 16 wire cages 20 cm by 25 cm by 36 cm, each cage with two horizontal_so , . infrared beams across the long axis 2 cm above the floor. Total photocellbeam interruptions and crossovers were recorded by a computer every 10minutes. Before the drug series, each rat was habituated to the photocell3o 5o _o _2o o cages overnight, and, prior to drug injection, the rats were habituated again30 60 to the photocell cages for at least 90 minutes.

_- A role for serotonin in the stimulant act ions of MDMA was tested by.. examining the effects in rats of the serotonin antagonist methysergide on?' _so, MDMA activation (Gold and Koob 1988). The locomotor-activating proper-

,' _i_ "_'' ties of MDMA, amphetamine, and methysorgide are seen in figure 6. Drag

_ * _ doses for amphetamine and MDMA were selected to produce similar in-'_ 100 * '_ 100'_ creases in activity, although MDMA appears to have a longer duration ofaction (Gold et al. 1988). Once the rats were habituated to the photocell

5o _ 50. _ apparatus, saline injection produced only transient arousal (lasting less than20 minutes) followed by relative inactivity (figure 6(2). MDMA at

o o 10 mg/kg produced an increase in beam interruptions that lasted for at least3o 6o _o _2o ao 6o 2 hours (figure 6A). Methysergide (2.5, 5, 10 mg/kg) significantlyC MinLKe$ Minutes potentiated the locomotor hyperactivity produced by MDMA (10 mg/kg)when compared to MDMA injection alone (figure 6A). This enhancementFIGURE 5. Timecourse effects ofMDMA (n=7 to 8 rats/group) and MDE of MDMA's locomotor effects was evident within the firs t 10 minutes and(n=9 to 12 rats/group) on A (crossovers), B (total lasted for the full 2-hour session. In contrast, methysergide only slightlyholepokes), and C (rearings)per 30 minutes in the BPM and nonsignificantly increased the locomotor hyperactivity produced by0.5 g/kg of amphetamine ( figure 6B). Methysergide alone at these doses'_xo.os. had no effect on locomotor activity (figure 6(2).

NOTE: Animals were injected 10 minutes before being placed in the c ha mbers. Effects of selecteddoses a re s hown as group means :/:SEM.110 111


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TABLE 1, Effects ofMDMA, MDE, and AMPH on spatial CV A ! ' ,'700 _,t;_;"" i 3o_Dose (mg/kg) CV5 CV9 _ og ....._,, i , o o o L L L L L I0 .485t:.02 _ soo .......MDMA 1.25 .709 + .1 _

MDMA.5 .730+.17 3 _ooMDMA 5.0 1.063 + .21 ' =MDMA 10.0 .995 +- .13' _ 300-_ 200e_

0 1.723 + .02 _ ,00MDE.0 1.737:.05MDE 3.0 2.209 + .18'MDB 10.0 2.007 + .11 i0 .522 + .04 _ _oo i ......... ' ':Il//IMPH 0.25 .379 + .06* = 40o : i ........ I 'AMPH0.5 .376:i:.03' _ _ /" _ .___ _AMPH.0 .373+.04* _ _0_k_'X_AMPH 2.0 .506 + .03 _ _0o*p


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A4oo0 In an additionalstudy, followingrecovery and saline injection, rats (sham:n=8, lesion: n=8)were injected with 0.5 ms/kg AMPH onday 9 or 10 and3ooo. 5 rog/kgMDMA 3 days later. On day 16 or 17 these rats received twoinjections: a serotonin antagonist,2.5 mg/kg methysergide;and 5 mg/kgMDMA. Rats were injected with 0.5 mg/kg AMPHon the next day and,

E 2o0o as in previous experiments,the locomotorhyperactivityproduced by AMPHo t ' was attenuatedin the group with6-OHDA lesions (figure 7B). The_ooo mean _+SEMs per 120 minutes for the sham and lesion groupswere1,995.9-t389.3and 906:k132,respectively. In the fa'st experimentdescribed

o. above,the means for these groups were 3,111.9t:421.8and 1,176.5+248.1,respectively. When the rats were injected with 5 mg/kg MDMA 3 days"_ Saline MDMA $ AMPH 0.S Salineo later, the sham-operatedgroup showeda large increase in locomotor activi-ty; this effect was significantlyreduced in therats with lesions. The-- Fi SHAMB m u_sr_ mean+ SEMs for the sham and lesion groups were 1,368+249.5ando 754.1-1-107.4,espectively. These values werenot different from those

401described in the first experiment (sham: 1,401.3.+_257.8,esion:-

a. 745.2+81.7). Therefore,a cross-sensitizationfrom AMPHto MDMAwas_ 3o0o not evident. On the next day, locomotor activity was measuredfollowingo injections of a serotoninantagonist and MDMA. Here, methysergide_- 2ooo_ V_ /IT potentiatedthe effects of MDMA. Both theeffects of surgery and theinfluenceof methysergidewere observed. However,a log transformationof

_i!'' _o thedataeliminatedhesignificantnteractionetweenhetwo,whichsuggests that the interactioneffect was due to scaling differences. Thus, the: response of both the sham rats and the mrswith lesions was increasedbySaline AMPH 0.5 MDMA 5 MDMA-mag the serotoninantagonist.

Drug Biochemicalanalysesof 6-OHDA-injectedanimalsrevealeda 93 percentF/GURE 7. Effectsof 5 rng/kgMDMA,0.5 mg/kgAMPH,or 5 depletion of dopamine. The tissue was assayed using electrochemicalMDMAplus 2.5 rog/kgmethysergideon lac.... rog/kg detection following separationby high-pressureliquid chromatography

' in ratswith6-OHDAor shamlesionsof thenucleus and comparedto control rats with sham lesions (sham=65.5+4.4,...... umowractivity (Felice et al. 1978),recorded asng/mgprotein in the nucleusaccumbensii_2" accumbens lesion--4.9+l.5; t(39)=23.4). A lesion was defined as complete if 75 percent*i,


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accumbens do not block caffeine, scopolamine, heroin, or CSF-induced etcharacterizedal.986). byWithanSDincreaseandnthertheallucinogens,diversityf locomotortheehavioralpatiemsPrOfileandiSlocomotor activation (Swerdlow and Koob 1985; Vaccarino et al. 1986). concomitant suppression of the exploration of novel and open areas (Adams9The neurochemical sites for psychomotor stimulant reward are likely to be and Geyer 1985a). When evaluated on this basis, MDMA and MDE arethe presynaptic dopamine terminals located in the region of the nucleus similar to hallucinogens in producing an avoidance of the center. Thiseffect is particularly notable in light of the simultaneous increases in theaccumbens, frontal cortex, and other forebrain structures that originate in the total amount of locomotor activity. Unlike LSD, however, MDMA pro-ventral tegmental area. Note, however, that intracranial self-administration duced a scopolamine- or apomorphine-like increase in perseverative andof cocaine is elicited from the frontal cortex, but not from the nucleus thigmotactic patterns of locomotion, reflected by increases in the spatial CVaccumbens (Goeders and Smith 1983). Thus, concomitant activation of measures. The MDMA profile was also similar to that of apomorphinestructures other than the nucleus accumbens may be an important part of insofar as both drugs reduced holepoking and rearing, behaviors that arethe circuitry involved in initiation of cocaine intravenous self-administration, increased by scopolamine. However, relative to apomorphine, the MDMA-as has been h yp oth esized fo r th e o piates (Sm ith and Lan e 1983 ; Sm ithet al, 1982). induced rotational patterns were less strictly unidirectional, and thereductions in investigatory responses were less complete. Rather, mostm ected with MDMA changed directions and exhibited investigatoryanimalsj . observedollowingIn addition, these neuropharmacological studies provide evidence to show responses at least occastonally, effects slmfiar to thosethat, in the rat, the neuml/neurochemical substrates for processing thereinforcing and stimulant properties of psychomotor stimulants may be variOUSprofilengendereddsesf scopolaminebyDMA(GeyerandDEetl.appears1986),oHence'beniquetheehavioralamonghesimilar, if not identical. Parallel manipulations using dopamine receptor various drugs that have been so characterized to date.antagonists and 6-OHDA lesions produce paral lel resul ts. How far thisparallelism continues in further processing is under current investigation; Investigation of the neurochemical substrates for the psychostimulant effectshowever, such an overlap brings additional impetus to earlier hypotheses of MDMA suggests a role for the mesol imbic dopamine system. Destmc-relating reinforcement and motor function (Glickman and Schiff 1967). tion of dopamine terminal fields in the nucleus accumbens significantlyattenuated the locomotor activation produced by MDMA. A similar bloc-The motor activation produced by MDMA and MDE has similarit ies to kade of amphetamine-induced locomotor hyperactivity is known and wasclassic psychostimulants, but also some important differences. In the BPM observed following amphetamine injection in these same rats. Such resultssystem, the stimulant-like properties of these drugs were reflected in support the hypothesis that at least one component of MDMA-induced_s do amine mediated and suggest that mesolimbic dopaminesignificant increases in horizontal locomotor activity measured across a wide hyperactivity ' P .......... -: ...... MDMA resembles otherdose range. Interestingly, medium to high doses of MDMA or MDE specifically is the critical sul_slraw, an u,,.* ,-,,j,produced_a transient decrease in horizontal locomotion for the first 10minutesl followed by a sustained increase. The increase in holepokes and classical psychostimulants like amphetamine and cocaine. Interestingly,rearings that typically accompanies the increase in ambulation seen with evidenCewhichn fOrinjectionfUnctionalofmphetamineCrss'sensitizatinfollowedwaSMDMAsuggestedinJectin'inhe study inamphetamine itself or other indirect sympathomimetics (Geyer et al. 1986)was not observed with MDMA or MDE. Instead, initial decreases in hole- The stimulant properties of MDMA were enhanced by the presence of apokes and rearings and a tendency to avoid the center were evident, a serotonin antagonist, methysergide. Thus, following serotonin-receptorbehaviot_} profile that is characteristic of hallucinogenic indoleamine or blockade, profound locomotor hyperactivity was observed. This result canphenylethYlamine derivatives (Adams and Geyer 1985a; Adams and Geyer be viewed as a disinhibition of the dopamine neurons from serotonin modu-1985h;Geyeret al. 1979). lation. ThesedataareconsistentwiththehypothesishatMDMAacts

predo min antly as a sero to nin ago nist w ith w eak d op am in e activ ity. In thisMDMA and MDE also produced locomotor patterns that differed signifi- , set ide did not potentiate the effect of amphetamine. However,cantly from other stimulants. Previous studies in rats have demonstrated stud.y._me, Y.', g_976' renorted that methysergide potentia?o locomouonI'iOUlSII_I _l. al,. \ / r -- 'that amphetamine-induced hyperactivity involves complex patterns of widely produced by 2 mg/kg amphetamine intraperitoneauY, in iact, andistributed locomotion with frequent directional changes (Geyer et al. 1986; enhancement of an amphetamine response after prior exposure to MDMAGeyer et al. 1987). In contrast, similar levels of behavioral activationproduced by scopolamine or apomorphine are associated with relatively has also been observed. It is possible that previous exposure to MDMAsmooth locomotor paths, in which the same movement patterns are frequent- may have resulted in neurotoxic damage to some serotonin neurons.Depletions of serotonin and its metabolites have been reported followingly repeated. Other stimulants, such as caffeine or nicot ine, increase theamount of locomotor activity without significantly altering its pattern (Geyer single injections of MDMA (Molder et al. 1987; Schmidt 1987; Stone

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et al. 1986). A decrease in sea:otonergic tone would also result in a is going to block the crossovers. But I don't know what methysergidedisinhibition of dopamine neurons and may explain the enhanced would block. I believe it would be incredibly interesting i f it would turnamphetamine response. Indeed, evidence for such a "functional lesion" has those rats into amphetamine-like rats, and they would explore and show lessbeen reported in an operant procedure in which MDMA-induced serotonin thigmotaxis and more nosepokes.depletion was found to potentiate its psychomotor st imulant effects (Liet al. 1986). In the case where amphetamine was given first , followed by QUESTION: How can you dissociate the locomotor effects from theMDMA, no change in responsiveness would have been expected, reinforcing effects? It has been agreed that lesions of the mesolimbicsystem affect locomotor activity and shown by Eberson with respect to theThe stimulation of locomotor activity by MDMA and the importance of dopaminergic system. How do you know you don't have a rat that ismesolimbic dopamine in this response reflect similarities with the prototype motorically compromised and can't press the lever to get the cocaine? Howphenylethylamine stimulant, amphetamine. It is important to note that these can you dissociate that from the reinforcement efficacy?parameters are frequently associated with rewarding aspects of drugs and

chug abuse. Additionally, the behavioral profiles of MDMA and MDE ANSWER: I think the only thing I can really argue strongly is that weshare certain characteristics with hallucinogen-like agents. This unique have made similar lesions in rats the lever pressed for heroin, so they aremixture of stimulus Properties and neurochemical actions may contribute to lever pressing in the exact paradigm as a reinforcer, and continue to takea dangerous behavioral toxicity and neurotoxic potential for drugs like heroin, although the cocaine self-administration extinguishes. I have a slideMDMAof a rat who keeps plugging along on heroin self-administration and at theDISCUSSION same time every other day is tested on cocaine. The paradigm was heroinon Monday, cocaine on Tuesday, heroin on Wednesday, cocaine on

QUESTION: Can you get animals to self-administer cocaine into the his heroin self-administration continued. This is one piece of evidence thatThursday. His cocaine self-administration was completely extinguished, yetn uc le us a cc umben s? looks like a real dissociat ion. The animals can lever press for anotherANSWER: No, I never tried that, but the l iterature there is complicated, as reinforcer, but they choose not to lever press for cocaine.you know. Animals will, however, self-administer cocaine into the frontal And the other part would be that they show locomotion with other drugs.cortex.lb Amphetamine is self-administered into the nucleus accumbens. It is just the indirect sympathomimetics where locomotion is blocked.Youi__ave t o know that we take out most of the mesocorticolimbic dopa- It could be said that the reason they are not pressing the lever for cocainemine, system with that lesion; we are not just takine out the nucleusnucleu s accumbens on my slide, of the is that it doesn't do anything for them. And then you get into a circuitcc_ns dopamine projection. I am very carefu_to put the r_ where it is the psychostimulant effects that produce the reinforcing effects.

I think the way Jim Smith and I have discussed this paradox is a follows: was a good extinction pattern and high levels of activity. I would considerCOMMENT: Your data showed that, at least with that one model rat , thereHe thinks that the frontal cortex has something to do with initiation of that to be a better piece of evidence.cocaine self-administration, and I think probably the whole system may beinvolved in maintaining the behavior once the animals have learned it. RESPONSE: Yes, it means that the animal is capable of moving aroundfor apomorphine. But then it gets subtle. In people, too, there is initially aQUESTION: Have you tried MDMA into the nucleus accumbens? high level of activity to exhaust residual dopamine stores and then theANSIVER: No, we haven't tried self-administration of MDMA. I am not activitygoesdowntoa verylowlevel.Theapomorphineanreinstatesure we would get rats to switch from cocaine to MDMA. some locomotion. I think the most convincing evidence is the heroin. It isn ot tru e m oto r a cti vit y.QUESTION: Have you had the oppor tuni ty to look at the impact of QUESTION: Do you have any explanation for sensitization within themethYsergide pretreatment on MDMA's effects on exploration and rearing? MDMA or the methysergide? There has been evidence of serotonergicinhibition.ANSWER: No, we just put that on the books. We would really like tolook in the behavioral pattern monitoring system. I predict that the lesion


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ANSWER: I think there are two ways to look at it. I would say one REFERENCESreason is MDMA doesn't look like amphetamine. Why doesn 't MDMAlook like amphetamine without any other chugs added on? The animal has Adams, L.M., and Geyer, M.A. A proposed model for hallucinogens basedthe psychedelic repertoi re, whatever that is, interfering. This is what Klans on LSD's effects on patterns of exploration in rats. Behav NeurosciMiczek and I were discussing. The animal perhaps has another behavioral 99:881-900, 1985a.repertoire interfering wi th the expression of motor activity, and that happens Adams, L.M., and Geyer M.A. Effects of DOM and DMT in a proposedto be that the animal is hanging close to the side of the cage and for what- animal model of hallucinogenic activity. Prog Neuropsychopharmacolever reason, if it is LSD-like, he doesn't want to go into the center because Biol Psychiatry 9:121-132, 1985b.it is frightening. He is hallucinating. I am speculating here. And if you Barnes, D. New data intensify the agony over Ecstasy. Science 239:864-then hake away that competing behavior or competing brain Gestalt of 866, 1988.psychedelic activity, then you are turning the drug into basically ampheta- Beardsley, P.; Balster, R.; and Harris, L. Self-administration of methylene-mine. That is one way of looking at it. dioxymethamphetamine (MDMA) by rhesus monkeys. Drug AlcoholDepend 18: 149- 15 7, 1986.Another way of viewing it would be as levers going off. Serotonin is Beck, J., andMorgan, P.A. Designer drug confusion: A focus on MDMA.inhibitory, dopamine is excitatory. That is naive, but there is evidence to J Drug Educ 16:287-302, 1986.Callahan, P.M., and Appel, J.B. Differences in the stimulus properties ofsuggest that in the neurochemislry of those compounds there has been akind of yin and yang. MDA and MDMA in animals trained to discriminate hallucinogens fromsaline. Society for Neuroscience Abstracts 13:1720, 1987.QUESTION: How do you explain MDMA sensitization for amphetamine? Creese, I., and Iversen, S.D. The pharmacological and anatomical substrates' of the amphetamine response in the rat. Brain Res 83:419-436, 1975.ANSWER: There is evidence that even one exposure of MDMA at Deminiere, J.M.; Simon, H.; Herman, J.P.; and Le Meal, M. 6-Hydroxy-l0 rog/kg can cause some serotonin neurotoxicity. Dr. Seiden has shown in (+)-amphetamine self-administration. Psychopharmacology 83:281-284,do pa min e lesio n o f th e d op am in e m eso co rtic olim bic cell bo dies in creasesDRL procedures with repeated exposure that there is more of anamphetamine-like effect after some of the serotonin has been depleted. 1984.D em in iere, J.M .; T ag hzou ti, K .; T assin , J.P.; L e M eal, M .; an d Sim on , H .QUESTION: Had you looked at that at all? Increased sensitivity to amphetamine and facilitation of amphetamine self-a dm in ist ra tio n a fte r 6 -h yd ro xy do pa min e le si on s o f th e a my gd ala .ANSWER: In terms of the biochemistry i tself, no, not at ali . Psychopharrnacology 94:232-236, 1988.D eW it, H ., and W ise, R .A . B lo ckad e o f co caine rein fo rcem ent in rats w ithCOMMENT: I am not sure the serotonin is inhibitory and dopamine the dopamine receptor blocker pimozide, but not with the noradrenergicexcitatory is all that naive. There were clinical studies published where blockers phentolamine and phenoxybenzamine. Can J Psychol 31:195-theyshowedthat serotoninagonistscouldcompletelysuppress theCNS 203, 1977.stimulant effects of amphetamine clinically in humans. So you may be Dowling, G.P.; McDonough, E.T.; and Best, R.O. "Eve" and "Ecstasy": Aseeingthe_rne thing. I amnot sure that it has to be a psychedelic reportof five deathsassociatedwith theuse of MDEAand MDMA.activity _ql_erimposed. It may simply be some kind of a synergistic JAMA 257:1615-1617, 1987.attenuatlll_n' Ettenberg, A.; Pettit, H.O.; Bloom, F.E.; and Koob, G.F. Heroin andcocaine intravenous self-administration in rats: Mediation by separateCOMMENT: Both Campbell and Harvey, in independent experiments, have neural systems. Psychopharrnacology 78:204-209, 1982.shown if you take away the serotonin input you can exacerbate the Evans, S., and Johanson, C. Discriminative stimulus properties ofpsychomotor stimulant effects of amphetamines. (+)-3,4-methylenedioxymethamphetamine and (+)-3,4-methylenedioxy-amphetamine in pigeons. Drug Alcohol Depend 18:159-164, 1986.RESPONSE: Yes, and there is some recent study too that was done by Felice, L.; Felice, J.; and Kissinger, P. Determination of catecholamines inLyness showing that i f the serotonin system is des_oyed, toxicity and rat brain parts by reverse-phase ion-pair liquid chromatography.self-administration of amphetamines are increased. There is a lot of J Neurochem 31:1461-1465, 1978.evidenc9 _thatsome of this interaction does occur at some level, but we Geyer, M. Variational and probabilistic aspects of exploratory behavior indon't know where yet. space: Four stimulant styles. PsychopharrnacolBull 18:48-51, 1982.

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Geyer, M.A.; Light, R.K.; Rose, GJ.; Petersen, L.R.; Horwitt, D.D.; Adams, Kamien, J.; Johanson, C.; Schuster, C.; and Woolverton, W. The effects ofL.M.; and Hawkins, R.L. A characteristic effect of hallucinogens on ()-3,4-methylenedioxymethamphetamine and ()-3,4-methylenedioxy-investigatory responding of rats. Paychopharmacology 65:35-40, 1979. amphetamine in monkeys trained to discriminate (+)-amphetamine from

Geyer, M.A.; Russo, P.V.; and Masten, V.L. Multivariate assessment of saline. Drug Alcohol Depend 18:139-147, 1986.locomotor behavior:. Pharmacological and behavioral analyses. Kelly, P.H., and Iversen, S.D. Selective 6-OHDA-induced destruction ofPharmacol Btochem Behav 25:277-288, 1986. mesolimbic dopamine neurons: Abolition of psychostimulant-inducedGeyer, M.A.; Russo, P.V.; Segal, D.S.; and Kuczenski, R. Effects of locomotor activity in rats. EurJ Pharmacol 40:45-56, 1976.apomorphine and amphetamine on patterns of locomotor and investigatory Kelly, P.H.; Seviour, P.; and Iversen, S.D. Amphetamine and apomorphinebehavior in rats. PharrnacolBiochem Behav 28:393-399, 1987. response in the rat following 6-OHDA lesions of the nucleus accumbensGlennon, R.A.; Yousif, M.; and Patrick, G. Stimulus properties of septi and corpus striatum. Brain Res 94:507-522, 1975.1-(3,4-methylenedioxyphenyl)-2.aminopropane (MDA) analogs. Koob, G.F.; Lc, H.T.; and Creese, I . D-1 receptor antagonist SCH 23390Pharmacol Biochem Behav 29:443-449, 1988. increases cocaine self-administration in the rat. Neurosci Lett 79:315-321,Glickman, S.E., and Schiff, B.B. A biological theory of reinforcement. 1987a.Psychol Rev 74:81-108, 1967. Koob, G.F.; Vaccarino, F.J. ; Amalric, M.; and Bloom, F.E. PositiveGoeders, N.E., and Smith, J.E. Cortical dopaminergic involvement in reinforcement properties of drugs: Search for neural substrates. In:cocaine reinforcement. Science 221:773-775, 1983. Engel, J., and Oreland, L., eds. Brain Reward Systems andAbuse.Gold, L.H.; Hubner, C.B.; and Koob, G.F. A role for the mesolimbic New York: Raven Press, 19870. pp. 35-50.d op am in e sy stem in th e p sy ch ostim ula nt a ctio ns o f M DMA .Psychopharrnacology, in press. Lamb, R., and Griffiths, R. Self-injection of d,l-3,4-methylenedioxy-methamphetamine (MDMA) in the baboon. PsychopharrnacologyGold, L.H. , and Koob, G.F. Methysergide potentiates the hyperactivity 91:268-272, 1987.produced by MDMA in rats. Pharmacol BiochernBehav 29:645-648,988. Li, A.; Marek, G.; Vosmer, G.; and Seiden, L. MDMA-induced serotonind ep letio n p oten tiate s th e p sy ch om oto r stim ulan t effe cts o f M DMA o n ratsGold, L.H.; Koob, G.F.; and Geyer, M.A. Stimulant and hallucinogenic performing on the differential-reinforcement-of-low-rate (DRL) schedule.behavioral profiles of 3,4-methylenedioxymethamphetamine (MDMA) and Society for Neuroscience Abstracts 12:609, 1986.N-ethyl-3,4-methylenedioxyamphe_unine (MI)E) in rats. J Pharmacol Exp Lyness, W.H.; Friedle, N.M.; and Moore, K.E. Destruction of dopaminergicher 247:547-555, 1988. nerve terminals in nucleus accumbens: Effect on d-amphetamine self-Grinspoon, L., and Bakaiar, J. Can drugs be used to enhance the administration. Pharmacol Biochem Behav 11:553-556, 1979.psychotherapeutic process? AmJ Psvchother 40:393-404, 1986. Martin-Iversen, M.T.; Szostak, C.; and Fibiger, H.C. 6-HydroxydopamineHoebel, B.G.; MonaCo, A.P.; Hemandez, L.; Aulisi, E.F.; Stanley, B.G.; and lesions of the medial prefrontal cortex fail to influence intravenous self-Lenard, L. Self-injection of amphetamine directly into the brain, administration of cocaine. Psychopharmacology 88:310-314, 1986.Psychopharmacology 81:158-163, 1983.

Mogenson, G.J., and Nielson, M.A. Nearopharmacological evidence toHollister, A.; Breese, G.; Moreton Kuhn, C.; Cooper, B.; and Schanberg, S. suggest that the nucleus accumbens and subpallidal regions contribute toAn inhibitory role for brain serotonin-containing systems in the locomotor exploratory locomotion. Behav Neural Biol 42:52-60, 1984.effects of d-amphetamine, j Pharmacol Exp Ther 198:12-22, 1976. Mokler, DJ.; Robinson, S.E.; and Rose.cms, J.A. (+)3,4-Methylenedioxy-Hubner, C.B.; Bird, M.; Rassnick, S.; and Kometsky, C. The threshold methamphetamine (MDMA) produces long-term reductions in brainlo werin g e ffec ts o f M DMA (ec sta sy ) o n b rain -stim ulatio n rew ard .Psyc'hOpharrnacology95:49-51, 1988. 5-hydroxytryptarnine in rats. Eur J Pharrnacol 138:265-268, 1987.M onaco, A .P.; H ernan dez, L.; and H oebel, B.G. N ucleus accu mben s: SiteJohnsofi; M.P.; Hoffman, A.J.; and Nichols, D.E. Effects of the of amphetamine self-injection: Comparison with the lateral ventricle. In:enantiomers of MDA, MDMA and related analogs on [sH] serotonin and Chronister, R.B., and DeFrance, J.F., eds. The Neurobiology of the[3H] dopamine release from superfused rat brain slices. Eur J Pharrnacol Nucleus Accumbens. Brunswick, ME: Haer Institute Press, 1981.132:269-276, 1986. p p. 3 3 8- 34 2 .Jonsson_iL.E. ; Anggard, E.; and Gunne, L.M. Blockade of intravenous Mucha, R.F.; van der Kooy, M.; O'Shaughnessy, M.; and Bucenieks, P.amphetamine euphoria in man. Clin Pharmacol Ther 12:889-896, 1971. Drug reinforcement studied by the use of place preference conditioning inJoyce, E.M., and Koob, G.F. Amphetamine-, scopolamine-, and caffeine- rat. Brain Res 243:91-105, 1982.

induced locomotor activity fo/lowing 6-hydroxydopamine lesions of the Nichols, D.; Lloyd, D.; Hoffman, A.; Nichols, M.; and Yim, G. Effects ofmesol imbic dopamine system. Psychopharmacology 73:311-313, 1981. certain hallucinogenic amphetamine analogs on the release of [_H]serotonin from rat brain synaptosomes. J Med Chem 25:530-535, 1982.


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NichOls, D.E.; Hoffman, AJ.; Oberlender, R.A.; Jacob, P.; and Shulgin, Schmidt, CJ.; Levin, J.A.; and Lovenberg, W. In vitro and in vivoA.T. 'Derivatives of l'(1,3-benzodioxol-5.yl).2.butanamine: Repre- neurochemical effects of MI)MA on striatal monoaminergic systems in ratsentatives of a novel therapeutic class. J Med Chem 29:2009-2015, 1986. brain. Biochem Pharmacol 36:747-755, 1987.

Ol_dl_adnd_R_.,and Nichols, D.E. Drug discrimination studies with MDMA Shulgin, A.T. Psychotomimetic drugs: Structure-activity relationships. In,amphetamine. P3'Ychophar#lacology95:71-76, 1988. Iversen, L.; Iversen, S.; and Snyder, S., eds. Handbook of Psychophar-Peroutka, S. Incidence of recreational use of 3,4-methylenedioxymetham_ macology. Vol. 11. New York: Plenum Press, 1978. pp. 1143-336.phetamine (MDMA, "Ecstasy") on an undergraduate campus. At Engl JMeal317:1542-1543, 1987. Shulgin, A.T. , and Nichols, D.E. Characterization of three newpsychotomimetics. In: Stillman, R.C. and WiUet te, R.E., eds. The

Phillips, A.G., and Rolls, E.T. Intracerebral seff-adminish,ation of Pharmacology of Hallucinogens. New York: Pergamon Press, 1978. pp.amphetamine by rhesus monkeys. Neurosci Lett 24:81-86, 1981. 74-83.Pickens, R.; Meisch, R.A.; and Dougherty, $.A. Chemical interactions in Smith, I.E.; Co, C.; Freeman, M.E.; and lame,/I.D. Brain neurotninsmitteramphetamine reinforcemenL Psychol Rep 23:1267-I270, 1968. turnover correlated with morphine-seeking behavior of rats. PharmacolPijnenburg, Ajj.; Honig, W.M.M.; and van Rossum, J.M. Inhibition of Biochem Behav 16:509-519, 1982.d-amphetamine induced locomotor activity by injection of haloperidol into Smith, J.E., and Lane, J.D. Brain neurotransmitter turnover correlated withtho nucleus accumbens of the nit. Psychopharmacologia (Berlin)41:87-95, 1975. morphine self-administration. In: Smith, $.E., and Lane, I.D., eds. TheAteurobiology of Opiate Reward Processes. Amsterdam: Elsevier, 1983.Pijnenburg, A., and van Rossum, 2. Stimulation of locomotor activityfollowing injection of dopamine into the nucleus accumbens, j Pharm pp. 361-402.Pharmacol 25:1003-1005, 1973. Spyraki, C.; Fibiger, H.C.; and Phi llips, A.G. Dopaminergic substrates ofamphetamine-induced place preference conditioning. Brain ResRicaurte, (3.; Bryan, G.; Strauss, L.; Seiden, L.; and Schuster, C. 253:185-193, 1982.Hallucinogenic amphetamine selectively destroys brain serotonin nerveterminals. Science 229:986-988, 1985. Stone, D.; Stahl, D.; Hanson, G.; and Gibb, J. The effects of3,4-methylenedioxymethamphetamine (lVlDMA) and 3,4-methylenedioxy-Risner, M., and Jones, B.E. Role of noradrenergic and dopaminergic amphetamine (MDA) on monoaminergic systems in the rat brain. Eur Jprocesses in amphetamine self-administration. Pharmacol Biochem Behav5:477-482, 1976. Pharmacol 128:41-48, 1986.Roberts, D.C.S.; Corcoran, M.E.; and Fibiger, H.C. On the role of conditioned locomotion, but not place preference. PsychopharmacologySwerdlow, N.R., and Koob, G.F. Restrained nits learn amphetamine-ascending catecholaminergic systems in intravenous seff-adminislration of 84:163-166, 1984.ocaine. Pharmacol Biochem Behav 6:615-620, 1977. Swerdlow, N.R., and Koob, G.F. Separate neural substrates of theRoberts, D.C.S., and Koob, GaY. Disruption of cocaine serf-administration locomotor-activating properties of amphetamine, heroin, caffeine andfollowing 6-hydroxydopamine lesions of the ventral tegmental area in rats.Pharmacol Biochem Behav 17:901-904, 1982. corticotropin releasing factor (CRF) in the rat. Pharmacol Biochem Behav23:303-307, 1985.Roberts, D.C.; Koob, G.F.; Klonoff, p.; and Fibiger, H.C. Extinction and Swerdlow, N.R.; Swanson, L.W.; and Koob, G.F. Substantia innominata:recovery of cocaine self-administration following 6-hydroxydopamine Critical link in the behavioral expression of mesolimbic dopamineesions of the nucleus accumbens. Pharmacol Biochem Behav12:781-787, 1980. stimulation in the rat. Neurosci Lett 50:19-24, 1984.

Roberts, D.C.S., and Vickers, G. Atypical neuroleptics increase self- subslrates for the motor-activating properties of psychostimulants: ASwerdlow, N.R.; Vaccarino, F .J .; Amalric, M.; and Koob, G.F. The neuraladminiswation of cocaine: An evaluation of a behavioral screen for review of recent findings. Pharmacol Biochem Behav 25:233-248, 1986.antipsychotic activity. Psychopharmacology 82:135-139, 1984. Vaccarino, F.J.; Amalric, M.; Swerdlow, N.R.; and Koob, G.F. Blockade ofRoberts, D.C.S., and Vickers, G. Increased motivation to self-administer amphetamine but not opiate induced locomotion following antagonism ofapomorphine following 6-hydroxydopamine lesion of the nucleus accum- dopamine function in the nit. Pharmacol Biochem Behav 24:61-65, 1986.bens. In: Kalivas, P.W., and Nemeroff, C.B., eds. The Mesocortico- Woolverton, W.L. Effects of a D1 and D2 dopamine antagonist on thelimbic Dopamine System. Vol. 537. New York: Annals of the NewYork Academy of Science, 1988. pp. 523-524. self-administration of cocaine and piribedil by rhesus monkeys.Pharmacol Biochem Behav 24:531-535, 1986.Schechter, M. Discriminative profile of MDMA. Pharmacol BtochemBehav 24:1533-1537, 1986. Yokel, R.A., and Wise, R.A. Increased lever pressing for amphetamineSchmidt, C. Neurotoxicity of the psychedelic amphetamine, methylene- after pimozide in rats: Implications for a dopamine theory of reward.dioxymethamphelamine. J Pharmacol Exp Ther 240:1-7, 1987. Science 187:547-549, 1975.

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Yokel, R.A., and Wise, R.A. Attenuation of intravenous amphetamine i'reinforcement by central dopamine blockade in rats. Psychopharmacology48:311-318,976. "ACKNOWLEDGMENTS ';

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This Work was supported in part by National Institute of Mental Health i'. Neuronal Actions of AmphetamineResearch Scientist Development Award MH00188, National Institute on ': in the Rat Brainrug Abuse Awards DA 02925 and DA 04398, and a Parkinson's Disease "Summe r F el lowsh ip .

Philip M. Groves, Lawrence J. Ryan, Marco Diana,AUTHORS Stephen J. Young, and Lisa J. FisherLisa H. Gold, B.S.Predoctoral Fellow INTRODUCTIONDivision of Preclinical Neuroscience and EndocrinologyDepartment of Basic and Clinical Research Amphetamine and related designer drugs have widespread actions on neu-Research Institute of Scripps Clinic renal activity in the brain. This is believed to be due in part to theLa lolla, CA 92037 enhanced release and blockade of reuptake of catecholamines (Kuczenski1983). The sites of action of such stimulant drugs of abuse include pre-Mark A. Geyer, Ph.D. synaptic neurons, by virtue of the action of released catecholamines onAssociate Professor of Psychiatry autoreceptors (Tepper et al. 1985), and postsynaptic targets of catecholamineDepartment of Psychiatry, T-004 axons, including neurons in the cerebral cortex, basal ganglia, cerebellum,University of California, San Diego reticular formation, and other neuron systems of the brainstem (Groves andLa Jolla, CA 92093 Rebec 1976).George F. Koob, Ph.D. The consequences of amphetamine administration include widespread neu-Associate Member renal pathology in the brains of experimental animals (Groves et al. 1987;Division of preclinical NeUroscienCe and Endocrinology Seiden and Kleven, this volume; Gibb et al., this volume) and significantDeparlment of Basic and Clinical Research changes in the pattern and intensity of neuronal activity throughout thebrain. One particularly useful approach to understanding the sites andResearch6Institute of Scripps ClinicLa Jells, CA 92037 mechanisms of action underlying the behavioral effects of amphetamine hasbeen to record the elect rophysiological consequences of amphetaminesadminislration in the rat brain (Groves and Rebec 1976; Groves and Tepper1983).

EFFECTS OF AMPHETAMINE ON CATECHOLAMINERGICNEURONSOne of the most widely known electrophysiological actions of amphetamineon the brain is to decrease the f'u-ingrate of dopaminergic and noradrenergicneurons recorded in vive from the rat brain (Bunney et al. 1973; Grahamand Aghajanian 1971). The underlying mechanisms include possible inhibi-tion by af ferent systems and by local inhibitory mechanisms involving localrelease of catecholamine (Groves et al. 1975). In the case of dopaminergic, neurons, this release occurs from dendrites, whereas, in noradrenergic nuclei,release occurs from axonal collateral innervation as well as from dendrites(G ro ves et al. 1979). T he effect o f am ph etam in e o n m on oam in e n eu ro ns is

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Lisa H. Gold et al- Neurochemical Mechanisms Involved in Behavioral Effects of Amphetamines and Related Designer Drugs