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									      Enhanced Neurobehavioral Effects of Cocaine
       With Chronic Neuroleptic Exposure in Rats
                                              by Therese A. Kosten




                                                                                                                                             Downloaded from http://schizophreniabulletin.oxfordjournals.org by on April 26, 2010
Abstract                                                              exposed patients with schizophrenia. This article presents
                                                                      evidence in support of this hypothesis.
Individuals with schizophrenia are often treated with
medications that block dopamlne (DA) neurotransmis-
sion. Chronic administration of many DA antagonists                   Dopamine (DA) Theory of
alters dopaminergic function, causing a supersensltiv-                Schizophrenia
ity to DA agonists. Because the DA agonist properties
of cocaine seem to be involved in its behavioral effects,             The antipsychotic effects of neuroleptic drugs were found
chronic DA antagonist treatments may enhance these                    to be potent treatments for schizophrenia in the 1950s
effects of cocaine. This article presents evidence to sup-            (Delay and Deniker 1952). At that time, however, the
port this hypothesis, as well as its implications for                 mechanisms of their therapeutic effects were unknown.
treating schizophrenia patients who abuse cocaine and                 Later research began to focus on the dopaminergic func-
suggestions for future research.                                      tion of these drugs and helped give rise to the DA theory
     Schizophrenia Bulletin, 23<2):203-213,1997.                      of schizophrenia, which postulated that schizophrenia
                                                                      may be mediated by abnormally high levels of DA.
                                                                      Support for the theory came from the observations that
Recent clinical studies indicate that cocaine abuse is a sig-         neuroleptics, which block DA transmission, alleviate
nificant problem among schizophrenia populations (Brady               some psychotic symptoms. Furthermore, the clinical
et al. 1990; Dixon et al. 1991). This dual-diagnosis phe-             potencies of these neuroleptic drugs were found to be cor-
nomenon seems inexplicable at first glance, given that                related highly with their affinity for DA receptors (Creese
cocaine use can cause psychoticlike behaviors, such as                et al. 1976). In addition, administration of drugs that
paranoia and hallucinations (Satel 1992). Moreover, a                 increase DA levels, such as amphetamine or L-dopa,
widely used animal model of schizophrenia posits a para-              sometimes produced symptoms similar to those seen in
digm of chronic exposure to amphetamine, a drug with                  schizophrenia, such as psychosis and paranoia (Bell
many pharmacological and behavioral similarities to                    1973). Indeed, this "amphetamine psychosis" effect was
cocaine. Thus, the abuse of cocaine in a person with a                the basis of assessing the locomotor activational effects of
schizophrenia diagnosis does not make sense at any level              chronic amphetamine administration in rats as an animal
of explanation, from the neurobiological to the behavioral.           model of schizophrenia (Snyder 1974).
However, a recent line of research in our laboratory has                   However, some data do not support the idea that the
begun to explore a possible neuropharmacological route                etiology of schizophrenia is related to a surplus of DA in
of inquiry that may help explain one basis of this dual               the brain. For example, neuroleptic drugs act at DA recep-
diagnosis. Our general hypothesis is that cocaine abuse               tors by blocking transmission soon after administration,
may be initiated and sustained more easily in persons who             yet their therapeutic effect—a decrease in psychotic
have been treated chronically with some neuroleptic                   symptoms—is usually not seen for several days or weeks
drugs. Such treatment seems to alter neural areas subserv-            (Spohn et al. 1977; Johnstone et al. 1978). There are also
ing drug reward in a way that may make the person more
sensitive to the effects of cocaine. Increased sensitivity to
                                                                           Reprint requests should be sent to Dr. T.A. Kosten, Ribicoff
the behavioral effects of cocaine may translate into                  Research Facilities, Rm. S-305, Connecticut Mental Health Center, 34
enhanced abuse liability of this drug among neuroleptic-              Park St., New Haven, CT 06508.




                                                                203
Schizophrenia Bulletin, Vol. 23, No. 2, 1997                                                                          T.A. Kosten




no data to support the idea that DA levels are higher in             in animals (Johanson and Fischman 1989). These behav-
patients with schizophrenia before they receive neurolep-            ioral characteristics include its ability to positively rein-
tic treatment, despite several attempts to find such a rela-         force self-administration behavior (Pickens and Thompson
tionship (Bowers 1974; Post et al. 1975; Berger et al.                1968), to support place conditioning (Carr et al. 1989), and
1980). Indeed, the data seem to suggest that DA turnover             to act as a discriminative stimulus (Colpaert et al. 1978).
may actually be lower in individuals with schizophrenia              Cocaine self-administration is a widely used model of
compared with controls (Karoum et al. 1987). Finally,                cocaine abuse (Pickens and Thompson 1968; Schuster and
current research has suggested that other neurotransmitter           Thompson 1969). In this operant conditioning paradigm,
systems may be involved not only in the etiology of schiz-           animals learn to make a response (e.g., pressing a lever in
ophrenia but also in the antipsychotic actions of neuro-             an operant chamber) to receive an intravenous infusion of
leptic drugs (Tamminga and Gerlach 1987).                            the drug. This behavior increases, presumably due to the
      Nonetheless, it is likely that some dysfunction in             positively reinforcing effect of these drug injections. Once




                                                                                                                                     Downloaded from http://schizophreniabulletin.oxfordjournals.org by on April 26, 2010
some DA systems is related to some aspects of certain                established, cocaine self-administration behavior shows an
schizophrenia symptoms. Moreover, neuroleptic drugs,                 inverted U-shaped dose response pattern in that lower
most of which block DA transmission, to some extent,                 doses lead to low responding, moderate doses are associ-
remain the pharmacological treatment of choice for schiz-            ated with increased response rates, and higher doses
ophrenia.                                                            decrease the response rate. The positive reinforcing or
                                                                     rewarding effects of cocaine are thought to underlie its
                                                                     ability to support place conditioning, another widely used
Behavioral Effects of Cocaine                                        animal model of cocaine effects (Carr et al. 1989). In this
                                                                     model, cocaine administration is paired with specific envi-
Cocaine has several behavioral effects. Moderate doses
                                                                     ronmental cues. How much the animal approaches or
stimulate locomotor activity, consistent with cocaine's
classification as a psychomotor stimulant. In animals,               avoids the cocaine-associated environment is then
high doses of cocaine can induce stereotypic responding,             assessed. In my experience, cocaine place conditioning
a motoric effect characterized by repetitive, in-place               also is associated with an inverted U-shaped curve, with
movements, such as head bobbing, weaving, or other                   moderate doses supporting the greatest degree of place
jerky movements (Lewander 1974). Repeated exposure to                conditioning. A third widely used animal model of the
the drug can enhance these motoric effects, a phenomenon             behavioral effects of cocaine is drug discrimination. In this
known as behavioral sensitization, such that lower doses             model, animals are trained to discriminate the presence or
of cocaine can elicit effects that are behaviorally equiva-          absence of a cocaine stimulus by differential lever selec-
lent to those seen originally with a higher dose or                  tion using a two-lever, food-reinforced operant task
increased responding to the same cocaine dose over time.             (Colpaert et al. 1978). Once discriminative stimulus con-
Thus, this phenomenon is often referred to as "reverse tol-          trol of behavior is established, the cocaine-occasioned
erance" because these effects are the converse of what is            responding to other cocaine doses occurs in a dose-related
often seen with repeated drug exposure (a decrease in the            manner, shows dose-related generalization to drugs of a
effectiveness of a dose or decreased responding to the               similar type (e.g., amphetamine), and does not generalize
same dose) as found in studies of morphine analgesia.                to drugs that are dissimilar to it such as (pentobarbital).
Behavioral sensitization has been suggested to be analo-                  Some of these animal models have been translated
gous to the development of cocaine-induced paranoia and              into the human laboratory. Researchers have found that
hallucinations in that these behavioral effects tend to              cocaine is self-administered in a dose-related manner
appear after chronic cocaine use and occur more readily              (Foltin and Fischman 1992), and its discriminative stimu-
after such exposure (Post and Kopanda 1976). Indeed,                 lus effects occasion dose-related responding in experi-
behavioral sensitization was first characterized with                enced cocaine users (Oliveto et al. 1995). Many studies
amphetamine, a drug that is simitar to cocaine in its phar-          use these models to test the involvement of neuropharma-
macological and behavioral effects. And because amphet-              cological factors in the behavioral effects of cocaine.
amine-induced psychosis in humans is believed to be
related to schizophrenia, the study of the behavioral and
pharmacologica] effects of chronic amphetamine exposure              Evidence for the Role of DA in the
in animals is a good model of this disorder.
                                                                     Behavioral Effects of Cocaine
     The reported euphorigenic effects of cocaine in
humans and its subsequent abuse potential are believed to            Many of the prominent behavioral effects of cocaine are
be related to other behavioral properties of cocaine studied         believed to involve the mesolimbocortical DA system



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Neurobehavioral Effects of Cocaine                                                      Schizophrenia Bulletin, Vol. 23, No. 2, 1997




(Koob and Bloom 1988; Wise and Rompre 1989). This                     increases in postsynaptic receptor binding (Burt et al.
pathway consists of DA cell bodies in the ventral tegmen-             1977; Seeger et al. 1982) and density in nigrostriatal
tal area (VTA) and its projection areas, including the                (MUller and Seeman 1978) and mesolimbic (i.e., NAcc)
nucleus accumbens (NAcc), medial prefrontal cortex                    structures (See et al. 1989), occurs in some dopaminergic
(mPFC), and other brain regions. Cocaine inhibits DA                  regions after long-term haloperidol treatment In addition
uptake into the presynaptic terminals through its actions at          to these postsynaptic effects, studies examining presynap-
the DA transporter (Harris and Baldessarini 1973). The                tic DA neurons in the VTA suggest that long-term DA
result is an accumulation of DA in the synapse of the                 antagonist treatment reduces the number of spontaneously
NAcc (Pettit and Justice 1989) and an enhanced stimula-               active cells, perhaps because of a state of depolarization
tion of these postsynaptic receptors. This ability of                 inactivation produced by the chronic blockade of post-
cocaine to enhance synaptic DA levels in this neural sys-             synaptic DA receptors (Chiodo and Bunney 1983; White
tem is thought to be related to its reinforcing (Ritz et al.          and Wang 1983). This depolarization inactivation seems




                                                                                                                                       Downloaded from http://schizophreniabulletin.oxfordjournals.org by on April 26, 2010
1987) and other behavioral effects (Spealman et al. 1989).            to be limited to DA neurons projecting to the NAcc and
     Consistent with these neuropharmacological findings,             does not include those projecting to the mPFC (Chiodo
DA antagonists tend to attenuate the behavioral effects of            and Bunney 1983).
cocaine, whereas DA agonists generally enhance these                       Long-term haloperidol treatment has several func-
behavioral effects (Woolverton and Johnson 1991). For                 tional consequences, including enhanced stereotypic
example, the neuroleptic and DA antagonist, haloperidol,              responses to DA agonists, such as apomorphine (Tarsy
partially blocks the behavioral effects of cocaine, includ-           and Baldessarini 1974; Seeger et al. 1982), amphetamine
ing its effects on intravenous self-administration (Roberts           (Rebec et al. 1982), quinpirole (LaHoste and Marshall
and Vickers 1984), drug discrimination (Colpaert et al.                1992), and cocaine (see below). Moreover, long-term
1978; Kleven et al. 1990; Callahan and Cunningham                     haloperidol treatment enhances the sensitivity to the
 1993), schedule-controlled behavior (Bergman and                     behavioral effects of cocaine in the place-conditioning
Spealman 1988), locomotor activity (Weiss et al. 1989;                and drug-discrimination procedures (Kosten et al. 1996;
Martin-Iverson and Reimer 1994), and place conditioning               see below). Consistent with these data are recent studies
(Kosten et al. 1996). In general, these behavioral studies            that find more rapid locomotor sensitization to cocaine
find that short-term haloperidol treatment is associated              with long-term haloperidol treatment (LeDuc and
with a partial attenuation of cocaine effects that may be             Mittleman 1993) and enhanced sensitivity to the effects of
due to the specific actions of haloperidol within the                 cocaine on schedule-controlled behavior after cessation of
mesolimbocortical DA system. That is, haloperidol may                 long-term administration of the DA antagonists, raclo-
act at postsynaptic DA receptors in the NAcc, but not in              pride and spiperone (Howell and Byrd 1992). Long-term
the mPFC. DA afferents projecting to the mPFC differ in               administration of the DA antagonist, SCH 23390, height-
many characteristics from those of the NAcc (see Roth et              ens stereotypic responses to apomorphine (Vaccheri et al.
al. 1987), and haloperidol does not seem to affect these              1987) and enhances sensitivity to the discriminative stim-
mPFC afferents as it does those projecting to the NAcc                ulus effects of the DA agonist, SKF 38393 (Gui-Hua et al.
(Thierry et al. 1986). This specific action of haloperidol in         1992). Moreover, enhanced behavioral effects of cocaine
the NAcc, but not in the mPFC, may be why some studies                have been found after long-term administration of
have failed to find an acute effect of haloperidol on the             SCH 23390 in some studies (Emmett-Oglesby and Mathis
discriminative stimulus (Barrett and Appel 1989; Witkin               1988; Kleven and Woolverton 1990), but not in another
et al. 1991) and place-conditioning effects (Spyraki et al.           (Howell and Byrd 1992).
1982) of cocaine.

                                                                      Long-Term Haloperidol Enhances the
Chronic DA Antagonist Treatment                                       Sensitivity to the Place-Conditioning
Leads to Neurobehavioral                                              Effects of Cocaine
Supersensitivity
                                                                      Based on the literature discussed above that long-term DA
Neurobiological research suggests that, whereas the                   antagonist treatment leads to neuronal supersensitivity
behavioral effects of cocaine may be attenuated partially             and is associated with enhanced sensitivity to the behav-
by short-term administration of many DA antagonists,                  ioral effects of DA agonists, my colleagues and I con-
long-term treatment may enhance these effects. For exam-              ducted the following experiments. We tested whether
ple, heightened functional responsiveness, including                  long-term administration of the classic DA antangonist.




                                                                205
Schizophrenia Bulletin, Vol. 23, No. 2, 1997                                                                                        T.A




haloperidol, would enhance sensitivity to the behavioral             Figure 1. Degree of conditioned place p
effects of cocaine using a place-conditioning procedure.             ence to cocaine (15 mg/kg Intraperito
This procedure was logical to use because we have had                shown by rats that had received daily hal
extensive experience with this paradigm using cocaine                dol Injections (1 mg/kg subcutaneous) 1
(Kosten and Nestler 1994; Kosten et al. 1994, 1996).                 days before and then continuing throuj
Haloperidol was the logical DA antagonist to try first,              place-conditioning training (closed bar) s
given the vast literature on its short- and long-term                rats receiving vehicle subcutaneous injec
effects. Rats were administered haloperidol (1 mg/kg,                (open bar) during these times
subcutaneously) or vehicle for 21 days before and during
training and testing of cocaine place conditioning in the
first study described below. In the second study, we
administered haloperidol in the drinking solution, based
on the method of See and Ellison (1990), for 30 days
before and during training and testing of cocaine place
conditioning. (This oral administration procedure resulted
in an average daily dose of 2.2 mg/kg, which was set
higher due to first-pass metabolism.) Continuation of
haloperidol administration during the cocaine training dis-
tinguishes these studies from many previous ones in
which the antagonist treatment was withdrawn before the                                                                      Hlloporidc*
                                                                                                        GROUP
effects of the DA agonist were examined. Maintenance of
the antagonist treatment is a better model of the clinical
situation in which stimulant abuse may occur while                   Place preference is shown as the amount of time (minutes) spen
                                                                     cocaine-paired side after place-conditioning training minus the ttrr
patients are on medications. Thus, these studies examined            there before training, wtth both sessions 30 minutes In length. The t
the combined effects of long-term pretreatment of a DA               dol-treated group showed significantly greater cocaine-conditlonc
antagonist, which presumably enhances the sensitivity of             preference than the vehicle-treated group.

at least certain aspects of the DA system, and of its short-
term effect of antagonizing certain effects of cocaine.
      In the first study, separate groups of rats (4 in each
group) were assigned to receive haloperidol or vehicle               effects of cocaine using lower cocaine doses (2.
injections as stated above. After 21 days of drug exposure,          mg/kg). Because these doses are normally below ti
the rats were trained in the place-conditioning procedure,           threshold for supporting place conditioning in ve
as described previously (Kosten and Nestler 1994; Kosten             treated rats, this study assessed whether chronic hal
et al. 1994, 19%) with 15 mg/kg cocaine intraperitioneal             dol administration would enhance the sensitiv
(i.p.). Rats received four training trials with cocaine and          cocaine. Our findings indicate that long-term halop
four with saline in which the cocaine administration was             treatment does enhance the sensitivity to the placen
paired with one side of the place-conditioning apparatus             tioning effects of cocaine, as these low doses were
and saline administration was paired with the other side             ble of supporting place conditioning in the halope
on separate days. During test days, the rats had access to           treated groups, but not in the vehicle-treated g
both sides, which differed in meir visual and tactile cues,          (Kosten etal. 1996).
for 30 minutes. We recorded the amount of time spent on                    Because these studies used a regimen of long
each side and compared the change in time spent on the               haloperidol administration that continued througho
cocaine-paired side after training with the time spent on            cocaine training and testing period, it was necessi
that side before training. As shown in figure 1, rats that           assess the effects of place conditioning to cocaine
had received haJoperidol spent more time on the cocaine-             the haloperidol was given during the training perioc
paired side after training than the group that had received          (i.e., acquisition) or during the testing period only
vehicle. This haloperidol group effect was significant,              expression). To study the effects of short-term halop>
(/(6) = 2.5; p < 0.05), suggesting that chronic DA receptor          treatment on the acquisition of place conditioni
blockade with haloperidol administration enhances the                cocaine, haloperidol or vehicle solutions were giver
rewarding properties of cocaine.                                     ing the training phase. Note that haloperidol (or its
      We also assessed the effects of long-term (30 days),           cle) was present during all training sessions (cocain
orally administered haloperidol on the place-conditioning            vehicle training days); thus, any possible behavioral




                                                               206
Neurobehavioral Effects of Cocaine                                                       Schizophrenia Bulletin, Vol. 23, No. 2, 1997




erties of the haloperidol would be masked (Shippenberg                responses on the injection-appropriate lever and receiving
and Herz 1988). Testing occurred in the absence of both               at least two reinforcers in a session for six consecutive
short-term haloperidol and cocaine administration in the              sessions. Once cocaine demonstrated stimulus control
acquisition study. For the expression study, separate                 over behavior, a cocaine dose-response function (0.3-17
groups of rats were trained in the place-conditioning pro-            mg/kg) was determined during one test session using a
cedure with either vehicle (0 mg/kg) or the two most                  multiple dosing procedure. In this procedure, rats were
effective cocaine doses (10 and 15 mg/kg) used in the                 injected with the first cocaine dose, and 10 minutes later, a
acquisition study. At the end of training, rats were given             10-minute test session began during which a maximum of
either vehicle or haloperidol solutions to drink for 3 days            10 reinforcers could be earned for completing FR10
to ensure that DA receptors would be occupied by the test             response requirements on either lever. Five minutes later,
day. The place-conditioning test was performed on the                 the second cocaine injection was given to bring the cumu-
third day of this treatment. The groups that received                 lative cocaine dose up to the second dose level, and test-




                                                                                                                                        Downloaded from http://schizophreniabulletin.oxfordjournals.org by on April 26, 2010
haloperidol during cocaine place-conditioning training                ing continued as before. This procedure was continued
(i.e., acquisition) showed an attenuation in its acquisition          until the cumulative cocaine dose reached either 10 or
as compared with the groups that received vehicle                      17 mg/kg.
haloperidol administration (Kosten et al. 1996). The                       Testing occurred under three conditions: vehicle,
groups that received haloperidol after cocaine place-con-             short-term, and long-term haloperidol administration.
ditioning training and during the test (i.e., expression) did         Rats were given the vehicle haloperidol solution to drink
not differ from vehicle-treated rats.                                 for 3 days. On the third day, a cocaine dose-response
      These results suggest that although the acquisition of          function was generated using the multiple dosing proce-
cocaine place conditioning is attenuated by haloperidol,              dure. Discrimination training continued for 4 days after
its expression is not Similar results have been shown with            this test day. At this point, the vehicle solutions were
context conditioning of locomotor activity to cocaine in              replaced by the haloperidol solution for 3 days. On the
that haloperidol (Weiss et al. 1989; Martin-Iverson and               third day, a second cocaine dose-response function was
Reimer 1994) and pimozide (Beninger and Herz 1986)                    generated as before. This 3-day administration procedure
blocked the acquisition, but not the expression, of condi-            was used to allow enough time for DA receptor blockade
tioned locomotor activity. That haloperidol attenuated the            to occur. At the completion of this short-term haloperidol
acquisition of cocaine place conditioning is consistent               phase of the study, discrimination training was suspended,
with known actions of haloperidol and cocaine in the                  and the rats were maintained on haloperidol and food
mesolimbic DA system and with many previous studies                   deprivation for 28 days. On the 28th day, a third cocaine
using other behavioral paradigms (see above). However,                dose-response function was determined as before.
this study is at odds with a previous report that found no                 Figure 2 presents the mean percent of cocaine-appro-
effect of haloperidol on place conditioning to cocaine                priate responding as a function of cocaine dose for two
(Spyraki et al. 1982), although procedural differences may            rats. The three dose-response functions shown are the
account for the discrepant results.                                   vehicle condition, the effects of acute (3 days) haloperidol
                                                                      administration, and the effects of chronic (28 days)
                                                                      haloperidol administration. After acute haloperidol admin-
Differential Effects of Chronic Versus                                istration, the cocaine dose-response curve shifted to the
Acute Haloperidol Treatment on                                        right of that determined in the absence of haloperidol
Cocaine Discrimination                                                administration. After chronic haloperidol administration,
                                                                      the cocaine dose-response curve shifted to the left of that
In this study, rats were trained to discriminate cocaine              determined in the absence of haloperidol administration.
(10 mg/kg) from saline under a fixed ratio 10 (FR10)                  These data suggest that acute haloperidol administration
schedule of food presentation. Fifteen minutes after                  attenuates the discriminative stimulus effects of cocaine,
cocaine injections, the completion of 10 responses on one             consistent with previous studies (Colpaert et al. 1978;
lever produced the delivery of a food pellet in a 15-minute           Kleven et al. 1990; Callahan and Cunningham 1993),
session during which a maximum of 50 reinforcements                   although not with some other studies (Barrett and Appel
could be earned. After i.p. saline injections, completion of          1989; Witkin et al. 1991). In contrast, chronic haloperidol
10 responses on the other lever produced a food pellet                administration enhances these effects, consistent with our
(times and maximum reinforcement were identical to the                place-conditioning data and with a previous report on the
cocaine sessions). The criterion for acquisition of the dis-          effects of chronic SCH 23390 on cocaine discrimination
crimination was completing at least 90 percent of the                 (Emmett-Oglesby and Mathis 1988).




                                                                207
Schizophrenia Bulletin, Vol. 23, No. 2, 1997




Figure 2. Percent of cocaine-appropriate                                          group given chronic haloperidol treatment showed
responding as a function of cocaine dose in rats                                  cantly greater stereotypy compared with the \
trained to discriminate cocaine (10 mg/kg                                         treated group, F = 23.67; df= 1,12; p < 0.0005. <
Intraperltoneal) from vehicle In a two-lever, food-                               dose had no effect. These results suggest that lo
reinforced discrimination procedure                                               haloperidol enhances the stereotypic effects of the
                                                                                  DA agonist, cocaine, similar to previous studies
                                                                                  effects of other DA agonists (Tarsy and Bald<
                                                                                   1974; Rebec et al. 1982; Seeger et al. 1982; LaHr.
                                                                                  Marshall 1992).
                                                                                       In contrast, we found that similar treatment
                                                                                  enhance the sensitivity to the locomotor activating
                                                                                  of cocaine. In fact, long-term haloperidol treatme
                                                                                  ally lowered horizontal, ambulatory activity. In thi
                                                                                  separate groups of rats (8 in each group) were give
                                                                                  cle or haloperidol solutions for 30 days. This adrr
                                                                                  tion continued throughout the subsequent test
                            1             10                100                   During the last week of the chronic haloperidol a
                          Cocaine Dose (mg/kg)                                    tration, the rats were adapted to the locomotor ch
                                                                                  for at least three 30-minute sessions. These chamt
                                                                                  circular and are designed to measure horizontal, s
Cocaine discrimination was assessed under three conditions: vehicle (open         tory activity, as described previously (Kosten et al.
squares), acute or 3 days (dosed squares), and chronic or 28 days (dosed
                                                                                  After 30 days of haloperidol (or vehicle) adminis
circles) of orally delivered hatoperidol administration. Compared to vehicle
conditions, acute halopendol administration was associated with a right-          rats received one i.p. cocaine injection per week at
ward shift, whereas chronic halopendol administration was associated with         the following doses: 0, 2.5, 5.0, or 7.5 mg/kg.
a leftward shift in the cocaine dose-response function. The former effect
likely reflects the ability of the DA antagonist, halopendol, to block the
                                                                                  cocaine doses were given in a counterbalanced des
behavioral effects of cocaine in the short-term. The latter effect can be         were chosen based on the fact that they were ass
explained as a chronic DA receptor blockade leading to a supersensltMty           with enhanced place conditioning (Kosten et al. 19
to the effects of the DA agonist, cocaine. This effect. In turn, enhanced the
sensitivity to the discriminative stimulus effects of cocaine.



                                                                                  Figure 3. Sum of stereotypy ratings
Long-Term Effects of Haloperidol on                                               across 30-minute test sessions that consis
Cocaine-Induced Stereotypy and                                                    six consecutive 5-mlnute rating periods
Locomotor Activity
We have assessed the effects of long-term haloperidol
treatment on the stereotypic and locomotor effects of
cocaine. Rats (in groups of 4 each) were maintained on
vehicle or haloperidol solutions, orally delivered as
described above, for 30 days. The stereotypic effects of
two doses of cocaine (10 and 15 mg/kg) were rated using
a scale modified from Ellinwood and Balster (1974) that
ranges from 1 (asleep) to 9 (dyskinetic-reactive). The pre-
sentation of cocaine doses was counterbalanced across
rats, and 1 week separated the two cocaine exposures.                                                         Cocaine DOM (nv*g)
Rats were brought into the test room and adapted to the
clear, Plexiglas testing containers for at least 15 minutes.
Cocaine injections were given and stereotypy ratings were                         The stereotypy rating scale ranged from 1 (asleep) to 9 (dyskine
                                                                                  trve). One group received orally delivered haloperidol (Hal) admir
made every 5 minutes for a 30-minute session by a rater                           for at least 30 days (dosed squares), and the other group was giv
blind to treatment condition. Long-term haloperidol expo-                         de (Veh) administration (open squares). Each group was teste
                                                                                  once each wttfi one of the two cocaine doses (10 and 15 mg/kg t
sure enhanced the stereotypic effects of cocaine. The
                                                                                  toneal) in a counterbalanced design with 1 week separating the
sums of the stereotypic ratings across the test sessions (six                     sessions. The Hal-treated rats showed significantly greater de
5-minute rating periods each) are shown in figure 3. The                          cocaine-induced stereotypy than the Veh-treated rats.




                                                                            208
Neurobehavioral Effects of Cocaine                                                                           Schizophrenia Bulletin, Vol. 23, No. 2, 1997




above). Locomotor activity was assessed in 30-minute                                      has also been associated with enhanced behavioral effects
sessions. As shown in figure 4, total locomotor counts                                    of cocaine. However, unlike in our procedure, the behav-
over these sessions increased by increasing cocaine dose,                                 ioral assessments in those studies were completed after
F = 8.28; df= 3,52; p < 0.0001. The haloperidol-treated                                   discontinuation of the DA antagonist treatment. Thus, it
group showed a small, but significant decrease in cocaine-                                would be of interest to determine whether such enhanced
induced activation overall, as evidenced by the significant                               behavioral effects of cocaine would be seen if DA antago-
group effect, F = 5.53; df= 1,52; p < 0.05. Although we                                   nist treatment is continued throughout the training and test
used different cocaine doses in the stereotypy and loco-                                  phases. This would be important for two reasons. First,
motor studies and only one of these effects was measured                                  DA antagonists have been suggested as potential treat-
per study, the enhancement of cocaine-induced stereotypy                                  ment agents for cocaine abuse, but these data would sug-
that occurs with chronic haloperidol exposure may have                                    gest that they would not be viable long-term medications
interfered with the animals' ambulatory activity. The                                     for this disorder. Second, perhaps one reason for the phe-




                                                                                                                                                            Downloaded from http://schizophreniabulletin.oxfordjournals.org by on April 26, 2010
expressions of these two motoric effects are incompatible                                 nomenon of cocaine abuse seen in schizophrenia patients
with each other, as stereotypic responding disrupts ambu-                                 is that chronic treatment with neuroleptic medications has
latory activity. Nonetheless, the enhanced behavioral                                     likely altered neural areas associated with drug reward
responding seen in drug discrimination, place condition-                                  (i.e., the mesolimbic DA system). These alterations could
ing, and stereotypy with chronic haloperidol administra-                                  make these patients more sensitive to the behavioral
tion occurs despite the tendency for this treatment to                                    effects of cocaine, a DA agonist. Increased sensitivity may
lower ambulatory activity.                                                                underlie an enhanced abuse potential for cocaine in this
                                                                                          population.
                                                                                                It would also be of interest to examine the effects of
Conclusions and Future Directions                                                         chronic versus acute administration of other neuroleptic
                                                                                          drugs. Although most neuroleptic drugs block DA trans-
Most of the behavioral data presented above, in which
                                                                                          mission, the degree to which they show affinity for the
enhanced behavioral effects of cocaine occurred, are seen
                                                                                          various types of DA receptors and for other neurotrans-
with chronic administration of the DA antagonist,
                                                                                          mitter systems varies (Tamminga and Gerlach 1987). In
haloperidol. Chronic administration of other DA antago-
                                                                                          addition, atypical neuroleptics, which are being developed
nist drugs, such as SCH 23390, raclopride, and sulpiride,
                                                                                          to avoid tardive dyskinesia and other conditions associ-
                                                                                          ated with chronic treatments, differ in their ability to
                                                                                          block other neurotransmitter receptors. Chronic adminis-
Figure 4. Total number of horizontal, locomotor                                           tration of one or more of these drugs may not be associ-
activity counts over four 30-minute test sessions                                         ated with enhancement of the behavioral effects of
in rats that received orally delivered haloperidol                                        cocaine. If so, these medications may be better treatments
(Hal) administration for at least 30 days (closed                                         for the dually diagnosed patient with schizophrenia, but
squares) and in rats that received vehicle (Veh)                                          more research is needed to assess this possibility.
administration (open squares)                                                                   One atypical neuroleptic that may be a potentially
                                                                                          good treatment choice for this population is clozapine.
1                                                                                         Clozapine has affinity for D,- and D2-like DA receptors,
                                                                                          as well as for D 3 and D 4 autoreceptors and for serotonin-2
    500
                —O--                                                                      (5-HT2A) and 5-HT2C receptor types (Farde et al. 1989;
                                                                                          Meltzer 1989; Canton et al. 1990). Our data suggest that
    400
                                                                                          short-term clozapine administration attenuates place con-
    300-
                                                                                          ditioning to cocaine (Kosten and Nestler 1994), consistent
                                                                                          with findings of a partial attenuation of the discriminative
    200-                                                                                  stimulus and self-administration effects of cocaine
                                                                                          (Vanover et al. 1993; but see Loh et al. 1982). The effects
    100
          -      2         0           2             4     6          8                   of long-term clozapine administration on behaviors main-
                               COCSXTM Dow (mo^tQ)                                        tained by cocaine are not known. Although the data are
                                                                                          ambiguous, some studies suggest that enhanced sensitivity
All rats were tested once each with lour cocaine d o s e s (0, 2.5, 5.0,                  to the behavioral effects of cocaine may not be seen with
7.5 mg/kg Intraperitoneal) in a counterbalanced design with 1 week sepa-                  long-term clozapine. Such treatment enhances D, receptor
rating the four test sessions. There was a dose-related increase in horizon-
tal locomotor activity with cocaine, with significantly less activity seen in the         binding and does not alter D2 binding in the NAcc (O'Dell
Hal-treated group compared with the Veh-treated group.                                    et al. 1990). Yet, significant increases in the density of D 2



                                                                                    209
Schizophrenia Bulletin, Vol. 23, No. 2, 1997                                                                          T.A. Kosten




binding sites are found in the mPFC after both long-term             American Journal of Psychiatry, 137:174-180, 1980.
clozapine and haloperidol treatments (Janowsky et al.                Bergman, J., and Spealman, R.D. Behavioral effects of
 1992). Long-term clozapine treatment does not alter basal           histamine HI antagonists: Comparison with other drugs
DA levels and does inhibit amphetamine-induced DA                    and modification by haloperidol. Journal of Pharma-
release in the NAcc, in contrast to long-term haloperidol            cology and Experimental Therapeutics, 245:471-478,
treatment, which decreased basal NAcc levels of DA in                1988.
one study (Ichikawa and Meltzer 1992), but not another
(See and Ellison 1990), and has no effect on amphetamine-            Bowers, M.B. Central dopamine turnover in schizophrenic
induced DA release in the NAcc (See and Ellison 1990;                syndrome. Archives of General Psychiatry, 31:50-54,
Ichikawa and Meltzer 1992). Behavioral responses to                  1974.
amphetamine after long-term clozapine treatment are                  Brady, K.; Anton, R.; Ballenger, J.C.; Lydiard, R.B.;
altered, but not in a manner consistent with an increase in          Adinoff, B.; and Selander, J. Cocaine abuse among schiz-




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sensitivity of dopamine receptors, as is seen with long-             ophrenic patients. American Journal of Psychiatry,
term haloperidol treatment (Rebec et al. 1982). However,             147:1164-1167, 1990.
long-term clozapine use is associated with enhanced loco-            Burt, D.R.; Creese, I.; and Snyder, S.H. Antischizophrenic
motion induced by the DA agonist, apomorphine, with no               drugs: Chronic treatment elevates dopamine receptor
effect on stereotypies, in contrast to long-term haloperidol         binding in brain. Science, 196:326-328, 1977.
administration that enhances both apomorphine-induced
locomotion and stereotypy (Seeger et al. 1982).                      Callahan, P.M., and Cunningham, K.A. Discriminative
                                                                     stimulus properties of cocaine in relation to dopamine D 2
     Clearly, more research is needed at various levels of           receptor function in rats. Journal of Pharmacology and
investigation from the molecular to the behavioral and               Experimental Therapeutics, 266:585-592, 1993.
clinical areas to ascertain the extent to which chronic
                                                                     Canton, H.; Verriele, L.; and Colpaert, F.C. Binding of
administration of antipsychotic medications alters the
                                                                     typical and atypical antipsychotics to 5-HT1C and 5-HT2
neural areas subserving drug reward and affects the subse-
                                                                     sites: Clozapine potently interacts with 5-HT1C sites.
quent behavioral effects to cocaine. Until this phenome-
                                                                     European Journal of Pharmacology, 191:93-96, 1990.
non is better understood, it may be advisable to consider
alternative antipsychotic medications for the dually diag-           Carr, G.D.; Fibiger, H.C.; and Phillips, A.G. Conditioned
nosed schizophrenia patient, such as one of the atypical             place preference as a measure of drug reward. In:
neuroleptic drugs. These alternative medications may be              Liebman, J.M., and Cooper, S.J., eds. The Neuro-
beneficial because chronic administration may not be                 pharmacological Basis of Reward. New York, NY: Oxford
associated with the neurobehavioral supersensitivity phe-            University Press, 1989. pp. 264-320.
nomenon discussed here. In addition, these medications               Chiodo, L.A., and Bunney, B.S. Typical and atypical
may be effective pharmacotherapies for the cocaine abuse             neuroleptics: Differential effects of chronic administration
disorder, although this possibility awaits further research.         on the activity of A9 and A10 midbrain dopaminergic
                                                                     neurons. Journal of Neuroscience, 3:1607-1619, 1983.
                                                                     Colpaert, F.C; Niemegeers, C.J.E.; and Janssen, P.A.
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                                                                    Acknowledgments




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Therapeutics, 266:780-789, 1993.                                    This work was supported by USPHS grants DA50-04060
Weiss, S.R.B.; Post, R.M.; Pert, A.; Woodward, R.; and              and 08227 from the National Institute on Drug Abuse and
Murman, D. Context-dependent cocaine sensitization:                 by the Abraham Ribicoff Facilities, Connecticut Mental
Differential effect of haloperidol on development versus            Health Center, State of Connecticut Department of Mental
expression. Pharmacology, Biochemistry, and Behavior,               Health.
24:655-661, 1989.
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chronic haloperidol treatment on A9 and A10 dopamine                The Author
neurons in the rat. Life Sciences, 32:983-993, 1983.
Wise, R.A., and Rompre, P.P. Brain dopamine and reward.             Therese A. Kosten, Ph.D., is Assistant Professor and
In: Rosenzweig, M.R., and Porter, L.W., eds. Annual                 Director, Behavioral Pharmacology Laboratory, Division
Review of Psychology. Palo Alto, CA: Annual Reviews,                of Substance Abuse, Yale University School of Medicine,
1989. pp. 191-226.                                                  New Haven, CT.




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