![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BEHAVIORAL PHARMACOLOGY
Centre de Recherche Pierre Fabre, Castres Cedex, France (F.C., J.B.); Department of Psychiatry, Alcohol and Drug Addiction Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas (W.K.); and Yaupon Therapeutics Inc., Radnor, Pennsylvania (M.K.)
Received for publication
January 5, 2007
Accepted
April 11, 2007.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
).
Rats that have been trained to discriminate fentanyl from saline can demonstrate an exquisite discrimination; the lever selection that is to be made early in the session is correct in nearly 100% of the sessions and occurs with great speed (short latency) and accuracy [the animal pressing the inappropriate lever little if at all before completing the first fixed ration (FR)10 schedule on the appropriate lever]. After having selected the appropriate lever, the rats continue to lever press, totaling some 1500 responses/session, which typically are all made on the appropriate, reward-associated lever (Colpaert, 1978, 1987; Colpaert and Janssen, 1984). This performance emerges after a training in the course of which all of the parameters progressively improve (Colpaert et al., 1980a,b, 2001), and it is presumably governed by an acquired "win-stay/lose-shift" rule (Harlow, 1949; Restle, 1958). In particular, the improvement of appropriate-lever pressing after lever selection has occurred and a first reward has been delivered reflects that the animal increasingly learns to continue to press the reward-delivering lever and to shift to the other lever when not rewarded. This win-stay/lose-shift and other rules (such as its opposite, win-shift/lose-stay) offer a powerful description of much of the behavior (e.g., foraging) that occurs in species ranging from insects to humans (Tremblay et al., 1998; Dietrich et al., 2001; Ferguson et al., 2001; Dietrich, 2003; Matsen and Nowak, 2004); with humans, the rules are considered as an attribute of consciousness (Harlow, 1949; Dietrich, 2003).
In rats that have been trained to discriminate fentanyl from saline, the injection of the antipsychotic haloperidol, not surprisingly, causes SL selection. Remarkably, however, after having selected the SL and having obtained a first food reward, the animals press the other lever, may again shift levers in the further course of the session, and eventually discontinue responding (Colpaert et al., 1977). Thus, while leaving the ability of conditioned stimuli to control (secondarily reinforced) behavior unaffected, haloperidol blocks the response control that is otherwise exerted by the primary reward; similar findings were obtained in saline-treated but nonrewarded animals (Colpaert et al., 1977; Colpaert, 1987). The haloperidol effect also occurred in rats discriminating the psychostimulant dl-cathinone from saline, indicating that the effect is not specific to the particular stimuli that are being discriminated (Goudie et al., 1986). Likewise, pimozide blocked the food-rewarded pressing of a single lever without affecting motor performance (Wise et al., 1978). These findings originated the anhedonia hypothesis of the role of dopamine in motivational and also cognitive processes (Wise, 2004; Berridge, 2007). In DD, the "shift" to the alternative lever after a reward has been obtained ("win"), constitutes a dramatic departure from the governing win-stay/lose-shift rule; where the effect occurs in a selective manner, we hereafter refer to it as "win-shift" induction.
Under the win-stay/lose-shift rule, a shift occurs if and when the organism loses. In one of the experiments reported here, DD-trained rats were treated with saline, allowed to select either lever, but they were given no reward; the experiment determined to what extent lose-shift effectively occurs under the conditions of the present study. Other experiments examined and compared the ability of antipsychotics and further central nervous system agents to induce win-shift while care was taken to ensure the behavioral specificity of the effect.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
), and the experimental protocol was approved (009) by the Institutional Ethical Committee. Apparatus. Experiments were conducted in standard operant conditioning chambers (model E10-10; Coulbourn Instruments, Lehigh Valley, PA) housed in light- and sound-attenuating enclosures that were ventilated by a fan, which also produced a masking noise. Each chamber contained a house light that was mounted above a food pellet receptacle located between two levers, which were situated 2.5 cm above the grid floor. Food pellets (45-mg dustless pellets; Bioserv, Frenchtown, NJ) were delivered by a pellet dispenser (model E14-12; Coulbourn Instruments). Scheduling of reinforcement contingencies, reinforcement delivery, and data recording were controlled by a MED Associates interface and WMPC software (MED Associates, St. Albans, VT) implemented on a desktop computer.
Drug Discrimination. The procedures have been described in detail previously (Colpaert and Janssen, 1984). After rats had initially been trained to complete an FR10 schedule for food reward on either of the two levers, drug discrimination training was instituted. Thirty minutes before every daily (5 days/week) 15-min "training" session, rats received an s.c. injection of either 0.04 mg/kg fentanyl or saline, and they could obtain food pellets by pressing (FR10) the DL or the SL, respectively. Responses on the inappropriate lever had no programmed consequences. The sum of the responses made on either lever before the first reinforcement (FRF) occurred was recorded. Every week, each rat was trained once a day, Monday through Friday. Daily drug (D) or saline (S) injections were given according to two monthly alternating sequences, i.e., 1) DSSDS, SDDSD, SDSDD, DSDSD, and 2) SDDSS, DSDSD, DSSDD, SDSDS. The discrimination was considered acquired when during 10 consecutive sessions the rat made at most two responses on the injection-inappropriate lever before the first reinforcement (and, thus, before having completed the first FR10 schedule on the injection-appropriate lever; FRF 
12).
"Test" sessions were run on Fridays only, whereas training sessions continued to be conducted on other days. During test sessions, the lever on which 10 responses accumulated first was defined as the selected lever and the FRF and the latency (in seconds) with which lever selection occurred, were recorded. Unless specified otherwise, after lever selection, the rat received a first food pellet, and subsequent reinforcement was made contingent upon pressing the selected lever. The number of responses made on both levers after lever selection and throughout the 15-min session was also recorded. To ensure the stability of performance and to avoid carryover effects of test conditions, testing was postponed to the next scheduled test day if 1) on either of the two most recent training days, the FRF value exceeded 15; 2) on either of the two most recent training days, the total response rate was less than 80% of that observed during the preceding training session of the same type (i.e., drug or saline); or 3) during the most recently preceding saline training session, the total number of responses was less than 500. In addition, test data were discarded and the test condition was later retested if the test session was followed by a training session of which the FRF value exceeded 15.
After the animals had reached the DD acquisition criterion and to familiarize them with the test procedure, a fentanyl dose response was conducted, involving tests with randomized 0.0025, 0.005, 0.01, 0.02, and 0.04 mg/kg doses of the training drug being injected s.c., 30 min before test sessions (data not shown). The experiments described below involved 89 rats that had reached this stage. The experiments called for various test conditions to which the animals were assigned randomly.
Although a priori any discriminandum and any discrimination procedure might be used for the purposes set out above, the experiments were conducted in fentanyl-saline-discriminating rats. This is because, in our experience with this procedure, it has proven difficult to obtain with other training drugs, or, for that matter, with external discriminanda, the degree of accuracy and reliability that can be achieved with fentanyl-saline discrimination. In addition, more so than most alternatives, the particular DD procedure used here usefully affords the assessment of different parameters in addition to stimulus discrimination.
Experiments. The experiments determined the dose-dependent effects of haloperidol and of other clinically established antipsychotics (i.e., chlorpromazine, thioridazine, raclopride, aripiprazole, nemonapride, ziprasidone, olanzapine, clozapine, and risperidone) as well as those of further agents currently being developed for the treatment of schizophrenia [i.e., F 15063 (Depoortère et al., 2007), bifeprunox, SLV313 (McCreary et al., 2007), and SSR181507 (Claustre et al., 2003)]. Also tested were compounds that may interfere with DD performance by different molecular and/or neurobiological mechanisms (see Discussion; e.g., scopolamine and dizocilpine) or that constitute useful tools in examining the possible involvement of some major neurotransmitter systems (e.g., ritanserin, naltrexone, and prazosin). Drugs were injected (n = 7/dose) either s.c. or i.p., as specified below, 60 min before the test session; 30 min before the session, and to conduct the tests in otherwise familiar training conditions (where either saline or 0.04 mg/kg fentanyl was injected s.c. at that time), saline was injected s.c.
To control for the drug tests described above, saline injections were given 60 min before the test session, either s.c. (n = 12) or i.p. (n = 10), followed by another (s.c.) saline injection 30 min before the session; here, as with drug tests, reward was delivered upon lever selection, and these animals are collectively referred to as "saline, reward" controls Two further conditions served to control for two nonpharmacologic manipulations. One condition examined the effects of withdrawing the primary reinforcer; rats were given saline either s.c. or i.p. (n = 7 in both cases) 60 min as well as 30 min (s.c.) before the session, and they were administered a test session as described above except that no food pellets were delivered upon selecting or pressing the selected, or, for that matter, the alternative lever (the empty food pellet dispenser nonetheless being activated and generating the same sound as that associated with actual food delivery, this condition is referred to as "saline, no-reward, sound"). In the DD paradigm used here, several stimulus conditions (e.g., injection procedure and introduction into the apparatus) predict or are associated with the eventual delivery of the food pellet/primary reinforcer, and they are potentially amenable to conditioning; one of these stimuli is the seemingly stark and salient sound produced by the pellet dispenser. Thus, another manipulation sought to explore the effects of dispenser-generated sound; rats were given an s.c. or i.p. (n = 7 in both cases) injection 60 min, and a s.c. saline injection 30 min before, and they were then administered a test session as described above except that the pellet dispenser was deactivated, delivering neither the pellet nor the sound ("saline, no-reward, no-sound"; collectively, the two latter conditions are referred to as "saline, no-reward").
Haloperidol and F 15063 excelled the other antipsychotics tested: they induced win-shift (see below) to the same (86%) extent to which maximal "lose-shift" was observed in saline, no-reward (control) animals; both compounds also maintained that effect at two consecutive doses (see Results). To examine the reproducibility of these findings, haloperidol and F 15063 were examined also in two different groups (n = 7/group) of newly trained rats that had not been tested before with any antipsychotic. In these further experiments, haloperidol and F 15063 were tested at incremental doses in an additional effort to minimize the possible carryover effects that might have occurred in the first series of experiments.
Data Analysis. Test sessions generated data on five variables: 1) the selected lever, i.e., SL or DL; 2) the latency to lever selection, i.e., the time between the start of the session and the occurrence of lever selection; 3) the FRF value, i.e., the total number of responses that were made on both levers before either lever was selected; 4) the percentage of responses on the selected lever after lever selection; and 5) the rate of responding after lever selection, i.e., the total number of responses made on both levers after lever selection divided by the number of seconds between lever selection and the end of the session. Effects on selection latency, FRF value, and percentage and rate of responses on the selected lever were examined for significance by comparing the mean value obtained during a test session with the mean control value of the five saline training sessions most recently preceding the test session by means of the Wilcoxon matched pairs signed rank test (NCSS, Kaysville, UT). In addition, the significance of effects in individual animals was evaluated by determining whether or not responding was within ±2 S.D. of the control values calculated from the five saline training sessions most recently preceding the test sessions. If a drug had significant effects in 50% or more of the animals, the dose that produced an effect in 50% of the animals (D50) was estimated by linear interpolation.
Win-shift was considered to have occurred when all of the following five conditions were met. 1) The animal selected the saline lever. Relative to the values calculated from the five saline training sessions that most recently preceded the test session, 2) the latency to lever selection and 3) the FRF were less than the mean + 2 S.D., and 4) the percentage of responses made on the nonselected lever after lever selection was more than the mean + 2 S.D. Finally, and avoiding that data be based on excessively small samples, 5) at least five of seven (or 71%) of the animals tested made a lever selection. These criteria were used to calculate for each treatment condition the percentage of animals showing win-shift.
Note that this composite operational definition not only requires that a shift occurred but also ensures as much as possible that the win occurred in a behaviorally selective manner. Indeed, antipsychotics can depress different behaviors, including total responding in the DD paradigm (Colpaert et al., 1977; Goudie et al., 1986), and all the parameters of the paradigm can be fully disrupted by different further agents and neurobiological mechanisms. A striking example is the deterioration by scopolamine of each of the parameters that are assessed before and after lever selection occurs and such that the behavior eventually resembles that seen at the very outset of discrimination training (Colpaert et al., 2001). With scopolamine, the shift thus is nonspecific; it and the other effects of the compound in the DD paradigm result from scopolamine causing state-dependent retrieval and a dose-dependent, regressive, temporally graded retrograde amnesia. Scopolamine eventually induces a failure to retrieve all that was learned in the paradigm, including the win-stay rule and the win itself (i.e., the instrumental relationship between appropriate lever pressing and obtaining the food reward; Colpaert et al., 2001; also see Koek et al., 1995).
For each drug, the maximal percentage animals showing win-shift was determined. The relationship between this maximum and the therapeutic classification of each drug as antipsychotic or nonantipsychotic was quantified by means of the point biserial correlation coefficient (NCSS). The results obtained during the different saline tests were analyzed by means of the Mann-Whitney U test (NCSS).
Drugs. Fentanyl citrate, haloperidol, S-(-) raclopride tartrate, chlorpromazine HCl, thioridazine HCl, clozapine, risperidone, (±)-8-hydroxy-2-(di-n-propylamino)tetralin HBr, phentolamine mesylate, chlorpheniramine maleate, prazosin HCl, propranolol HCl, naltrexone HCl, diazepam, (+)-dizocilpine maleate, and ritanserin were purchased from Sigma/RBI (Natick, MA), scopolamine HBr was purchased from Acros (Geel, Belgium), and cocaine HCl was purchased from Coopération Pharmaçeutique Française (Melun, France). F 15063, ziprasidone HCl, aripiprazole, nemonapride, olanzapine, bifeprunox (DU127090 [GenBank] ), and SSR181507 HCl were synthesized in house. SLV313 was kindly donated by Solvay Pharmaceuticals (Weesp, The Netherlands). Haloperidol, nemonapride, olanzapine, thioridazine, clozapine, risperidone, prazosin, ritanserin, and SLV313 were dissolved in distilled water with a drop of lactic acid, after which the pH was adjusted to 5 to 7 with 1 N sodium hydroxide. F 15063, aripiprazole, ziprasidone, diazepam, and bifeprunox were suspended in distilled water by adding Tween 80 (2 drops/10 ml). All other compounds were dissolved and administered in distilled water. Drugs and saline were injected in a volume of 1 ml/100 g; doses refer to the weight of free base.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
In (saline, reward) tests that controlled for drug administrations, SL selection occurred in 95% of the 22 animals, with a mean (S.E.M.) selection latency of 24 (3.3) s, a mean FRF value of 10.4 (0.26), a mean percentage of responses on the selected lever of 100 (0.01), and a mean rate of responding after lever selection of 2.04 (0.10) responses/s (Fig. 1, open circles labeled saline, reward). In addition, none of the animals failed to select a lever, and the percentage of animals with increased selection latency, increased FRF values, and decreased response rate after lever selection was 4.5, 9, 4.5, and 0%, respectively (Fig. 1, closed circles labeled saline, reward). Most importantly, only one rat (4.5%) demonstrated a decreased percentage of responses on the selected lever (i.e., "shifted" to the alternative lever), and win-shift thus occurred in 4.5% of the animals.
|
When saline was tested in the absence of both reward and feeder sound (saline, no-reward, no-sound; n = 14), the response rate after lever selection was even more decreased, to 0.33 (0.05) responses/s (P < 0.01), but none of the other measures were changed further. The combined results of all saline tests in the absence of reward (n = 28) are represented in Fig. 1 by the symbols labeled saline, no-reward. Most importantly, under these conditions, all 28 animals demonstrated a decrease in the percentage of responding that was made on the selected lever; four of them performed poorly on other measures (i.e., lever selection, FRF, or latency), so that a composite lose-shift criterion (identical to the win-shift criterion, but no food was actually delivered) was satisfied in 86, not 100% of the animals. In summary, after saline treatment, the composite criterion in rewarded and nonrewarded conditions was satisfied in 4.5% ("false positives") and 86% ("true positives") of the observations, respectively.
Detailed accounts of data obtained with different pharmacological agents are provided in Table 1 and Figs. 1, 2, 3 and 5; a summary of the win-shift results is provided in Figs. 4 and 6.
|
|
|
|
|
|
Haloperidol exerted no effect on the SL selection, the lowest percentage being 86% (Fig. 1, top left). As the dose of haloperidol was increased, the percentage of animals failing to select a lever increased, as did the lever selection latency; FRF was not significantly affected, and the percentage of responses on the selected lever as well as the rate of responding after lever selection were significantly decreased (Fig. 1, left). Note that the results obtained at intermediate doses of haloperidol were similar to the results obtained when saline was administered, but no food pellets were delivered (Fig. 1, saline, no-reward): in both cases, the behavior before lever selection occurred (i.e., SL selection, selection latency, FRF) was normal (i.e., similar to the behavior during saline training sessions), but the percentage of responses on the selected lever and rate of responding after lever selection were decreased.
All other antipsychotics had similar effects in that they tended to decrease the percentage of selected lever responding (i.e., to produce a shift) and the rate of responding after lever selection (see next-to-lowest and lowest panels, respectively, in Figs. 1, 2, 3). However, the doses at which these latter (postlever selection) effects occurred relative to those at which effects occurred on the other, antecedent parameters seemed to differ among the antipsychotics. Note that the further antipsychotics in Figs. 1, 2, 3 are shown in an order based on the number of doses that significantly decreased the percentage of responses on the selected lever. This number of doses ranged from five with aripiprazole to zero with clozapine and risperidone, in spite of the fact that clozapine and risperidone, like the other compounds, were tested up to doses that significantly increased lever selection latency as well as the percentage of animals that failed to select a lever.
Based on the results shown in Figs. 1, 2, 3, the percentage of animals showing win-shift (i.e., normal saline lever selection parameters, followed by increased responding on the nonselected lever) was determined (Fig. 4). The antipsychotics differed markedly in their ability to induce win-shift; the maximal percentage of animals showing win-shift ranged from 86% for haloperidol to 29% for clozapine and risperidone (Fig. 4; Table 1). Nonantipsychotics were either unable to produce win-shift, or they produced it in at most 29% of the animals (Fig. 4, inset; Table 1). Note that all nonantipsychotics, except phentolamine, chlorpheniramine, naltrexone and ritanserin, were tested up to and including doses that significantly increased lever selection latency. The maximal percentage win-shift obtained with the different compounds correlated significantly with their therapeutic classification as "antipsychotic" or "other" (Fig. 4, inset; point biserial correlation = 0.80, P < 0.0001). In this correlation, haloperidol seemed to be a significant outlier (externally studentized residual = 2.47), being more efficacious to induce win-shift than expected from the results obtained with all other compounds. Similar results were obtained with haloperidol when incremental doses were tested in a separate, newly trained group of rats that had not been tested before with any antipsychotic (Fig. 4, open triangles).
The effects of the potential antipsychotics F 15063, bifeprunox, SLV313, and SSR181507 were similar to those obtained here with established antipsychotics: all four compounds decreased the percentage of selected lever responding and the rate of responding after lever selection at doses lower than those affecting lever selection (Fig. 5; Table 1) and produced win-shift in 71 to 100% of the animals tested (Fig. 6; Table 1). The results obtained with F 15063 when incremental doses were tested in a separate group of newly trained rats that had not been tested before with any antipsychotic (Fig. 6, open triangles) were similar to those observed with random-ordered doses of F 15063 in rats that had been tested with other antipsychotics (Fig. 6, open circles).
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The results also confirm that when administered haloperidol, and in spite of obtaining food reward upon lever selection (win), the rats significantly shift responding to the alternative, nonreinforced lever (Colpaert et al., 1977; Goudie et al., 1986). The data extend this finding to other established antipsychotics albeit that the effect did not reach statistical significance with clozapine and risperidone. With several antipsychotics, the shift significantly occurred (Figs. 1, 2, 3; next-to-lowest panel) at doses that also began to impair lever selection, and any shift that clozapine and risperidone might possibly produce may have been masked by such an impairment.
Compounds in the present paradigm may produce a shift and, in fact, act to deteriorate some or all of the further four parameters that characterize behavior in this paradigm (see Materials and Methods); therefore, we analyzed the data (Figs. 4 and 6) to determine the extent to which antipsychotics may cause the shift in a behaviorally specific manner, i.e., in the absence of any significant effect on the parameters that characterize behavior before any shift can occur (that is, before lever selection).
This analysis shows that all established antipsychotics tested produced behaviorally specific win-shift; the extent to which they did so varied from 29 to 86% and starkly differentiated (P < 0.0001) antipsychotics from a host of other central nervous system agents. Some currently developed, putative antipsychotics also produced win-shift, and this to an extent that compared favorably with established antipsychotics. Thus, the ability to induce win-shift seems to constitute a distinguishing feature of antipsychotic agents.
The largest extent to which win-shift occurred with established antipsychotics was by 86%, and this occurred with two consecutive haloperidol doses (i.e., 0.04 and 0.08 mg/kg). That is, the animals, appropriately, selected the saline lever and did so with normal speed and accuracy; thereafter, the rats shifted to the alternative lever and little further responding on any lever occurred during the remainder of the session. The extent to which this occurred with haloperidol was identical to that (i.e., 86%) to which the omission of reward did so in saline-treated rats. This indicates that haloperidol can counteract the effects on behavior of (positive) primary reinforcement while leaving intact the (antecedent) behavior that is driven by conditioned, secondary reinforcement. Haloperidol demonstrated this capability in a complete manner over a 2-fold dose range; with higher doses, selectivity with haloperidol and other antipsychotics was compromised, causing the win-shift dose-response curve to reach asymptote or to assume an inverted U shape (Figs. 4 and 6). This suggests that all antipsychotics may perhaps be capable of inducing a shift but that the extent to which a selective win-shift is observed is obscured, to a varying degree, by other, detrimental effects.
The motor, extrapyramidal actions and sedation that DA antagonists may produce are unlikely to account for the present findings; behavior before the advent of reward was adequately initiated and performed normally, and the win-shift actually required the rats to "productively" initiate a behavior (i.e., alternative lever responding) that did not occur in (rewarded) saline-control conditions. There also is no apparent involvement of antipsychotic drug effects on memory; in fact, haloperidol-treated rats did not merely stop responding on the selected lever, and their alternative lever responding suggests that they actually continue to implement the acquired, lose-shift part of the rule. Although random responding and response bias can occur in the present paradigm (Colpaert, 1978), haloperidol at 0.04 and 0.08 mg/kg led all rats to select the saline lever and only then consistently press the alternative lever.
Whereas chlorpromazine produced (selective) win-shift in no more than 33% of rats, haloperidol here was particularly effective; it induced win-shift to an extent (i.e., 86%) that is identical to the maximal extent to which lose-shift occurred in nonrewarded saline-control animals, and it maintained that effect at two consecutive doses (see the surface under the curve in Fig. 4). Haloperidol has been described clinically as a particularly "incisive" antipsychotic (Bobon et al., 1972; Flach, 1975; Gerard et al., 1984), referring to the selective ability to reduce such productive features as delirium and hallucinations as opposed to inducing the prominent sedation that is characteristic of chlorpromazine (Simon et al., 1984; Colonna et al., 1989). Haloperidol blocks dopamine receptors selectively, contrasting with chlorpromazine's potent noradrenaline and histamine-antagonist properties (Niemegeers and Janssen, 1979; Leysen et al., 1993; Blin, 1999); thus, the differential extent to which haloperidol and chlorpromazine induced win-shift is consistent with a proposed incisive versus sedative discriminant in the analysis of clinical antipsychotic drug action (Simon et al., 1984). Interestingly, chlorpromazine and haloperidol are two of the only three antipsychotics that the World Health Organization considers as essential medicines. Having been introduced in 1958, haloperidol continues to be widely used, often as a first treatment option, both with newly diagnosed, acutely agitated patients and as a chronic therapy (Hamann et al., 2003); it also continues to serve as the comparator when new antipsychotics are introduced (Andrezina et al., 2006). The exceptional selectivity of haloperidol, both in inducing win-shift and in blocking clinical features of psychosis, are surprising inasmuch as the compound is known to potently induce extrapyramidal effects. However, in rats, D2-antagonist-induced catalepsy becomes prominent by a neuroadaptive, sensitization mechanism that develops after repeated injection (Schmidt et al., 1999); in schizophrenics, relative improvement declines with prolonged treatment (Kapur et al., 2005). Further work should determine to what extent haloperidol maintains its selectivity after repeated administration in the present conditions. The potential antipsychotics characterized here also induced win-shift to a relatively large extent (Fig. 6); like all established antipsychotics, these compounds act at D2 receptors (Leysen et al., 1993; Blin, 1999; Newman-Tancredi et al., 2007), but, in addition, they activate 5-hydroxytryptamine1A receptors (Depoortère et al., 2007). 5-Hydroxytryptamine1A receptor activation counteracts DA receptor blockade-induced catalepsy (Broekkamp et al., 1988). Conceivably, therefore, these compounds may share clinical antipsychotic features of haloperidol while avoiding sensitization to extrapyramidal effects.
That antipsychotics can selectively block the response control exerted by primary food reward has been demonstrated in the DD (Colpaert et al., 1977; Goudie et al., 1986) as well as in nondiscriminative paradigms (Wise et al., 1978; Ettenberg and Camp, 1986), and these agents reportedly block the reinforcing action of diverse rewards (Salamone et al., 2003; Wise, 2004). It is unclear whether antipsychotics can block the control of negative primary reinforcers in a similarly selective manner; in stark contrast with the present findings, in the conditioned (shock) avoidance paradigm, antipsychotics demonstrate an opposite selectivity, reportedly requiring doses to inhibit the conditioned response that are lower than or equal to, but never higher than, those inhibiting escape (Wadenberg and Hicks, 1999).
That antipsychotics block the response control by rewards suggests that their therapeutic action may in part consist of blocking the control that rewards, in schizophrenics, exert in a pathogenic, possibly excessive manner. One current theory suggests that excessive incentive learning is instrumental in causing such pathological features as delirium (Kapur et al., 2005; Schmidt and Beninger, 2006), but the role of dopamine and the effects of DA receptor blockade in reward-related processes remains complex and a matter of debate (Wise, 2004; Berridge, 2007).
In conclusion, in a two-lever, food-reinforced DD paradigm that is governed by a win-stay/lose-shift rule, antipsychotics induce win-shift; in spite of receiving food reward upon the selection of any lever, rats shift responding to the alternative, nonrewarded lever. The ability to induce behaviorally selective win-shift (i.e., in the absence of detrimental effects on secondarily reinforced behaviors) constitutes a feature that is specific to and perhaps a prerequisite for antipsychotics. Possibly relating to its alleged incisive action on delirium and hallucinations haloperidol demonstrates win-shift to an exceptional extent. It would be of interest for further studies to investigate the receptor mechanisms of win-shift and to similarly analyze antipsychotic drug actions while implementing negative reinforcement.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
ABBREVIATIONS: DD, drug discrimination; DL, drug-appropriate lever; SL, saline-appropriate lever; FR, fixed ratio; FRF, sum of the responses made on either lever before the first reinforcement; F 15063, (3-cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-amine fumarate; SLV313, 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine; SSR181507, (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine; DA, dopamine; D50, dose that produced an effect in 50% of the animals.
Address correspondence to: Dr. Francis C. Colpaert, Centre de Recherche Pierre Fabre, 17, avenue Moulin, F-81106 Castres Cedex, France. E-mail: francis.colpaert{at}pierre-fabre.com
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Andrezina R, Josiassen, Marcus RN, Oren DA, Manos G, Stock E, and Carson WH, and Iwamoto T (2006) Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with haloperidol. Psychopharmacology 188: 281-292.[CrossRef][Medline]
Berridge KC (2007) The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl) 191: 391-431.[CrossRef][Medline]
Blin O (1999) A comparative review of new antipsychotics. Can J Psychiatry 44: 235-244.[Medline]
Bobon J, Pinchard A, Collard J, and Bobon PB (1972) Clinical classification of neuroleptics, with special reference to their antimanic, antiautistic, and ataraxic properties. Compr Psychiatry 13: 123-131.[CrossRef][Medline]
Broekkamp CLE, Oosterloo SK, Berendsen HHG, and van Delft AML (1988) Effect of metergoline, fenfluramine, and 8-OD-DPAT on catalepsy induced by haloperidol or morphine. Naunyn-Schmiedeberg's Arch Pharmacol 338: 191-195.[Medline]
Claustre Y, Peretti DD, Brun P, Gueudet C, Allouard N, Alonso R, Lourdelet J, Oblin A, Damoiseau G, Francon D, et al. (2003) SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile. Neuropsychopharmacology 28: 2064-2076.[Medline]
Colonna L, Petit M, and Lépine JP (1989) Dictionnaire des Neuroleptiques, JB Baillière, Paris, France.
Colpaert FC (1978) Some properties of drugs as physiological signals: the FR procedure and signal detection theory, in Stimulus Properties of Drugs: Ten Years of Progress (Colpaert FC and Rosecrans JA eds) pp 217-242, Elsevier, Amsterdam, The Netherlands.
Colpaert FC (1987) Drug discrimination: methods of manipulation, measurement and analysis, in Methods of Assessing the Reinforcing Properties of Abused Drugs (Bozarth MA ed) pp 341-372, Springer, New York.
Colpaert FC and Janssen PAJ (1984) Agonist and antagonist effects of prototype opiate drug in rats discriminating fentanyl from saline: characteristics of partial generalization. J Pharmacol Exp Ther 230: 193-199.
Colpaert FC, Koek W, and Bruins Slot LA (2001) Evidence that mnesic states govern normal and disordered memory. Behav Pharmacol 12: 575-589.[Medline]
Colpaert FC, Niemegeers CJE, and Janssen PAJ (1977) Differential haloperidol effect on two indices of fentanyl-saline discrimination. Psychopharmacology 53: 169-173.[CrossRef][Medline]
Colpaert FC, Niemegeers CJE, and Janssen PAJ (1980a) Factors regulating drug cue sensitivity: limits of discriminability and the role of a progressively decreasing training dose in fentanyl-saline discrimination. J Pharmacol Exp Ther 212: 474-480.
Colpaert FC, Niemegeers CJE, and Janssen PAJ (1980b) Factors regulating drug cue sensitivity: the effects of training dose in fentanyl-saline discrimination. Neuropharmacology 19: 705-713.[CrossRef][Medline]
Depoortère R, Bardin L, Auclair AL, Kleven MS, Prinssen E, Colpaert F, Vacher B, and Newman-Tancredi A (2007) F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (II) Activity in models of positive symptoms of schizophrenia. Br J Pharmacol 151: 253-265.[CrossRef][Medline]
Dietrich A (2003) Functional neuroanatomy of altered states of consciousness: the transient hypofrontality hypothesis. Conscious Cogn 12: 231-256.[CrossRef][Medline]
Dietrich A, Taylor JT, and Passmore CE (2001) AVP(4-8) improves concept learning in PFC-damaged but not in hippocampal-damaged rats. Brain Res 919: 41-47.[CrossRef][Medline]
Ettenberg A and Camp HC (1986) Haloperidol induces a partial reinforcement extinction effect in rats: implications for a dopamine involvement in food reward. Pharmacol Biochem Behav 25: 813-821.[CrossRef][Medline]
Ferguson HJ, Cobey S, and Smith BH (2001) Sensitivity to a change in reward is heritable in the honeybee, Apis mellifera. Anim Behav 61: 527-534.[CrossRef]
Flach J (1975) Neuroleptiques: Vingt ans Après, p 277, Specia, Paris, France.
Gerard A, Loo H, Olie JP, and Zarifian E (1984) Séminaire de Psychiatrie Biologique, p 158, Fharmuka SF, Gennevilliers, France.
Goudie AJ, Atkinson J, and West CR (1986) Discriminative properties of the psychostimulant dl-cathinone in a two-lever operant task. Lack of evidence for dopaminergic mediation. Neuropharmacology 25: 85-94.[CrossRef][Medline]
Institute of Laboratory Animal Resources (1996) Guide for the Care and Use of Laboratory Animals, 7th ed. Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, Washington DC.
Koek W, Kleven MS, and Colpaert FC (1995) Effects of the NMDA antagonist, dizocilpine, in various drug discriminations: characterization of intermediate levels of drug lever selection. Behav Pharmacol 6: 590-600.[Medline]
Hamann J, Ruppert A, Auby P, Pugner K, and Kissling W (2003) Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription base. Int Clin Psychopharmacol 18: 237-242.[CrossRef][Medline]
Harlow HF (1949) The formation of learning sets. Psychol Rev 56: 51-65.[CrossRef][Medline]
Kapur S, Mizrahi R, and Li M (2005) From dopamine to salience to psychosis-linking biology, pharmacology and phenomenology of psychosis. Schizophr Res 79: 59-68.[CrossRef][Medline]
Leysen JE, Janssen PFM, Schotte A, Luyten WHML, and Megens AAHP (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo. Relation to pharmacological and clinical effects: role of 5-HT2 receptors. Psychopharmacology 112: S40-S54.[CrossRef][Medline]
Matsen FA and Nowak MA (2004) Win-stay, lose-shift in language learning from peers. Proc Natl Acad Sci U S A 101: 18053-18057.
McCreary AC, Glennon JC, Ashby CR Jr., Meltzer HY, Li Z, Reinders JH, Hesselink MB, Long SK, Herremans AH, van Stuivenberg H, et al. (2007) SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride): a novel dopamine D2 receptor antagonist and 5-HT1A receptor agonist potential antipsychotic drug. Neuropsychopharmacology 32: 78-94.[CrossRef][Medline]
Newman-Tancredi A, Assié MB, Martel JC, Cosi C, Bruins Slot L, Palmier C, Rauly-Lestienne I, and Cussac D (2007) F 15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: (I) in vitro receptor affinity profile. Br J Pharmacol 151: 237-252.[CrossRef][Medline]
Niemegeers CJ and Janssen PA (1979) A systematic study of the pharmacological activities of dopamine antagonists. Life Sci 24: 2201-2216.[CrossRef][Medline]
Restle F (1958) Toward a quantitative description of learning set data. Psychol Rev 65: 77-91.[CrossRef][Medline]
Salamone JD, Correa M, Minigote S, and Weber SM (2003) Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry and drug abuse. J Pharmacol Exp Ther 305: 1-8.
Schmidt WJ and Beninger RJ (2006) Behavioural sensitization in addiction, schizophrenia, Parkinson's disease and dyskinesia. Neurotox Res 10: 161-166.[Medline]
Schmidt WJ, Tzschentke TM, and Kretschmer BD (1999) State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801. Eur J Neurosci 11: 3365-3368.[CrossRef][Medline]
Simon P, Lecrubier Y, and Puech AJ (1984) Classification des neuroleptiques. Rev Prat 34: 589-594.[Medline]
Tremblay L, Hollerman JR, and Schultz W (1998) Modifications of reward expectation-related neuronal activity during learning in primate striatum. J Neurophysiol 80: 964-977.
Wadenberg ML and Hicks PB (1999) The conditioned avoidance response test reevaluated: is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci Biobehav Rev 23: 851-862.[CrossRef][Medline]
Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5: 483-494.[Medline]
Wise RA, Spindler J, and Legault L (1978) Major attenuation of food reward with performance-sparing doses of pimozide in the rat. Can J Psychol 32: 77-85.[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
