- Email: [email protected]
Haloperidol-induced supersensitivity to the discrimination of apomorphine
European Journal of Pharmacology, 74 (1981) 343-346 Elsevier/North-Holland Biomedical Press
343
H A L O P E R I D O L - I N D U C E D S U P E R S E N S I T I V I T Y T O T H E D I S C R I M I N A T I O N OF APOMORPHINE MARTIN D. SCHECHTER Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, U.S.A.
Received 9 April 1981, accepted 6 July 1981
M.D. SCHECHTER, Haloperidol-induced supersensitivity to the discrimination of apomorphine, European J. Pharmacol. 74 (1981) 343- 346. Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Once trained, the rats were tested with the EDs0 of apomorphine (0.02 mg/kg) or saline before and 1-22 days after a ten-day regimen of daily 2.0 mg/kg administrations of haloperidol. Chronic haloperidol treatment produced increased discrimination of, and lever selection perseverance to, the low dose of apomorphine when rats were tested at 12 days after the withdrawal of haloperidol and this increased discrimination returned to pre-haloperidollevels by the sixteenth day. The results suggest the development of supersensitivity by prolonged pharmacologic blockade of central dopaminergic receptors with haloperidol and indicate the peak and duration of this effect. Haloperidol
Supersensitivity Dopamine Apomorphine Drug-inducedstimuli
1. Introduction Numerous reports have indicated that apomorphine is capable of producing a discriminative stimulus complex in rats (Colpaert et al., 1975; 1976; Schechter, 1980) and it appears that the action underlying the ability of apomorphine to produce discriminative control of rat behavior is consistent with its dopamine-mimicking activity at postsynaptic d o p a m i n e receptors. Thus, discriminative control by apomorphine joins other behavioral paradigms that have been used to assess the dopaminergic activity of drugs, such as apomorphine-induced stereotypy (Jeste et al., 1979) and rotational behavior in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra (Ungerstedt and Arbuthnott, 1980). In addition, it has been reported that acute a n d / o r chronic treatment of rats with neuroleptic agents can elicit dopaminergic supersensitivity and, when this is attained, the effects of apomorphine challenge in both stereotypy and rotational behavior are increased. Thus, Tarsy and Baldessarini (1974) have reported that haloperidol administered for 11
Discrimination
days to rats p r o d u c e s hypersensitivity of dopaminergic neurons in the corpus striatum as manifested in the production of stereotyped behavior in response to subthreshold doses of apomorphine and Sayers et al. 91975) observed that a similar regimen of haloperidol administration increases the quantified rotational behavior of 6-OHDA-lesioned rats after apomorphine administration. The present investigation sought to determine the effects of apomorphine as a drug that controls discriminative performance in rats treated with chronic haloperidol administration. Thus, an ED50 of apomorphine was administered before and after a ten-day regimen of haloperidol administration to test the ability of this low dose to produce discriminative control in rats trained to discriminate between 0.16 m g / k g apomorphine and saline. A relatively new behavioral procedure, known as extended schedule performance (Schechter, 1981), was employed to indicate the strength of the discriminative cue at the lower apomorphine dose and the time course for the dopaminergic supersensitization effect was investigated.
0014-2999/81/0000-0000/$02.50 © 1981 Elsevier/North-Holland Biomedical Press
344
2. Materials and methods
2.1. Subjects The subjects were 4 male ARS/Sprague-Dawley rats weighing 260--+ l0 g at the beginning of experimentation. They were housed in individual living cages and their weights were adjusted (by daily rationing of rat chow) to approximately 85% of their free-feeding values as determined by daily weighing of a control free-feeding rat purchased from the supplier (Zivic-Miller, Allison Park, PA) at the same time. Water was continuously available.
2.2. Apparatus The experimental space was a standard rodent Skinner test cage (Lafayette Instrument Co.) equipped with 2 operant levers placed 7 cm apart and 7cm above the grid floor. A food pellet receptacle was mounted 2 cm above the grid floor at an equal distance between the levers. The test cage was housed in a sound-attenuating cubicle equipped with an exhaust fan and house light. Solid-state programming equipment (LVB Corp.) was used to control and record the sessions and was located in an adjacent room.
2.3. Training procedure The procedure used to train rats to discriminate between apomorphine and saline has been described in detail elsewhere (Colpaert et al., 1976). Briefly, rats were magazine-trai~aed and shaped to lever press on an FR-10 schedule of food reinforcement. Once animals were reliably responding, they were injected on a daily basis with either apomorphine (0.16 mg/kg, as base) or an equal volume of saline (1 ml/kg) on alternating days and trained to press one lever after receiving the injection of the drug and the other lever after the administration of saline. Injections were made 30 min prior to the animals being placed into the experimental space and 10 responses on the appropriate lever resulted in the delivery of a 45 mg Noyes food pellet. Responses on the incorrect lever did not result in reinforcement. Training
trials were conducted on 5 days a week with apomorphine or saline injected on an alternating schedule.
2.4. Extended schedule testing Once an animal made no more than 2 responses on the incorrect lever before making l0 responses on the correct lever for 10 consecutive days it was considered to have met the criterion for discrimination. Thereafter, training sessions of 15 min duration with alternating administration of freshly prepared apomorphine or saline were continued on Mondays, Wednesdays and Fridays for the remainder of the experimentation. On Tuesdays and Thursdays, the rats were administered either the training dose of apomorphine or saline and 30 min later they were placed in the experimental chamber and were allowed to lever press, in extinction, until 10 responses were made on the lever that was not the first lever selected. Thus, for example, when a rat pressed the apomorphine lever (AL) 10 times that lever was designated as the 'selected lever' and the rat was allowed to continue pressing, without reinforcement, until it accumulated 10 presses upon the saline lever (SL). The number of lever presses made on the AL prior to 10 presses on the SL was recorded. Likewise, if the SL was the selected lever, the rat was allowed to continue pressing until 10 responses were made on the AL. These extended schedule performance measurements (Schechter, 1981) were conducted in 2 trials each with the training dose of apomorphine and with saline.
2.5. Chronic haloperidol administration In a previous study investigating the doseresponse effects of various doses of apomorphine in the same behavioral paradigm, it was established that 0.02 mg/kg was the EDso of apomorphine (Schechter, 1980). Therefore, this dose was administered on different randomlyassigned test days to all animals on 2 occasions each and the animals were tested according to the extended schedule performance described. Subsequently, the rats were administered 2.0 mg/kg haloperidol intraperitoneally daily for a 10-day
345
period without continued training. After this chronic treatment, the EDs0 for apomorphine was administered to each rat 48 h after the last haloperidol dose and on every fifth following day for a 22 day period. To control for the possible effects of time on performance deficits, saline was likewise tested on every fifth day following the chronic administration of haloperidol. On each trial, the lever pressed 10 times first was designated as the selected lever and perseverance, in extinction, was determined.
3. Results
The perseverance of lever pressing after the administration of 0.02 mg/kg apomorphine and saline, before and 1-22 days following chronic haloperidol treatment, is presented.in table 1. Prior to haloperidol treatment, the 0.02 mg/kg dose of apomorphine administered on 2 trials to each rat produced first lever-selection (pressed I0 times) on the apomorphine lever (AL) in 50% (4 of 8) trials with a mean perseverance of 11.0 responses on the
AL prior to the accumulation of 10 responses on the saline levels (SL). Saline administration resuited in all first choice responses on the SL with a mean perseverance of 125.3 responses, whereas 0.16 mg/kg apomorphine (not shown in table) produced all AL first selections with a mean perseverance on that lever of 121.9 responses (-+-78.8) and no responses on the SL prior to 10 responses on the AL. For the 3 week period after the chronic administration of haloperidol, saline administration continued to produce solely first choice lever selection upon the SL with a significantly greater perseverance upon that lever than upon the AL. This indicated that, although training trials with apomorphine and saline did not continue for this period, no decrease in saline discrimination occurred. During the same post-haloperidol period, the EDs0 apomorphine dose produced AL first choice selections of 25-100% with the maximal AL selection occurring on the 12th day after haloperidol withdrawal.
TABLE 1 Perseverance of lever pressing in a discrimination between a subthreshold dose of apomorphine and saline prior to and after chronic haloperidol treatment. AL responses prior to 10 SL presses ( ± S.D.)
AL selections/ trials conducted
SL responses prior to 10 AL presses (+__S.D.)
0
0/8
125.3 (88.0)
Saline Pre-haloperidol Post-haloperidol Day 1 7 I1
0.3 (0.5) 0.3 (0.5) 1.5 (2.4)
0/4 0/4 0/4
54.5 (31.0) * 69.8 (24.3) * 61.8 (33.3) *
17
1.3 (1.5)
0/4
108.3 (105.5) *
21
2.0 (0.0)
0/4
33.3 (18.7) *
11.0 (I 5.4)
4/8
42.3 (40.5)
17.0 (30.7) 19.5 (16.8) 50.3 (17.0) 58.3 (92.7) 3.0 (5.2)
I/4 3/4 4/4 2/4 1/4
41.5 (37.6) I 1.0 (11.6) 3.0 (2.2) * 23.3 (25.5) 20.7 (12.7)
Apomorphine (0.02 mg/kg) Pre-haloperidol Post-haloperidol Day 2 6 12 16 22
* Significant from mean AL responses in same trials (paired t-test; P<0.05).
346
4. Discussion Numerous studi6s have demonstrated that the chronic administration of haloperidol induces behavioral hypersensitivity to direct and indirect dopamine agonists (Baldessarini and Tarsy, 1980; Hornykiewicz, 1977; Muller and Seeman, 1978). Although the dose and duration of administration, the length of withdrawal period and the behavioral paradigm used have varied, these observations suggest the production of postsynaptic dopaminergic supersensitivity. The 6-hydroxydopamine rotational model and amphetamine- and apomorphine-induced stereotypy are animal models that have been developed to evaluate central dopaminergic neuronal activity and the use of apomorphine as a discriminative stimulus in rats has, likewise, been reported to be dopaminergically mediated (Colpaert et al., 1975, 1976). In the present study, chronic (10 days) haloperidol administration was observed to increase the discriminative properties of a subthreshold dose of apomorphine and, by investigating the time course of this effect, it was shown to peak on the 12th day after haloperidol withdrawal. Although the time course of development of dopaminergic supersensitivity has received some attention, few studies have investigated the disappearance of this phenomenon. Nonetheless, it appears that the length of time needed for reversal of dopaminergic supersensitivity correlates with the duration of neuroleptic administration regardless of the type and dose of neuroleptic administration and regardless of the type of dopaminergically mediated behavior measured (Muller and Seeman, 1978). Indeed, when the persistance (in days) of dopaminergic supersensitivity is plotted against the days of neuroleptic pretreatment, from results reported in studies measuring stereotypy, rotational behavior and neuroleptic binding, there is a linear correlation, and 10 days of neuroleptic treatment results in approximately 9 days of supersensitivity persistance (Muller and Seeman, 1978). In the present study, the peak effect of supersensitivity was seen at 12 days after haloperidol withdrawal with a return to pre-haloperidol discrimination of apomorphine by the 16th day. The results indicate the production of increased
discrimination of a subthreshold (EDs0) dose of apomorphine produced by 10 days of haloperidol administration and this may correlate with the development of dopaminergic supersensitivity by prolonged pharmacologic blockade of dopamine receptors in the rat brain.
Acknowledgement The author would like to thank Ms. D. Lovano for her excellent technical assistance.
References Baldessarini, R.J. and D. Tarsy, 1980, Dopamine and the pathophysiology of dyskinesis induced by antipsychotic drugs, Ann. Rev. Neurosci. 3, 23. Colpaert, F.C., J.E,M.F. Leysen, C.J.E. Niemegeers and P.A.J. Janssen, 1976, Blockade of apomorphine's discriminative stimulus properties: Relation to neuroleptic activity in neuropharmacological and biochemical assays, Pharmacol. Biochem. behav. 5,671. Colpaert, F.C., C.J.E. Niemegeers, J.J.M.D. Kuyps and P.A.J. Janssen, 1975, Apomorphine as a discriminative stimulus and its antagonism by haloperidol, European J. Pharmacol. 32, 383. Hornykiewicz, O., 1977, Pharmacological implications of dopamine and dopamine antagonists: A critical evaluation of current evidence, Ann. Rev. Pharmacol. Toxicol. 17, 545. Jeste, D.V., M.J, Perlow, R.J. Wyatt and D.M. Stoff, 1979, Behavioral effects of amfonelic acid in rats: A comparison with amphetamine and apomorphine, Commun. Psychopharmacology 3, 41. Muller, P. and P. Seeman, 1978, Dopaminergic supersensitivity after neuroleptics: Time course and specificity, Psychopharmacology 60, I. Sayers, A.C., HR. B6rke. W. Ruth and H. Asper, 1975, Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. 'Effects of clozapine, haloperidol, loxapine and chlorpromazine, Psychopharmacologia 41, 97, Schechter, M.D., 1980, Caffeine potentiation of apomorphinc discrimination, Pharmacol. Biochem Behav. 13, 307. Schechter, M.D., 1981, Extended scheduled transfer of ethanol discrimination, Pharmacol. Biochem. Behav. 14, 23. Tarsy, D. and R.J. Baldessarini, 1974, Behavioral supersensitivity to apomorphine following chronic treatment wih drugs that interfere with the synaptic function of catecholamines, Neuropharmacol. 13,927. Ungerstedt, U. and G.W. Arbuthnott, 1970, Quantitative recording of rotational behavior in rats after 6hydroxydopamine lesions of the nigra-striatal dopamine system, Brain Res. 24, 485.
343
H A L O P E R I D O L - I N D U C E D S U P E R S E N S I T I V I T Y T O T H E D I S C R I M I N A T I O N OF APOMORPHINE MARTIN D. SCHECHTER Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, U.S.A.
Received 9 April 1981, accepted 6 July 1981
M.D. SCHECHTER, Haloperidol-induced supersensitivity to the discrimination of apomorphine, European J. Pharmacol. 74 (1981) 343- 346. Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Once trained, the rats were tested with the EDs0 of apomorphine (0.02 mg/kg) or saline before and 1-22 days after a ten-day regimen of daily 2.0 mg/kg administrations of haloperidol. Chronic haloperidol treatment produced increased discrimination of, and lever selection perseverance to, the low dose of apomorphine when rats were tested at 12 days after the withdrawal of haloperidol and this increased discrimination returned to pre-haloperidollevels by the sixteenth day. The results suggest the development of supersensitivity by prolonged pharmacologic blockade of central dopaminergic receptors with haloperidol and indicate the peak and duration of this effect. Haloperidol
Supersensitivity Dopamine Apomorphine Drug-inducedstimuli
1. Introduction Numerous reports have indicated that apomorphine is capable of producing a discriminative stimulus complex in rats (Colpaert et al., 1975; 1976; Schechter, 1980) and it appears that the action underlying the ability of apomorphine to produce discriminative control of rat behavior is consistent with its dopamine-mimicking activity at postsynaptic d o p a m i n e receptors. Thus, discriminative control by apomorphine joins other behavioral paradigms that have been used to assess the dopaminergic activity of drugs, such as apomorphine-induced stereotypy (Jeste et al., 1979) and rotational behavior in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra (Ungerstedt and Arbuthnott, 1980). In addition, it has been reported that acute a n d / o r chronic treatment of rats with neuroleptic agents can elicit dopaminergic supersensitivity and, when this is attained, the effects of apomorphine challenge in both stereotypy and rotational behavior are increased. Thus, Tarsy and Baldessarini (1974) have reported that haloperidol administered for 11
Discrimination
days to rats p r o d u c e s hypersensitivity of dopaminergic neurons in the corpus striatum as manifested in the production of stereotyped behavior in response to subthreshold doses of apomorphine and Sayers et al. 91975) observed that a similar regimen of haloperidol administration increases the quantified rotational behavior of 6-OHDA-lesioned rats after apomorphine administration. The present investigation sought to determine the effects of apomorphine as a drug that controls discriminative performance in rats treated with chronic haloperidol administration. Thus, an ED50 of apomorphine was administered before and after a ten-day regimen of haloperidol administration to test the ability of this low dose to produce discriminative control in rats trained to discriminate between 0.16 m g / k g apomorphine and saline. A relatively new behavioral procedure, known as extended schedule performance (Schechter, 1981), was employed to indicate the strength of the discriminative cue at the lower apomorphine dose and the time course for the dopaminergic supersensitization effect was investigated.
0014-2999/81/0000-0000/$02.50 © 1981 Elsevier/North-Holland Biomedical Press
344
2. Materials and methods
2.1. Subjects The subjects were 4 male ARS/Sprague-Dawley rats weighing 260--+ l0 g at the beginning of experimentation. They were housed in individual living cages and their weights were adjusted (by daily rationing of rat chow) to approximately 85% of their free-feeding values as determined by daily weighing of a control free-feeding rat purchased from the supplier (Zivic-Miller, Allison Park, PA) at the same time. Water was continuously available.
2.2. Apparatus The experimental space was a standard rodent Skinner test cage (Lafayette Instrument Co.) equipped with 2 operant levers placed 7 cm apart and 7cm above the grid floor. A food pellet receptacle was mounted 2 cm above the grid floor at an equal distance between the levers. The test cage was housed in a sound-attenuating cubicle equipped with an exhaust fan and house light. Solid-state programming equipment (LVB Corp.) was used to control and record the sessions and was located in an adjacent room.
2.3. Training procedure The procedure used to train rats to discriminate between apomorphine and saline has been described in detail elsewhere (Colpaert et al., 1976). Briefly, rats were magazine-trai~aed and shaped to lever press on an FR-10 schedule of food reinforcement. Once animals were reliably responding, they were injected on a daily basis with either apomorphine (0.16 mg/kg, as base) or an equal volume of saline (1 ml/kg) on alternating days and trained to press one lever after receiving the injection of the drug and the other lever after the administration of saline. Injections were made 30 min prior to the animals being placed into the experimental space and 10 responses on the appropriate lever resulted in the delivery of a 45 mg Noyes food pellet. Responses on the incorrect lever did not result in reinforcement. Training
trials were conducted on 5 days a week with apomorphine or saline injected on an alternating schedule.
2.4. Extended schedule testing Once an animal made no more than 2 responses on the incorrect lever before making l0 responses on the correct lever for 10 consecutive days it was considered to have met the criterion for discrimination. Thereafter, training sessions of 15 min duration with alternating administration of freshly prepared apomorphine or saline were continued on Mondays, Wednesdays and Fridays for the remainder of the experimentation. On Tuesdays and Thursdays, the rats were administered either the training dose of apomorphine or saline and 30 min later they were placed in the experimental chamber and were allowed to lever press, in extinction, until 10 responses were made on the lever that was not the first lever selected. Thus, for example, when a rat pressed the apomorphine lever (AL) 10 times that lever was designated as the 'selected lever' and the rat was allowed to continue pressing, without reinforcement, until it accumulated 10 presses upon the saline lever (SL). The number of lever presses made on the AL prior to 10 presses on the SL was recorded. Likewise, if the SL was the selected lever, the rat was allowed to continue pressing until 10 responses were made on the AL. These extended schedule performance measurements (Schechter, 1981) were conducted in 2 trials each with the training dose of apomorphine and with saline.
2.5. Chronic haloperidol administration In a previous study investigating the doseresponse effects of various doses of apomorphine in the same behavioral paradigm, it was established that 0.02 mg/kg was the EDso of apomorphine (Schechter, 1980). Therefore, this dose was administered on different randomlyassigned test days to all animals on 2 occasions each and the animals were tested according to the extended schedule performance described. Subsequently, the rats were administered 2.0 mg/kg haloperidol intraperitoneally daily for a 10-day
345
period without continued training. After this chronic treatment, the EDs0 for apomorphine was administered to each rat 48 h after the last haloperidol dose and on every fifth following day for a 22 day period. To control for the possible effects of time on performance deficits, saline was likewise tested on every fifth day following the chronic administration of haloperidol. On each trial, the lever pressed 10 times first was designated as the selected lever and perseverance, in extinction, was determined.
3. Results
The perseverance of lever pressing after the administration of 0.02 mg/kg apomorphine and saline, before and 1-22 days following chronic haloperidol treatment, is presented.in table 1. Prior to haloperidol treatment, the 0.02 mg/kg dose of apomorphine administered on 2 trials to each rat produced first lever-selection (pressed I0 times) on the apomorphine lever (AL) in 50% (4 of 8) trials with a mean perseverance of 11.0 responses on the
AL prior to the accumulation of 10 responses on the saline levels (SL). Saline administration resuited in all first choice responses on the SL with a mean perseverance of 125.3 responses, whereas 0.16 mg/kg apomorphine (not shown in table) produced all AL first selections with a mean perseverance on that lever of 121.9 responses (-+-78.8) and no responses on the SL prior to 10 responses on the AL. For the 3 week period after the chronic administration of haloperidol, saline administration continued to produce solely first choice lever selection upon the SL with a significantly greater perseverance upon that lever than upon the AL. This indicated that, although training trials with apomorphine and saline did not continue for this period, no decrease in saline discrimination occurred. During the same post-haloperidol period, the EDs0 apomorphine dose produced AL first choice selections of 25-100% with the maximal AL selection occurring on the 12th day after haloperidol withdrawal.
TABLE 1 Perseverance of lever pressing in a discrimination between a subthreshold dose of apomorphine and saline prior to and after chronic haloperidol treatment. AL responses prior to 10 SL presses ( ± S.D.)
AL selections/ trials conducted
SL responses prior to 10 AL presses (+__S.D.)
0
0/8
125.3 (88.0)
Saline Pre-haloperidol Post-haloperidol Day 1 7 I1
0.3 (0.5) 0.3 (0.5) 1.5 (2.4)
0/4 0/4 0/4
54.5 (31.0) * 69.8 (24.3) * 61.8 (33.3) *
17
1.3 (1.5)
0/4
108.3 (105.5) *
21
2.0 (0.0)
0/4
33.3 (18.7) *
11.0 (I 5.4)
4/8
42.3 (40.5)
17.0 (30.7) 19.5 (16.8) 50.3 (17.0) 58.3 (92.7) 3.0 (5.2)
I/4 3/4 4/4 2/4 1/4
41.5 (37.6) I 1.0 (11.6) 3.0 (2.2) * 23.3 (25.5) 20.7 (12.7)
Apomorphine (0.02 mg/kg) Pre-haloperidol Post-haloperidol Day 2 6 12 16 22
* Significant from mean AL responses in same trials (paired t-test; P<0.05).
346
4. Discussion Numerous studi6s have demonstrated that the chronic administration of haloperidol induces behavioral hypersensitivity to direct and indirect dopamine agonists (Baldessarini and Tarsy, 1980; Hornykiewicz, 1977; Muller and Seeman, 1978). Although the dose and duration of administration, the length of withdrawal period and the behavioral paradigm used have varied, these observations suggest the production of postsynaptic dopaminergic supersensitivity. The 6-hydroxydopamine rotational model and amphetamine- and apomorphine-induced stereotypy are animal models that have been developed to evaluate central dopaminergic neuronal activity and the use of apomorphine as a discriminative stimulus in rats has, likewise, been reported to be dopaminergically mediated (Colpaert et al., 1975, 1976). In the present study, chronic (10 days) haloperidol administration was observed to increase the discriminative properties of a subthreshold dose of apomorphine and, by investigating the time course of this effect, it was shown to peak on the 12th day after haloperidol withdrawal. Although the time course of development of dopaminergic supersensitivity has received some attention, few studies have investigated the disappearance of this phenomenon. Nonetheless, it appears that the length of time needed for reversal of dopaminergic supersensitivity correlates with the duration of neuroleptic administration regardless of the type and dose of neuroleptic administration and regardless of the type of dopaminergically mediated behavior measured (Muller and Seeman, 1978). Indeed, when the persistance (in days) of dopaminergic supersensitivity is plotted against the days of neuroleptic pretreatment, from results reported in studies measuring stereotypy, rotational behavior and neuroleptic binding, there is a linear correlation, and 10 days of neuroleptic treatment results in approximately 9 days of supersensitivity persistance (Muller and Seeman, 1978). In the present study, the peak effect of supersensitivity was seen at 12 days after haloperidol withdrawal with a return to pre-haloperidol discrimination of apomorphine by the 16th day. The results indicate the production of increased
discrimination of a subthreshold (EDs0) dose of apomorphine produced by 10 days of haloperidol administration and this may correlate with the development of dopaminergic supersensitivity by prolonged pharmacologic blockade of dopamine receptors in the rat brain.
Acknowledgement The author would like to thank Ms. D. Lovano for her excellent technical assistance.
References Baldessarini, R.J. and D. Tarsy, 1980, Dopamine and the pathophysiology of dyskinesis induced by antipsychotic drugs, Ann. Rev. Neurosci. 3, 23. Colpaert, F.C., J.E,M.F. Leysen, C.J.E. Niemegeers and P.A.J. Janssen, 1976, Blockade of apomorphine's discriminative stimulus properties: Relation to neuroleptic activity in neuropharmacological and biochemical assays, Pharmacol. Biochem. behav. 5,671. Colpaert, F.C., C.J.E. Niemegeers, J.J.M.D. Kuyps and P.A.J. Janssen, 1975, Apomorphine as a discriminative stimulus and its antagonism by haloperidol, European J. Pharmacol. 32, 383. Hornykiewicz, O., 1977, Pharmacological implications of dopamine and dopamine antagonists: A critical evaluation of current evidence, Ann. Rev. Pharmacol. Toxicol. 17, 545. Jeste, D.V., M.J, Perlow, R.J. Wyatt and D.M. Stoff, 1979, Behavioral effects of amfonelic acid in rats: A comparison with amphetamine and apomorphine, Commun. Psychopharmacology 3, 41. Muller, P. and P. Seeman, 1978, Dopaminergic supersensitivity after neuroleptics: Time course and specificity, Psychopharmacology 60, I. Sayers, A.C., HR. B6rke. W. Ruth and H. Asper, 1975, Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. 'Effects of clozapine, haloperidol, loxapine and chlorpromazine, Psychopharmacologia 41, 97, Schechter, M.D., 1980, Caffeine potentiation of apomorphinc discrimination, Pharmacol. Biochem Behav. 13, 307. Schechter, M.D., 1981, Extended scheduled transfer of ethanol discrimination, Pharmacol. Biochem. Behav. 14, 23. Tarsy, D. and R.J. Baldessarini, 1974, Behavioral supersensitivity to apomorphine following chronic treatment wih drugs that interfere with the synaptic function of catecholamines, Neuropharmacol. 13,927. Ungerstedt, U. and G.W. Arbuthnott, 1970, Quantitative recording of rotational behavior in rats after 6hydroxydopamine lesions of the nigra-striatal dopamine system, Brain Res. 24, 485.