- Email: [email protected]
Conditioned place preference produced by the psychostimulant cathinone
European Journal of Pharmacology, 232 (1993) 135-138
135
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 21193
Short communication
Conditioned place preference produced by the psychostimulant cathinone M a r t i n D. S c h e c h t e r a n d S u s a n n e M. M e e h a n Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA Received 27 August 1992, revised MS received 30 December 1992, accepted 5 January 1993
Previous work has indicated that the psychostimulant cathinone produces a location preference in the conditioned place preference task. The present study expanded upon this earlier work by examining the dose-response nature of cathinone-induced conditioned place preference, as well as testing its effect upon spontaneous locomotor activity. At doses ranging from 0.2 to 1.6 mg/kg, cathinone produced a conditioned place preference at all but the lowest dose, and the highest dose but not the lowest dose increased locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and the relationship between conditioned place preference and locomotion being subserved by the same neuronal system. Cathinone; Conditioned place preference; Dopamine; Locomotion; (Rat)
1. Introduction
Cathinone is an alkaloid found in the leaves of the Khat plant (Catha edulis), a shrub indigenous to the Arabian Peninsula and eastern Africa (Kalix, 1990). The psychostimulatory properties of this compound have been known for centuries and the practice of chewing Khat leaves to elicit its central nervous system effects is widespread as it induces subjective effects similar to other central stimulants, e.g., euphoria, enhanced intellectual efficiency and alertness. The chemical structure of cathinone is similar to that of amphetamine, in that cathinone has an oxygen substituted for the two hydrogens on the/3 carbon. It is, therefore, not surprising that numerous behavioral studies in animals have found cathinone capable of producing effects similar to both amphetamine and cocaine (Kalix, 1990). For example, by employing the drug discrimination paradigm, which requires an animal to associate one response (typically the pressing of a designated lever) with a drug state and a second response (pressing of a second lever) with the non-drug state, researchers have found generalized responding between cocaine, amphetamine and cathinone (Huang and Wilson, 1986). If, like amphetamine and cocaine, cathinone produces its central nervous system effects by enhancing dopamine system activity, then the rewarding effects of
Correspondence to: M.D. Schechter, Northeastern Ohio Universities, College of Medicine, P.O. Box 95, Rootstown, OH 44272, USA.
dopamine stimulation could be investigated by using the conditioned place preference paradigm. This behavioral task, which involves the pairing of drug cues with a distinctive environment and non-drug cues with an alternative environment, has been shown to produce dose-responsive location preferences with both cocaine and amphetamine (Hoffman, 1989). It is of interest, therefore, to investigate if similar dose-responsive preference effects would be observed after the administration of 0.2-1.6 m g / k g of cathinone. In addition, the lowest and highest dose of cathinone will be administered to determine if conditioned place preference occurs in conjunction with the reported increase in locomotor activity in rats (Yanagita, 1979).
2. Materials and methods
2.1. Subjects Sixty experimentally-naive, male Sprague-Dawley rats were purchased from Zivic-Miller Laboratories (Allison Park, PA) and weighed 150-175 g at the beginning of the experimentation. The rats were individually housed in hanging wire mesh cages with food and water available ad libitum in a colony room maintained on a 12/12 h light-dark cycle with light onset at 06:00 h. Subjects were randomly assigned to one of six groups (n = 10/groups). Each group was conditioned with either 0.0 (saline), 0.2, 0.4, 0.8, 1.2 or 1.6 m g / k g cathinone.
136
2.2. Apparatus The apparatus consisted of four stainless steel units (Lafayette Instrument Co., Lafayette, IN, Model No. 85000) each divided into three distinctive chambers. The 'white' chamber was 30 x 20.5 x 18 cm and illuminated by a 9 W lightbulb fixed directly above a translucent white plastic lid. The floor of this chamber consisted of stainless steel rods with clean pine wood shavings placed beneath. The 'black' chamber was of the same dimensions and equipped with a duplicate light source. However, red plastic placed between the bulb and the lid produced red illumination within the chamber. The floor on this side was covered with black smooth Plexiglas. The third, middle, chamber consisted of an open ended gray-colored stainless steel box. This box could be isolated from the black and white chambers during conditioning by insertion of a metal plate (Model No. 80009) or left open to allow locomotion between the black and white sides during testing. During the test trials, entry into either the white or black side closed a microswitch which, in turn, started a timer and, thus, the time (in seconds) that a rat spent in each of the three chambers could be recorded by a computer. In a separate apparatus, activity was measured by the interruption of one of four photosensor light sources placed in the wall of a 45.5 x 35.5 x 20.5 cm plastic cage. The sensors were located 5.5 cm above the floor and 9.5 cm apart along the wall of the longer side. Each photocell interruption constituted one activity count. Activity counts were simultaneously recorded from four cages by a C o m m o d o r e 64 computer.
chambers was monitored for 15 min; this constituted the baseline test. On the next day (day 6), baseline activity measures were taken in which animals designated to be conditioned with 0.2 or 1.6 m g / k g cathinone received an i.p. injection of saline 10 min prior to placement into the activity apparatus. Activity was monitored, in 5 min intervals, over a 30 min period. Place conditioning began on day 7 and continued through day 14. Each animal was given eight pairings, four with either saline or one of five doses of cathinone in their non-preferred side and four with saline on their preferred side, beginning with the drug and alternating with saline on successive days. Each pairing consisted of an i.p. injection of cathinone or saline given 10 min prior to confinement in the designated chamber. Animals remained in the chamber for 30 min and were then returned to their home cage. On day 15, testing was conducted in a manner identical to the baseline preference test of day 5, in that animals were tested in the absence of the drug. On day 16, the ten rats conditioned with 0.2 m g / k g cathinone and the 10 rats administered 1.6 m g / k g cathinone were assessed for activity effects of the dose of cathinone used in their conditioning. Activity was monitored identically to the baseline activity session of day 6 except that each animal received an i.p. injection of cathinone 10 rain prior to placement in the apparatus.
3. Results
Data from the vehicle-treated animals (0.0 m g / k g dose of cathinone, fig. 1) were analysed with a two-way,
2.3. Conditioning and testing of place preference For animals conditioned with saline (n = 10) or cathinone (n = 50), the conditioning procedure followed a standard cycle across consecutive days. The cycle consisted of habituation to the training room, free access to the apparatus and baseline preference measurement, assessment of baseline activity levels, place conditioning, test of place preference, and activity testing with drug administration. Habituation occurred on days 1 and 2. Animals remained in their home cages and were transferred from the colony room to the training room where they remained for 1 h each day. During this time each animal was handled for 2 - 3 min. On days 3 and 4, each animal was given 15 min of free access to the conditioned place preference apparatus with the center chamber opened to allow free entry into both the black and white sides. The apparatus was cleaned after each exposure to preclude olfactory cues. On day 5, animals were placed into the center chamber of the apparatus and the time spent (in seconds) in each of the three
120
100
80
60 o
40 t,9
20 0.0 0
H 0.2
-20
0.4
0.8
1.2
1.8
Dose o! Cathinone ( m g / k g )
Fig. 1. P e r c e n t c h a n g e b e t w e e n p o s t - c o n d i t i o n i n g trial and b a s e l i n e p r e f e r e n c e trial, for the n o n - p r e f e r r e d c h a m b e r as a function of c a t h i n o n e dosage. E a c h dose was a d m i n i s t e r e d to 10 rats. Significance at * P < 0.05; * * P < 0.01.
137
repeated measures A N O V A comparing baseline and post-conditioning tests across training on preferred and non-preferred sides. Results indicated no significant between or within group effects (F = 0.27 and F = 0.008, respectively) and there was no significant interaction (F = 0.02). These results clearly indicate that the exposure to the black and white sides of the apparatus incurred during training does not alter side preference. Since each dose of cathinone was assessed independently, Student's t-test analyses were conducted on the data. Comparisons between free access baseline scores to post-conditioning test scores indicated that cathinone produced a conditioned place preference at doses of 1.6, 1.2, 0.8 and 0.4 m g / k g (t = 2.88, t = 3.54, t = 5.18 and t = 2.87, respectively; fig. 1). The 0.2 m g / k g dose of cathinone proved to be ineffective in producing a conditioned place preference (t = 2.03; NS). Thus, the magnitude of conditioned place preference produced by cathinone did not appear to be dose-related, rather the effectiveness of the cathinone proceeded in a 'stepup' fashion. Activity levels after 0.2 m g / k g cathinone (day 16) were observed to be 20% greater than after saline (day 6); a difference that was not significantly different (t = 1.12) In contrast, the 1.6 m g / k g cathinone dose significantly increased spontaneous locomotor activity by 57% (P < 0.01).
cantly increased the time spent in that side, whereas an 8 /~g dose did not. Likewise, the two larger doses significantly increased activity, whereas the lowest dose did not. This suggests that the effects of cathinone in producing conditioned place preference are of central origin. As with intracerebroventricular administration, the conditioned place preference produced by increasing doses of cathinone is represented by a 'step-upfunction', i.e., no significant increase at 0.2 m g / k g and a maximum increase with the next highest dose. This is frequently observed in dose-responsive conditioned place preference studies (Carr et al., 1989). The observation that the lowest dose of (0.2 mg/kg) cathinone produced neither a conditioned place preference nor a significant increase in activity, whereas the highest (1.6 m g / k g ) dose of cathinone produced both, may suggest that increased activity plays an important role in conditioned place preference. However, Carr et al. (1989) demonstrated that the conditioned place preference produced by amphetamine is seen to occur even when rats' activity is physically restrained. Nevertheless, the possibility still remains that the cathinone-induced conditioned place preference is mediated by dopaminergic neurons (Kalix, 1990; Calcagnetti and Schechter, 1993) and that these same dopaminergic mechanisms subserve increased activation following psychostimulant administration.
4. Discussion Acknowledgements The results of conditioned place preference experiments with cathinone extend earlier work from this laboratory indicating that this psychostimulant drug can produce a conditioned place preference in rats (Schechter, 1991). It is not surprising that cathinone, which acts to facilitate dopamine release (Kalix, 1990), would produce a conditioned place preference. Other dopamine receptor agonists, such as amphetamine and cocaine, have been repeatedly shown to condition a location preference (Hoffman, 1989). Furthermore, co-administration of dopamine receptor antagonists (e.g., haloperidol or a-flupenthixol)with amphetamine block the acquisition of conditioned place preference (Spyraki et al., 1982; Mackey and Van der Kooy, 1985; Mithani et al., 1986). Similar effects also have been seen following 6-hydroxydopamine lesions of the nucleus accumbens (Spyraki et al., 1982; Carr et al., 1989). These results implicate central dopamine release, and subsequent receptor activation, as the substrate for the affective properties mediating the development of place preference. Recent evidence from this laboratory (Calcagnetti and Schechter, 1993) indicated that intracerebroventricular injection of either 16 or 32/~g cathinone, when paired with confinement in the non-preferred side of the conditioned place preference apparatus, signifi-
The authors gratefully acknowledge Lauri M~lolo for her experimental expertise, Dr. Daniel J. Calcagnetti and Timothy L. Gordon for their critical reviews and advice on the early versions of this manuscript, and Martha Hilgert and Sheila Formick for their patience and skill in processing the words. This work was funded by NIDA (Grant No. 03591 to M.D.S.) which also provided the cathinone.
References Calcagnetti, D.J. and M.D. Schechter, 1993, Place preference for the psychostimulant cathinone is blocked by pretreatment with a dopamine release inhibitor, Prog. Neuropsychopharmacol. Biol. Psychiat. 17 (in press). Carr, G.D., H.C. Fibiger and A.G. Phillips, 1989, Conditioned place preference as a measure of drug reward, in: The Neuropharmacological Basis of Reward, eds. J.M. Liebman and S.J. Cooper (Oxford University Press, New York) p. 264. Hoffman, D.C., 1989, The use of place conditioning in studying the neuropharmacology of drug reinforcement, Brain Res. Bull. 23, 373. Huang, D. and M.C. Wilson, 1986, Comparative discriminative stimulus properties of dl-cathinone, d-amphetamine, and cocaine in rats, Pharmacol. Biochem. Behav. 24, 205. Kalix, P., 1990, Pharmacological properties of the stimulant khat, Pharmacol. Ther. 48, 397. Mackey, W.B. and D. Van der Kooy, 1985, Neuroleptics block the positive reinforcing effects of amphetamine but not morphine as
138 measured by place conditioning, Pharmacol. Biochem. Behav. 22, 101. Mithani, S., M,T. Martin-Iverson, A.G. Phillips and H.C. Fibiger, 1986, The effects of haloperidol on amphetamine and methylphenidate-induced conditioned place preferences and locomotor activity, Psychopharmacology (Berlin) 90, 247. Schechter, M.D., 1991, Effect of learned behavior upon preference to cathinone, Pharmacol. Biochem. Behav. 38, 7.
Spyraki, C., H.C. Fibiger and A.J. Phillips, 1982, Dopaminergic substrate of amphetamine-induced place preference conditioning, Brain Res. 253, 185. Yanagita, T., 1979, Studies on cathinone: Cardiovascular and behavioral effects in rats and self-administration experiments in monkeys, in: Problems of Drug Dependence, NIDA Res. Monograph (U.S. Government Printing Office, Washington, D.C.) 19. 326.
135
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 21193
Short communication
Conditioned place preference produced by the psychostimulant cathinone M a r t i n D. S c h e c h t e r a n d S u s a n n e M. M e e h a n Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA Received 27 August 1992, revised MS received 30 December 1992, accepted 5 January 1993
Previous work has indicated that the psychostimulant cathinone produces a location preference in the conditioned place preference task. The present study expanded upon this earlier work by examining the dose-response nature of cathinone-induced conditioned place preference, as well as testing its effect upon spontaneous locomotor activity. At doses ranging from 0.2 to 1.6 mg/kg, cathinone produced a conditioned place preference at all but the lowest dose, and the highest dose but not the lowest dose increased locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and the relationship between conditioned place preference and locomotion being subserved by the same neuronal system. Cathinone; Conditioned place preference; Dopamine; Locomotion; (Rat)
1. Introduction
Cathinone is an alkaloid found in the leaves of the Khat plant (Catha edulis), a shrub indigenous to the Arabian Peninsula and eastern Africa (Kalix, 1990). The psychostimulatory properties of this compound have been known for centuries and the practice of chewing Khat leaves to elicit its central nervous system effects is widespread as it induces subjective effects similar to other central stimulants, e.g., euphoria, enhanced intellectual efficiency and alertness. The chemical structure of cathinone is similar to that of amphetamine, in that cathinone has an oxygen substituted for the two hydrogens on the/3 carbon. It is, therefore, not surprising that numerous behavioral studies in animals have found cathinone capable of producing effects similar to both amphetamine and cocaine (Kalix, 1990). For example, by employing the drug discrimination paradigm, which requires an animal to associate one response (typically the pressing of a designated lever) with a drug state and a second response (pressing of a second lever) with the non-drug state, researchers have found generalized responding between cocaine, amphetamine and cathinone (Huang and Wilson, 1986). If, like amphetamine and cocaine, cathinone produces its central nervous system effects by enhancing dopamine system activity, then the rewarding effects of
Correspondence to: M.D. Schechter, Northeastern Ohio Universities, College of Medicine, P.O. Box 95, Rootstown, OH 44272, USA.
dopamine stimulation could be investigated by using the conditioned place preference paradigm. This behavioral task, which involves the pairing of drug cues with a distinctive environment and non-drug cues with an alternative environment, has been shown to produce dose-responsive location preferences with both cocaine and amphetamine (Hoffman, 1989). It is of interest, therefore, to investigate if similar dose-responsive preference effects would be observed after the administration of 0.2-1.6 m g / k g of cathinone. In addition, the lowest and highest dose of cathinone will be administered to determine if conditioned place preference occurs in conjunction with the reported increase in locomotor activity in rats (Yanagita, 1979).
2. Materials and methods
2.1. Subjects Sixty experimentally-naive, male Sprague-Dawley rats were purchased from Zivic-Miller Laboratories (Allison Park, PA) and weighed 150-175 g at the beginning of the experimentation. The rats were individually housed in hanging wire mesh cages with food and water available ad libitum in a colony room maintained on a 12/12 h light-dark cycle with light onset at 06:00 h. Subjects were randomly assigned to one of six groups (n = 10/groups). Each group was conditioned with either 0.0 (saline), 0.2, 0.4, 0.8, 1.2 or 1.6 m g / k g cathinone.
136
2.2. Apparatus The apparatus consisted of four stainless steel units (Lafayette Instrument Co., Lafayette, IN, Model No. 85000) each divided into three distinctive chambers. The 'white' chamber was 30 x 20.5 x 18 cm and illuminated by a 9 W lightbulb fixed directly above a translucent white plastic lid. The floor of this chamber consisted of stainless steel rods with clean pine wood shavings placed beneath. The 'black' chamber was of the same dimensions and equipped with a duplicate light source. However, red plastic placed between the bulb and the lid produced red illumination within the chamber. The floor on this side was covered with black smooth Plexiglas. The third, middle, chamber consisted of an open ended gray-colored stainless steel box. This box could be isolated from the black and white chambers during conditioning by insertion of a metal plate (Model No. 80009) or left open to allow locomotion between the black and white sides during testing. During the test trials, entry into either the white or black side closed a microswitch which, in turn, started a timer and, thus, the time (in seconds) that a rat spent in each of the three chambers could be recorded by a computer. In a separate apparatus, activity was measured by the interruption of one of four photosensor light sources placed in the wall of a 45.5 x 35.5 x 20.5 cm plastic cage. The sensors were located 5.5 cm above the floor and 9.5 cm apart along the wall of the longer side. Each photocell interruption constituted one activity count. Activity counts were simultaneously recorded from four cages by a C o m m o d o r e 64 computer.
chambers was monitored for 15 min; this constituted the baseline test. On the next day (day 6), baseline activity measures were taken in which animals designated to be conditioned with 0.2 or 1.6 m g / k g cathinone received an i.p. injection of saline 10 min prior to placement into the activity apparatus. Activity was monitored, in 5 min intervals, over a 30 min period. Place conditioning began on day 7 and continued through day 14. Each animal was given eight pairings, four with either saline or one of five doses of cathinone in their non-preferred side and four with saline on their preferred side, beginning with the drug and alternating with saline on successive days. Each pairing consisted of an i.p. injection of cathinone or saline given 10 min prior to confinement in the designated chamber. Animals remained in the chamber for 30 min and were then returned to their home cage. On day 15, testing was conducted in a manner identical to the baseline preference test of day 5, in that animals were tested in the absence of the drug. On day 16, the ten rats conditioned with 0.2 m g / k g cathinone and the 10 rats administered 1.6 m g / k g cathinone were assessed for activity effects of the dose of cathinone used in their conditioning. Activity was monitored identically to the baseline activity session of day 6 except that each animal received an i.p. injection of cathinone 10 rain prior to placement in the apparatus.
3. Results
Data from the vehicle-treated animals (0.0 m g / k g dose of cathinone, fig. 1) were analysed with a two-way,
2.3. Conditioning and testing of place preference For animals conditioned with saline (n = 10) or cathinone (n = 50), the conditioning procedure followed a standard cycle across consecutive days. The cycle consisted of habituation to the training room, free access to the apparatus and baseline preference measurement, assessment of baseline activity levels, place conditioning, test of place preference, and activity testing with drug administration. Habituation occurred on days 1 and 2. Animals remained in their home cages and were transferred from the colony room to the training room where they remained for 1 h each day. During this time each animal was handled for 2 - 3 min. On days 3 and 4, each animal was given 15 min of free access to the conditioned place preference apparatus with the center chamber opened to allow free entry into both the black and white sides. The apparatus was cleaned after each exposure to preclude olfactory cues. On day 5, animals were placed into the center chamber of the apparatus and the time spent (in seconds) in each of the three
120
100
80
60 o
40 t,9
20 0.0 0
H 0.2
-20
0.4
0.8
1.2
1.8
Dose o! Cathinone ( m g / k g )
Fig. 1. P e r c e n t c h a n g e b e t w e e n p o s t - c o n d i t i o n i n g trial and b a s e l i n e p r e f e r e n c e trial, for the n o n - p r e f e r r e d c h a m b e r as a function of c a t h i n o n e dosage. E a c h dose was a d m i n i s t e r e d to 10 rats. Significance at * P < 0.05; * * P < 0.01.
137
repeated measures A N O V A comparing baseline and post-conditioning tests across training on preferred and non-preferred sides. Results indicated no significant between or within group effects (F = 0.27 and F = 0.008, respectively) and there was no significant interaction (F = 0.02). These results clearly indicate that the exposure to the black and white sides of the apparatus incurred during training does not alter side preference. Since each dose of cathinone was assessed independently, Student's t-test analyses were conducted on the data. Comparisons between free access baseline scores to post-conditioning test scores indicated that cathinone produced a conditioned place preference at doses of 1.6, 1.2, 0.8 and 0.4 m g / k g (t = 2.88, t = 3.54, t = 5.18 and t = 2.87, respectively; fig. 1). The 0.2 m g / k g dose of cathinone proved to be ineffective in producing a conditioned place preference (t = 2.03; NS). Thus, the magnitude of conditioned place preference produced by cathinone did not appear to be dose-related, rather the effectiveness of the cathinone proceeded in a 'stepup' fashion. Activity levels after 0.2 m g / k g cathinone (day 16) were observed to be 20% greater than after saline (day 6); a difference that was not significantly different (t = 1.12) In contrast, the 1.6 m g / k g cathinone dose significantly increased spontaneous locomotor activity by 57% (P < 0.01).
cantly increased the time spent in that side, whereas an 8 /~g dose did not. Likewise, the two larger doses significantly increased activity, whereas the lowest dose did not. This suggests that the effects of cathinone in producing conditioned place preference are of central origin. As with intracerebroventricular administration, the conditioned place preference produced by increasing doses of cathinone is represented by a 'step-upfunction', i.e., no significant increase at 0.2 m g / k g and a maximum increase with the next highest dose. This is frequently observed in dose-responsive conditioned place preference studies (Carr et al., 1989). The observation that the lowest dose of (0.2 mg/kg) cathinone produced neither a conditioned place preference nor a significant increase in activity, whereas the highest (1.6 m g / k g ) dose of cathinone produced both, may suggest that increased activity plays an important role in conditioned place preference. However, Carr et al. (1989) demonstrated that the conditioned place preference produced by amphetamine is seen to occur even when rats' activity is physically restrained. Nevertheless, the possibility still remains that the cathinone-induced conditioned place preference is mediated by dopaminergic neurons (Kalix, 1990; Calcagnetti and Schechter, 1993) and that these same dopaminergic mechanisms subserve increased activation following psychostimulant administration.
4. Discussion Acknowledgements The results of conditioned place preference experiments with cathinone extend earlier work from this laboratory indicating that this psychostimulant drug can produce a conditioned place preference in rats (Schechter, 1991). It is not surprising that cathinone, which acts to facilitate dopamine release (Kalix, 1990), would produce a conditioned place preference. Other dopamine receptor agonists, such as amphetamine and cocaine, have been repeatedly shown to condition a location preference (Hoffman, 1989). Furthermore, co-administration of dopamine receptor antagonists (e.g., haloperidol or a-flupenthixol)with amphetamine block the acquisition of conditioned place preference (Spyraki et al., 1982; Mackey and Van der Kooy, 1985; Mithani et al., 1986). Similar effects also have been seen following 6-hydroxydopamine lesions of the nucleus accumbens (Spyraki et al., 1982; Carr et al., 1989). These results implicate central dopamine release, and subsequent receptor activation, as the substrate for the affective properties mediating the development of place preference. Recent evidence from this laboratory (Calcagnetti and Schechter, 1993) indicated that intracerebroventricular injection of either 16 or 32/~g cathinone, when paired with confinement in the non-preferred side of the conditioned place preference apparatus, signifi-
The authors gratefully acknowledge Lauri M~lolo for her experimental expertise, Dr. Daniel J. Calcagnetti and Timothy L. Gordon for their critical reviews and advice on the early versions of this manuscript, and Martha Hilgert and Sheila Formick for their patience and skill in processing the words. This work was funded by NIDA (Grant No. 03591 to M.D.S.) which also provided the cathinone.
References Calcagnetti, D.J. and M.D. Schechter, 1993, Place preference for the psychostimulant cathinone is blocked by pretreatment with a dopamine release inhibitor, Prog. Neuropsychopharmacol. Biol. Psychiat. 17 (in press). Carr, G.D., H.C. Fibiger and A.G. Phillips, 1989, Conditioned place preference as a measure of drug reward, in: The Neuropharmacological Basis of Reward, eds. J.M. Liebman and S.J. Cooper (Oxford University Press, New York) p. 264. Hoffman, D.C., 1989, The use of place conditioning in studying the neuropharmacology of drug reinforcement, Brain Res. Bull. 23, 373. Huang, D. and M.C. Wilson, 1986, Comparative discriminative stimulus properties of dl-cathinone, d-amphetamine, and cocaine in rats, Pharmacol. Biochem. Behav. 24, 205. Kalix, P., 1990, Pharmacological properties of the stimulant khat, Pharmacol. Ther. 48, 397. Mackey, W.B. and D. Van der Kooy, 1985, Neuroleptics block the positive reinforcing effects of amphetamine but not morphine as
138 measured by place conditioning, Pharmacol. Biochem. Behav. 22, 101. Mithani, S., M,T. Martin-Iverson, A.G. Phillips and H.C. Fibiger, 1986, The effects of haloperidol on amphetamine and methylphenidate-induced conditioned place preferences and locomotor activity, Psychopharmacology (Berlin) 90, 247. Schechter, M.D., 1991, Effect of learned behavior upon preference to cathinone, Pharmacol. Biochem. Behav. 38, 7.
Spyraki, C., H.C. Fibiger and A.J. Phillips, 1982, Dopaminergic substrate of amphetamine-induced place preference conditioning, Brain Res. 253, 185. Yanagita, T., 1979, Studies on cathinone: Cardiovascular and behavioral effects in rats and self-administration experiments in monkeys, in: Problems of Drug Dependence, NIDA Res. Monograph (U.S. Government Printing Office, Washington, D.C.) 19. 326.