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Behavioral evidence for midbrain dopamine depolarization inactivation
Brain Research, 477 (1989) 152-156 Elsevier
152 BRE 14159
Behavioral evidence for midbrain dopamine depolarization inactivation Pierre-Paul Rompr(~and Roy A. Wise Departmentof Psychology, Centerfor Studies in BehavioralNeurobiology, Concordia University, Montreal, Que., (Canada) (Accepted 28 June 1988) Key words: Dopamine; Depolarization inactivation; Pimozide; Morphine; Muscimol; Reward
High (2.5-5/~g) doses of ventral tegmental morphine, which normally facilitate brain stimulation reward, were found to cause a complete cessation of bar pressing for brainstem stimulation in animals pretreated with systemic pimozide (0.175-0.35 mg/kg). It was hypothesized that the behavioral failure was due to depolarization inactivation of the dopamine system. Electrophysiologicai evidence indicates that sufficient doses of morphine or neuroleptics can each cause inactivation by.themselves. The behavior was reinstated by ventral tegmental muscimol, which normally suppresses both the behavior and dopamine cell firing but which reinstates dopamine cell firing in depolarization-inactivated cells. This behavioral reinstatement appears to confirm the hypothesis that depolarization inactivation of the dopamine system caused the behavioral failure, and appears to establish depolarization inactivation as a phenomenon of behavioral, and thus potential clinical, importance.
INTRODUCTION In a previous study, we showed that injections of low and moderate doses of morphine in the ventral tegmental area (VTA) facilitated brainstem selfstimulation (SS) and reversed the attenuation of reward induced by systemic pimozide 13. However, in 2 of 6 rats tested, moderate doses of morphine, instead of reversing the effect of pimozide, added to it and resulted in complete inhibition of brainstem SS. To explain these unexpected results, we proposed that the combined neuroleptic and morphine treatment drove the dopaminergic neurons into depolarization inactivation. This hypothesis was based on electrophysiological studies showing that chronic 3'6a5 and acute neuroleptics 7, and morphine itselis, can induce depolarization inactivation of midbrain dopaminergic neurons. The present study was designed to test this depolarization inactivation hypothesis. We attempted to reinstate bar pressing in animals
pretreated with systemic pimozide and VTA morphine, by injecting muscimol, a G A B A agonist, into the VTA. In normal conditions, G A B A hyperpolarizes dopamine neurons and inhibits their firing 3a6. However, its effect on dopaminergic neurons that are in a state of depolarization inactivation is the opposite; by moving the m e m b r a n e potential back towards its resting value, it restores the ability of the inactivated dopaminergic neurons to respond to excitatory inputs 3'6. Consequently, it was hypothesized that ventral tegmental muscimol administered after a combined pimozide and morphine treatment might reinstate bar pressing. MATERIALS AND METHODS The animals tested in this experiment were the six animals tested for reversal of pimozide effect by central morphine injection in our previous study 13. Each animal h~d a stimulation electrode in the metence-
Correspondence: P.-P. Rompr~, Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, 1455 de Maisonneuve West, Montreal, Que., Canada H3G 1M8. 0006-8993/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)
153 phalic central gray area and a guide cannula above the ventral tegmental area. The details are reported elsewherem3. At least one week after completion of our previous study, the animals were retested. The first testing session consisted of 4 determinations of baseline SS threshold (see ref. 13 for definition of threshold). At the end, each animal was injected with pimozide (0.175 mg/kg i.p. (3 rats) or 0.35 mg/kg i.p. (3 rats)) and returned to its home cage. The choice of dose was based on the sensitivity of the animal, as determined in the earlier study n3. The second testing session began 4.5 h later and consisted of 4 determinations of SS threshold (30 rain). At the end of this test
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session, each animal was given a central injection of morphine at a concentration two times larger than that required to induce a significant decrease in SS threshold (2.5/~g for 1 rat and 5.0/~g for the other 5 rats); it was then tested for another 4 threshold determinations (30 rain). At the end of this 3rd set of determinations, each animal received a central injection of muscimol (25 ng/0.25/ll) and was tested again for 12 additional threshold determinations (90 min). One week after this test, the animals were retested in the same way with systemic tartaric acid, followed by central saline, followed by central muscimol (25
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Fig. 1. Changes in SS threshold (expressed as percentage of baseline thresholdon a log scale)as a function of time after injection of each drug in individual rats tested. Drug doses were: pimozide 0.175 mg/kg (Panel A, C and D) and 0.35 mg/kg (Panel B, E and F); morphine2.5 t~g/0.25/zl (Panel C) and 5.0/~g/0.25 #l (Panel A, B, D, E and F); muscimo125ng/0.25pl. NO SS means that no bar pressing could be elicited at any frequencyof stimulationtested.
154 RESULTS Changes in SS threshold observed after sequential injections of systemic pimozide, central morphine, and central muscimol are presented in Fig. 1. In those animals receiving 0.35 mg/kg, pimozide induced an increase in SS threshold; in animals receiving the lower dose there was no significant change. In each of the 6 animals, the addition of VTA morphine completely abolished bar pressing and in each of the 6 animals muscimol reinstated responding. The reinstated responding under muscimoi usually involved thresholds lower than those seen under pimozide alone, and in all but one case approached the prepimozide baseline level. The effects of muscimol alone are shown in Fig. 2. Ventral tegmental muscimoi had a moderate but significant suppressive effect, such that 20-30% more stimulation than normal was required to initiate responding. The suppressive effect of muscimol was significant 15-30 min after injection (Fs,25 = 3.15, P < 0.05, least significant difference (LSD) = 17.2) and reached a peak after 90 min. Neither systemic tartaric acid nor central saline produced a significant change in SS threshold. DISCUSSION We can offer no explanation for the present data other than the tested hypothesis that the combination of pimozide with VTA morphine can drive the dopa-
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Fig. 2. Changesin SS thresholdas a functionof time after injection of tartaric acid, followedby saline, followedby muscimol (25 ng/0.25/zi, into the ventral tegmental area). Mean scores from 6 rats _+S.E.M. (verticalbars) are presented. The asterisk denotes a significantdifferencefrom baseline SS threshold (e < 0.05).
mine system - - on which brainstem SS critically depends 1°'t3 - - into depolarization inactivation. Pimozide has a high affinity for the D-2 receptor t4 and blocks both pre- and postsynaptic receptors; this blockade results in a significant increase in cell firing presumably because of a decrease of inhibitory feedback input to the cell body from both feedback pathway and autoreceptor activation3"7'~5. Acute injectiods of D-2 antagonists do not usually cause depolarization inactivation by themselves3, though they can if given in high doses 7. The addition of sufficient morphine, however, is likely to summate with neuroleptics to cause an acute depolarization inactivation, since morphine can increase dopamine cell firing9a2 and can, in sufficient doses, cause dopaminergic depolarization inactivation by itself9. The addition of muscimol, in contrast, should reverse depolarization inactivation. Indeed, Grace and Bunney6, using extracellular recording techniques, have shown acute depolarization inactivation in dopamine cells by administration of the excitatory agent glutamate, and have reinitiated dopamine cell firing with microiontophoretic applications of GABA. Our reinstatement of behavior with the GAB A agonist, muscimol, could be explained by reinstatement of dopamine cell firing, but not by the usual effects of muscimol, which were shown to inhibit the behavior under normal conditions. The possibility - - seemingly confirmed by the present observations - - that dopamine depolarization inactivation can have significant behavioral consequences has potential clinical implications. Dopamine blockers are relatively ineffective in treating primary symptoms of schizophrenia in the first few days of treatment and induce no immediate Parkinson side-effects despite the fact that dopamine receptor blockade occurs immediately after neuroleptic medication. White and Wang t5 and Bunney and Grace 3'6 have suggested that this is due to the facts that: (1) drug-induced depolarization inactivation is required for neuroleptics to have their full behavioral effectiveness, and (2) that such depolarization inactivation only develops over several days of chronic treatment with dopamine blockers. Our data suggest that acute dopaminergic depolarization inactivation can occur with the combination of two classes of drugs (opiate and neuroleptic) that influence dopaminergic impulse flow.
155 The second important implication of these findings is that they provide even more subtle evidence than that of simple postsynaptic blockade in support of the hypothesis that dopamine plays an important role in metencephalic brain stimulation reward. Gallistel s and Mifiaressis et al. 1° have recently argued that the dopamine system does not carry the reward signal properly, but rather serves to modulate reward signals carried by other circuitry. Their hypothesis is based on the observation that increases in the number of rewarding pulses are not able to compensate for neuroleptic treatment to anywhere near the degree that they are able to compensate for reduced stimulation intensity, These authors argued that if the dopaminergic neurons themselves carried the reward signal, then pimozide must cause some abrupt and dramatic cessation of function in the system, and that since the postsynaptic effects of pimozide were not known to have such characteristics, the dopamine system must modulate the reward pathway rather than serving as a primary carrier of the reward signal. The present data, however, suggest a likely alternative to the hypotheses of Gallistel 5 and Miliaressis et al.~°. The present data suggest that stimulation of the mesencephalic dopamine neurons can add to the feedback-mediated activation of these neurons by neuroleptics, producing sufficient depolarization to completely inactivate the system. In the case of brain stimulation reward, the stimulation itself, if it transsynaptically activates the dopaminergic fibers, should summate with pimozide effects in the same way. Thus the combination of increased levels of rewarding stimulation with relatively moderate neuroleptic doses could cause complete failure of the system just as morphine appeared to do in combination with moderate stimulation and pimozide in the present study; this could explain the failure of pimozide to shift the rate-frequency function more than 0.3 log units. The present data add further support to the oh-
REFERENCES 1 Bozarth, M.A. and Wise, R.A., Intracranial self-administration of morphine into the ventral tegmental area of rats, Life Sci., 28 (1981) 551-555. 2 Bozarth, M.A. and Wise, R.A., Heroin reward is dependent on a dopaminergic substrate, Life Sci., 29 (1981) 1881-1886.
servation that the reward system is influenced by the same treatments that are known to influence the dopamine system. Finally, our findings suggest that one must be careful in the interpretation of experiments aimed at studying the behavioral effects of dopamine receptor blockers on the effect of opiates or other treatments that can increase dopamine cell firing. For example, Ettenberg et al.4 have concluded that neuroleptics do not attenuate the effects of opiates on the grounds that low doses of neuroleptics fail to cause the compensatory accelerations of responding that are seen when neuroleptics are used to challenge stimulant self-administration or when naloxone is used to challenge opiate self-administration. However, high neuroleptic doses do cause animals to cease self-administering heroin4; the animals usually decrease or cease responding abruptly. The present experiment provides a potential explanation of this finding; the combination of opiates and neuroleptics can cause a sudden failure of the system that opiates stimulate t'2 and neuroleptics antagonize. That such sudden failure explains the lack of compensatory responding observed by Ettenberg and others is suggested by the finding that the D-1 antagonist SCH 23390 - - which does not stimulate dopaminergic cell firings m does cause robust compensatory heroin self-administration and does so over a broad range of antagonist doses 11.
ACKNOWLEDGEMENTS We wish to thank Claude Bouchard for his excellent technical assistance. This study was supported by grants from the 'Fonds de la Recherche en Sant6 du Qu6bec' (FRSQ, 850061 to P.P.R.) and the National Institute on Drug Abuse (NIDA, DA1720 to R.A.W.). P.P.R. is a University Research Fellow sponsored by FRSQ.
3 Bunney, B.S. and Grace, A.A., Acute and chronic haloperidol treatment: comparisonsof effects on nigral dopaminergic cell activity, Life Sci., 23 (1978) 1715-1728. 4 Ettenberg, A., Pettit, H.O., Bloom, F.E. and Koob, G.F., Heroin and cocaine intravenous self-administrationin rats: mediation by separate neural systems, Psychopharmacology, 78 (1982) 204-209. 5 Gallistel, C.R., The role of the dopaminergicprojectionsin
156 MFB self-stimulation, Behav. Brain Res., 20 (1986) 313-321. 6 Grace, A.A. and Bunney, B.S., Induction of depolarization block in midbrain dopamine neurons by repeated administrat!on of haloperidol: analysis using in vivo intracellular re~.ording, J. Pharmacol. Exp. Ther., 238 (1986) 1092-1100. 7 Hand, T.H., Hu, X.T. and Wang, R.Y., Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatai (A9) dopamine neurons, Brain Research, 415 (1987) 257-269. 8 Hand, T.H., Kasser, K.J. and Wang, R.Y., Effects of acnte thioridazine, metoclopramide and SCH 23390 on the basal activity of A9 and A10 dopamine cells, Fur. J. Pharmacol., 137 (1987) 251-255. 9 Matthews, R.T. and German, D.C., Electrophysiological evidence for excitation of rat ventral tegmental area dopaminergic neurons by morphine, Neuroscience, 11 (1~4) 617-626. 10 Miliaressis, E., Malette, J. and Coulombe, D., The effects
of pimozide on the reinforcing efficacyof central gray stimulation, Behav. Brain Res., 21 (1986) 95-100. 11 Nakajima, S. and Wise, R.A., Heroin self-administration in the rat suppressed by SCH 23390, Soc. Neurosci. Abstr., 13 (1987) 1545. 12 Ostrowski, N.L., Hatfield, C.B. and Cagginla, A.R., The effects of low doses of morphine on the activityof dopamine containing cells and on behavior, Life Sci., 31 (1982) 2347-2350. 13 gompr6, P.F. and Wise, R.A., Opioid-neuroleptic interaction in brainstem self-stimulation, Brain Research, 477 (1989) 144-151. 14 Seeman, P., Brain dopamine receptors, Pharmacol. Rev., 32 (1981) 229-313. 15 White, F.J. and Wang, R.Y., Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat, Life Sci., 32 (1983)983-993. 16 White, F.J. and Wang, R.Y., A10 dopamine neurons: role of autoreceptors in determining rate and sensitivity to dopamine agonists, Life Sci., 34 (1984) 1161-1170.
152 BRE 14159
Behavioral evidence for midbrain dopamine depolarization inactivation Pierre-Paul Rompr(~and Roy A. Wise Departmentof Psychology, Centerfor Studies in BehavioralNeurobiology, Concordia University, Montreal, Que., (Canada) (Accepted 28 June 1988) Key words: Dopamine; Depolarization inactivation; Pimozide; Morphine; Muscimol; Reward
High (2.5-5/~g) doses of ventral tegmental morphine, which normally facilitate brain stimulation reward, were found to cause a complete cessation of bar pressing for brainstem stimulation in animals pretreated with systemic pimozide (0.175-0.35 mg/kg). It was hypothesized that the behavioral failure was due to depolarization inactivation of the dopamine system. Electrophysiologicai evidence indicates that sufficient doses of morphine or neuroleptics can each cause inactivation by.themselves. The behavior was reinstated by ventral tegmental muscimol, which normally suppresses both the behavior and dopamine cell firing but which reinstates dopamine cell firing in depolarization-inactivated cells. This behavioral reinstatement appears to confirm the hypothesis that depolarization inactivation of the dopamine system caused the behavioral failure, and appears to establish depolarization inactivation as a phenomenon of behavioral, and thus potential clinical, importance.
INTRODUCTION In a previous study, we showed that injections of low and moderate doses of morphine in the ventral tegmental area (VTA) facilitated brainstem selfstimulation (SS) and reversed the attenuation of reward induced by systemic pimozide 13. However, in 2 of 6 rats tested, moderate doses of morphine, instead of reversing the effect of pimozide, added to it and resulted in complete inhibition of brainstem SS. To explain these unexpected results, we proposed that the combined neuroleptic and morphine treatment drove the dopaminergic neurons into depolarization inactivation. This hypothesis was based on electrophysiological studies showing that chronic 3'6a5 and acute neuroleptics 7, and morphine itselis, can induce depolarization inactivation of midbrain dopaminergic neurons. The present study was designed to test this depolarization inactivation hypothesis. We attempted to reinstate bar pressing in animals
pretreated with systemic pimozide and VTA morphine, by injecting muscimol, a G A B A agonist, into the VTA. In normal conditions, G A B A hyperpolarizes dopamine neurons and inhibits their firing 3a6. However, its effect on dopaminergic neurons that are in a state of depolarization inactivation is the opposite; by moving the m e m b r a n e potential back towards its resting value, it restores the ability of the inactivated dopaminergic neurons to respond to excitatory inputs 3'6. Consequently, it was hypothesized that ventral tegmental muscimol administered after a combined pimozide and morphine treatment might reinstate bar pressing. MATERIALS AND METHODS The animals tested in this experiment were the six animals tested for reversal of pimozide effect by central morphine injection in our previous study 13. Each animal h~d a stimulation electrode in the metence-
Correspondence: P.-P. Rompr~, Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, 1455 de Maisonneuve West, Montreal, Que., Canada H3G 1M8. 0006-8993/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)
153 phalic central gray area and a guide cannula above the ventral tegmental area. The details are reported elsewherem3. At least one week after completion of our previous study, the animals were retested. The first testing session consisted of 4 determinations of baseline SS threshold (see ref. 13 for definition of threshold). At the end, each animal was injected with pimozide (0.175 mg/kg i.p. (3 rats) or 0.35 mg/kg i.p. (3 rats)) and returned to its home cage. The choice of dose was based on the sensitivity of the animal, as determined in the earlier study n3. The second testing session began 4.5 h later and consisted of 4 determinations of SS threshold (30 rain). At the end of this test
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session, each animal was given a central injection of morphine at a concentration two times larger than that required to induce a significant decrease in SS threshold (2.5/~g for 1 rat and 5.0/~g for the other 5 rats); it was then tested for another 4 threshold determinations (30 rain). At the end of this 3rd set of determinations, each animal received a central injection of muscimol (25 ng/0.25/ll) and was tested again for 12 additional threshold determinations (90 min). One week after this test, the animals were retested in the same way with systemic tartaric acid, followed by central saline, followed by central muscimol (25
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Fig. 1. Changes in SS threshold (expressed as percentage of baseline thresholdon a log scale)as a function of time after injection of each drug in individual rats tested. Drug doses were: pimozide 0.175 mg/kg (Panel A, C and D) and 0.35 mg/kg (Panel B, E and F); morphine2.5 t~g/0.25/zl (Panel C) and 5.0/~g/0.25 #l (Panel A, B, D, E and F); muscimo125ng/0.25pl. NO SS means that no bar pressing could be elicited at any frequencyof stimulationtested.
154 RESULTS Changes in SS threshold observed after sequential injections of systemic pimozide, central morphine, and central muscimol are presented in Fig. 1. In those animals receiving 0.35 mg/kg, pimozide induced an increase in SS threshold; in animals receiving the lower dose there was no significant change. In each of the 6 animals, the addition of VTA morphine completely abolished bar pressing and in each of the 6 animals muscimol reinstated responding. The reinstated responding under muscimoi usually involved thresholds lower than those seen under pimozide alone, and in all but one case approached the prepimozide baseline level. The effects of muscimol alone are shown in Fig. 2. Ventral tegmental muscimoi had a moderate but significant suppressive effect, such that 20-30% more stimulation than normal was required to initiate responding. The suppressive effect of muscimol was significant 15-30 min after injection (Fs,25 = 3.15, P < 0.05, least significant difference (LSD) = 17.2) and reached a peak after 90 min. Neither systemic tartaric acid nor central saline produced a significant change in SS threshold. DISCUSSION We can offer no explanation for the present data other than the tested hypothesis that the combination of pimozide with VTA morphine can drive the dopa-
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Fig. 2. Changesin SS thresholdas a functionof time after injection of tartaric acid, followedby saline, followedby muscimol (25 ng/0.25/zi, into the ventral tegmental area). Mean scores from 6 rats _+S.E.M. (verticalbars) are presented. The asterisk denotes a significantdifferencefrom baseline SS threshold (e < 0.05).
mine system - - on which brainstem SS critically depends 1°'t3 - - into depolarization inactivation. Pimozide has a high affinity for the D-2 receptor t4 and blocks both pre- and postsynaptic receptors; this blockade results in a significant increase in cell firing presumably because of a decrease of inhibitory feedback input to the cell body from both feedback pathway and autoreceptor activation3"7'~5. Acute injectiods of D-2 antagonists do not usually cause depolarization inactivation by themselves3, though they can if given in high doses 7. The addition of sufficient morphine, however, is likely to summate with neuroleptics to cause an acute depolarization inactivation, since morphine can increase dopamine cell firing9a2 and can, in sufficient doses, cause dopaminergic depolarization inactivation by itself9. The addition of muscimol, in contrast, should reverse depolarization inactivation. Indeed, Grace and Bunney6, using extracellular recording techniques, have shown acute depolarization inactivation in dopamine cells by administration of the excitatory agent glutamate, and have reinitiated dopamine cell firing with microiontophoretic applications of GABA. Our reinstatement of behavior with the GAB A agonist, muscimol, could be explained by reinstatement of dopamine cell firing, but not by the usual effects of muscimol, which were shown to inhibit the behavior under normal conditions. The possibility - - seemingly confirmed by the present observations - - that dopamine depolarization inactivation can have significant behavioral consequences has potential clinical implications. Dopamine blockers are relatively ineffective in treating primary symptoms of schizophrenia in the first few days of treatment and induce no immediate Parkinson side-effects despite the fact that dopamine receptor blockade occurs immediately after neuroleptic medication. White and Wang t5 and Bunney and Grace 3'6 have suggested that this is due to the facts that: (1) drug-induced depolarization inactivation is required for neuroleptics to have their full behavioral effectiveness, and (2) that such depolarization inactivation only develops over several days of chronic treatment with dopamine blockers. Our data suggest that acute dopaminergic depolarization inactivation can occur with the combination of two classes of drugs (opiate and neuroleptic) that influence dopaminergic impulse flow.
155 The second important implication of these findings is that they provide even more subtle evidence than that of simple postsynaptic blockade in support of the hypothesis that dopamine plays an important role in metencephalic brain stimulation reward. Gallistel s and Mifiaressis et al. 1° have recently argued that the dopamine system does not carry the reward signal properly, but rather serves to modulate reward signals carried by other circuitry. Their hypothesis is based on the observation that increases in the number of rewarding pulses are not able to compensate for neuroleptic treatment to anywhere near the degree that they are able to compensate for reduced stimulation intensity, These authors argued that if the dopaminergic neurons themselves carried the reward signal, then pimozide must cause some abrupt and dramatic cessation of function in the system, and that since the postsynaptic effects of pimozide were not known to have such characteristics, the dopamine system must modulate the reward pathway rather than serving as a primary carrier of the reward signal. The present data, however, suggest a likely alternative to the hypotheses of Gallistel 5 and Miliaressis et al.~°. The present data suggest that stimulation of the mesencephalic dopamine neurons can add to the feedback-mediated activation of these neurons by neuroleptics, producing sufficient depolarization to completely inactivate the system. In the case of brain stimulation reward, the stimulation itself, if it transsynaptically activates the dopaminergic fibers, should summate with pimozide effects in the same way. Thus the combination of increased levels of rewarding stimulation with relatively moderate neuroleptic doses could cause complete failure of the system just as morphine appeared to do in combination with moderate stimulation and pimozide in the present study; this could explain the failure of pimozide to shift the rate-frequency function more than 0.3 log units. The present data add further support to the oh-
REFERENCES 1 Bozarth, M.A. and Wise, R.A., Intracranial self-administration of morphine into the ventral tegmental area of rats, Life Sci., 28 (1981) 551-555. 2 Bozarth, M.A. and Wise, R.A., Heroin reward is dependent on a dopaminergic substrate, Life Sci., 29 (1981) 1881-1886.
servation that the reward system is influenced by the same treatments that are known to influence the dopamine system. Finally, our findings suggest that one must be careful in the interpretation of experiments aimed at studying the behavioral effects of dopamine receptor blockers on the effect of opiates or other treatments that can increase dopamine cell firing. For example, Ettenberg et al.4 have concluded that neuroleptics do not attenuate the effects of opiates on the grounds that low doses of neuroleptics fail to cause the compensatory accelerations of responding that are seen when neuroleptics are used to challenge stimulant self-administration or when naloxone is used to challenge opiate self-administration. However, high neuroleptic doses do cause animals to cease self-administering heroin4; the animals usually decrease or cease responding abruptly. The present experiment provides a potential explanation of this finding; the combination of opiates and neuroleptics can cause a sudden failure of the system that opiates stimulate t'2 and neuroleptics antagonize. That such sudden failure explains the lack of compensatory responding observed by Ettenberg and others is suggested by the finding that the D-1 antagonist SCH 23390 - - which does not stimulate dopaminergic cell firings m does cause robust compensatory heroin self-administration and does so over a broad range of antagonist doses 11.
ACKNOWLEDGEMENTS We wish to thank Claude Bouchard for his excellent technical assistance. This study was supported by grants from the 'Fonds de la Recherche en Sant6 du Qu6bec' (FRSQ, 850061 to P.P.R.) and the National Institute on Drug Abuse (NIDA, DA1720 to R.A.W.). P.P.R. is a University Research Fellow sponsored by FRSQ.
3 Bunney, B.S. and Grace, A.A., Acute and chronic haloperidol treatment: comparisonsof effects on nigral dopaminergic cell activity, Life Sci., 23 (1978) 1715-1728. 4 Ettenberg, A., Pettit, H.O., Bloom, F.E. and Koob, G.F., Heroin and cocaine intravenous self-administrationin rats: mediation by separate neural systems, Psychopharmacology, 78 (1982) 204-209. 5 Gallistel, C.R., The role of the dopaminergicprojectionsin
156 MFB self-stimulation, Behav. Brain Res., 20 (1986) 313-321. 6 Grace, A.A. and Bunney, B.S., Induction of depolarization block in midbrain dopamine neurons by repeated administrat!on of haloperidol: analysis using in vivo intracellular re~.ording, J. Pharmacol. Exp. Ther., 238 (1986) 1092-1100. 7 Hand, T.H., Hu, X.T. and Wang, R.Y., Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatai (A9) dopamine neurons, Brain Research, 415 (1987) 257-269. 8 Hand, T.H., Kasser, K.J. and Wang, R.Y., Effects of acnte thioridazine, metoclopramide and SCH 23390 on the basal activity of A9 and A10 dopamine cells, Fur. J. Pharmacol., 137 (1987) 251-255. 9 Matthews, R.T. and German, D.C., Electrophysiological evidence for excitation of rat ventral tegmental area dopaminergic neurons by morphine, Neuroscience, 11 (1~4) 617-626. 10 Miliaressis, E., Malette, J. and Coulombe, D., The effects
of pimozide on the reinforcing efficacyof central gray stimulation, Behav. Brain Res., 21 (1986) 95-100. 11 Nakajima, S. and Wise, R.A., Heroin self-administration in the rat suppressed by SCH 23390, Soc. Neurosci. Abstr., 13 (1987) 1545. 12 Ostrowski, N.L., Hatfield, C.B. and Cagginla, A.R., The effects of low doses of morphine on the activityof dopamine containing cells and on behavior, Life Sci., 31 (1982) 2347-2350. 13 gompr6, P.F. and Wise, R.A., Opioid-neuroleptic interaction in brainstem self-stimulation, Brain Research, 477 (1989) 144-151. 14 Seeman, P., Brain dopamine receptors, Pharmacol. Rev., 32 (1981) 229-313. 15 White, F.J. and Wang, R.Y., Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat, Life Sci., 32 (1983)983-993. 16 White, F.J. and Wang, R.Y., A10 dopamine neurons: role of autoreceptors in determining rate and sensitivity to dopamine agonists, Life Sci., 34 (1984) 1161-1170.