Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist

doi:10.1016/0024-3205(85)90159-6

Life Sciences

Volume 36, Issue 19, 13 May 1985, Pages 1857-1864

https://doi.org/10.1016/0024-3205(85)90159-6 Get rights and content

Abstract

SCH 23390, an apparently selective antagonist of central D₁ dopamine receptors, produced profound catalepsy at low doses (0.1 mg/kg, s.c.). Pretreatment with the selective D₂ receptor agonists LY 141865, RU 24213 or LY 171555, the active (−) enantiomer of LY 141865, elicited a dose-dependent inhibition of the cataleptic response. Pergolide and apomorphine were also effective. This effect was not due to altered disposition or penetration of SCH 23390 into the brain since pretreatment with a dose of LY 171555 which completely blocked catalepsy had no effect on the ID₅₀ of SCH 23390 to inhibit ³H-cis-piflutixol binding to D₁ receptors measured $ex$ $vivo$ . Alternative mechanisms are considered to explain the results, which offer new insights into striatal dopaminergic regulation of motor activity.

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Cited by (87)

The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal
2022, Neuroscience
Citation Excerpt :
Importantly, we do not mean to claim that SCH did not induce any kind of motor impairment in our rats. The periods of freezing in the receptacle that we observed after SCH administration are more likely to represent catalepsy than sleep, in agreement with other reports of SCH-induced catalepsy (Meller et al., 1985; Morelli and Di Chiara, 1985). However, the degree of catalepsy induced by the dose of SCH used in this study was small enough to allow animals to respond efficiently to cues when their level of arousal was high, which might be at least in part due to the alleviation of SCH-induced catalepsy by arousal.
Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine’s roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal’s state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine’s contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.
Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats
2008, European Journal of Pharmacology
Typical antipsychotics such as the dopamine D₂ receptor antagonist, haloperidol are known to cause movement disorders or catalepsy in experimental animals. Catalepsy is believed to result from blockade of dopamine D₂ receptors. In this study two drugs that differ in antipsychotic potency but are similar in blocking dopamine D₂ receptors were used to investigate the mechanism for catalepsy and its sensitization. Metoclopramide is a strong postsynaptic dopamine D₂ receptor blocker with no antipsychotic potency. At low doses of 5 or 10 mg/kg given subcutaneously (s.c.), metoclopramide did not produce catalepsy or movement disturbance for seven days after drug treatment. Also metoclopramide at 10 mg/kg given for five days, failed to induce catalepsy. Haloperidol, another potent dopamine D₂ receptor blocker at 0.5 mg/kg (s.c.) rapidly produced catalepsy and suppressed movement 1 h after a single dose of the drug. Chronic as well as acute treatment with metoclopramide caused sensitization of haloperidol-induced catalepsy. Neurochemical analyses revealed significant dopamine D₂ receptor up-regulation in both frontal cortex and striatum of rats chronically treated with metoclopramide. However, no changes in dopamine D₂ receptor numbers were noted in these areas after chronic treatment with low doses of haloperidol. Significant increases in N-Methyl-d-aspartate (NMDA) receptor numbers were observed in both frontal cortex and striatum of metoclopramide treated animals, while haloperidol elicited significant decreases in NMDA receptor numbers in both brain areas. These observations plus previous reports have led us to propose a model for catalepsy and its sensitization. According to this model the increase in NMDA receptors by metoclopramide sensitizes the brain to haloperidol-induced catalepsy. Thus, catalepsy appears to be elicited by simultaneous activation of glutamatergic NMDA and dopamine D₁ receptors as well as a blockade of dopamine D₂ receptors.
Changes in muscle tone are regulated by D1 and D2 dopamine receptors in the ventral striatum and D1 receptors in the substantia nigra
2001, Neuropsychopharmacology
Muscle rigidity associated with antipsychotic drug treatment is believed to result from reduced striatal dopamine neurotransmission. In the current study the regulatory roles of dopamine D1 and D2 receptor subfamilies in the dorsal (DSTR) and ventral striatum (VSTR) and substantia nigra (SN) were investigated on muscle tone, assessed as increases in tonic electromyographic (EMG) activity. Rats were injected with the irreversible D1/D2 antagonist N-ethoxycarbonyl-2-ethoxy, -1,2-dihydroquinoline (EEDQ), the reversible D1 antagonist SCH23390, or D2 antagonist sulpiride. Increased EMG activity was observed following injection of EEDQ and SCH23390 into the SN or VSTR, and sulpiride into the VSTR. Mapping, using quantitative autoradiographic analysis of dopamine receptor occupancy after striatal injections, showed D1 and D2 receptors in discrete ventral sites were associated with EMG increases. Overall the results support roles for dopamine D1and D2 receptors in the ventral striatum, and D1 receptors in the substantia nigra, in the regulation of muscle tone.
Modification of cataleptic responses to dopamine receptor antagonists after withdrawal from chronic cocaine or cocaine plus dopamine antagonist administration
1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. In mice pretreated chronically with cocaine (indirect dopamine agonist: 10 mg/Kg S.C. on alternating days for 15 days), haloperidol (dopamine D₂ antagonist: 0.3 mg/kg i.p.) exerted an enhanced cataleptic response, but SCH23390 (dopamine D₁ antagonist: 0.3 mg/kg i.p.) produced an attenuated response at 24 h, which converted to a supernormal response, when it was administered 15–60 days after withdrawal from cocaine.
- 2.
  2. A challenge dose of SCH23390 exhibited enhanced catalepsy when given 15 days, but not at 24 h, after the last pretreatment dose of SCH23390 (0.1–1.0 mg/kg s.c.). In contrast, haloperidol catalepsy was not affected by the SCH23390 pretreatment.
- 3.
  3. However, in animals chronically pretreated with haloperidol (0.1–1.0 mg/kg s.c.), a challenge dose of SCH23390 as well as haloperidol exhibited attenuated cataleptic effects at 24 h and normal cataleptic responses at 15 days after the last dose of the pretreatment regimen.
- 4.
  4. Challenge doses of haloperidol or SCH23390 given to mice 24 h after chronic cocaine pretreatment produced enhanced and attenuated cataleptic responses, respectively; however, these responses were no longer produced when haloperidol or SCH23390 was given to mice pretreated chronically with a combination of cocaine and either haloperidol or SCH23390.
- 5.
  5. The enhanced catalepsy produced by a challenge dose of SCH23390 (15–60 days after chronic cocaine) was further potentiated when it was administered to animals that had been pretreated chronically with a combination of SCH23390 and cocaine, but was antagonized in animals pretreated chronically with haloperidol and cocaine. In contrast, the degree of enhanced cataleptic responses produced by a challenge dose of haloperidol 30–60 days after pretreatment chronically with a combination of cocaine + SCH23390 was similar to that seen after chronic cocaine alone. However, this enhanced response was antagonized in animals that had been pretreated chronically with the combination of cocaine+haloperidol.
- 6.
  6. The results suggest that the coadministration of SCH23390 with cocaine was able to block indirectly dopamine D₂ receptor inhibition (subsensitivity) induced during the early withdrawal period from chronic cocaine, despite the fact that by itself SCH23390 did not have an effect on haloperidol catalepsy. Accordingly, the stimulatory effects of dopamine D₂ receptors by a single administration of cocaine may be mediated mainly by an indirect stimulation of dopamine D₂ receptor function via its D₁ receptor stimulating action.
- 7.
  7. The coadministration of SCH23390 with cocaine rather aggravate the subsensitive effect of dopamine D₁ receptors (increased SCH23390 catalepsy) produced during long-term withdrawal period from chronic cocaine, but did not affect that of the dopamine D₂ receptor. On the other hand, the coadministration of haloperidol with cocaine normalized both D₁ and D₂ receptor subsensitive effect.
- 8.
  8. These result suggest that a single administration of SCH23390 or haloperidol after long-term withdrawal periods from chronic cocaine may not be effective as antipsychotic drugs because of further aggravation of suppressive behaviors. These results also provide evidence that D₂ receptor antagonists may be more effective as antipsychotic drugs than dopamine D₁ receptor antagonist, since the coadministration of haloperidol with cocaine normalized the abnormal behaviors seen during early and long-term withdrawal periods from chronic cocaine.
Dopaminergic and cholinergic interaction in cataleptic responses in mice
1997, Pharmacology Biochemistry and Behavior
The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.
Psychopharmacology of dopamine: The contribution of comparative studies in inbred strains of mice
1997, Progress in Neurobiology
Comparative studies of behavioral responses to centrally acting drugs in inbred strains of mice which show differences in brain neurotransmitter activity represent a major strategy in the investigation of the neurochemical bases underlying behavioral expression. Moreover, these studies represent a preliminary stage in behavioral genetic research since they allow quantitative scales to be established and suggest correlations to be tested in recombinant inbred strains. The present review evaluates results obtained in mice of the C57BL/6 (C57) and DBA/2 (DBA) inbred strains which have been used for studies of the behavioral pharmacology of dopamine (DA) and investigated for the functional and anatomical characteristics of their brain DA systems. Differences between C57 and DBA strain involve susceptibility and sensitivity as well as qualitative differences in the type or direction of the behavioral effects of DA agonists. Moreover, data on strain-dependent differences for DA metabolism, release and receptor densities and distribution provide important indications about the relationship between behavioral and central effects of DA agonists and, more generally, about the involvement of brain DA in behavior.
Comparative studies in C57 and DBA mice have also revealed differences in susceptibility to context-dependent, context-independent and stress-induced behavioral sensitization to psychostimulants. Consequently, they support the view that the term “behavioral sensitization” may define different phenomena in which different, independent genotype-related factors play a major role. Finally, studies on the behavioral and central effects of stressful experiences in C57 and DBA mice together with psychopharmacogenetic analyses, indicate that different symptomatological profiles may derive from genotype-dependent adaptation of brain DA receptors to environmental pressure. © 1997 Elsevier Science Ltd. All Right Reserved.

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Selective D2 dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D1 antagonist

Abstract

Neuropharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Neuropharmacol.

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Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

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Psychopharmacol.

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Nature

Selective D₂ dopamine receptor agonists prevent catalepsy induced by SCH 23390, a selective D₁ antagonist