Cocaine-induced behaviour: dopamine D1 receptor antagonism by SCH 23390 prevents expression of conditioned sensitisation following repeated administration of cocaine

doi:10.1016/0028-3908(93)90161-U

Neuropharmacology

Volume 32, Issue 4, April 1993, Pages 387-391

https://doi.org/10.1016/0028-3908(93)90161-U Get rights and content

Abstract

Repeated administration of cocaine (15 mg/kg) (once a week for 4 weeks, day 1, 7, 14 and 21) in a conditioned environment produced significant hyperactivity and head bobbing effects which showed sensitisation. Pretreatment with the D₁ antagonist SCH 23390 (0.05 mg/kg), a dose that blocked d-amphetamine (2.5 mg/kg)-induced hyperactivity, antagonised the locomotor effects of cocaine after the second (day 7), third (day 14) and fourth (day 21) administration of cocaine but not the first day (day 1). Antagonism of head bobbing occurred on all 4 (1, 7, 14 and 21) days of treatment. In contrast, haloperidol (0.1 mg/kg) significantly reduced amphetamine-induced hyperactivity but potentiated the locomotor and stereotypic effects of cocaine, after administration of cocaine on days 1 and 7 and had no effect on cocaine-induced behaviour on days 14 and 21. The results suggest that the locomotor effects and head bobbing produced by cocaine, together with the expression of sensitisation to these effects in the conditioned environment, involve activation of post-synaptic D₁ receptors. The potentiation of the effects of cocaine by a small dose of haloperidol may indicate increased release of dopamine due to blockade of pre-synaptic D₂ autoreceptors.

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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase implicated in numerous physiological processes and cellular functions through its ability to regulate the function of many proteins, including transcription factors and structural proteins. GSK-3β has been demonstrated to function as a regulator of multiple behavioral processes induced by drugs of abuse, particularly psychostimulant drugs. In this review, we provide an overview of the regulation of GSK-3β activity produced by psychostimulants, and the role of GSK-3β signaling in psychostimulant-induced behaviors including drug reward, associative learning and memory which play a role in the maintenance of drug-seeking. Evidence supports the conclusion that GSK-3β is an important component of the actions of psychostimulant drugs and that GSK-3β is a valid target for developing novel therapeutics. Additional studies are required to examine the role of GSK-3β in distinct cell types within the mesolimbic and memory circuits to further elucidate the mechanisms related to the acquisition, consolidation, and recall of drug-related memories, and potentially countering neuroadaptations that reinforce drug-seeking behaviors that maintain drug dependence.
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Interestingly, the locomotor sensitization observed in the MDRI group was associated to a dopamine release sensitization in the nucleus accumbens after a cocaine challenge (Puig et al., 2012). As previous studies showed that D1 and D2 dopamine receptors play a role in the development and expression of behavioral sensitization (Li et al., 2000; McCreary and Marsden, 1993; Nelson et al., 2012; Sim et al., 2013; Tobón and Kuzhikandathil, 2014; Thompson et al., 2010), it was also interesting to evaluate the consequences of the ODRI and MDRI cocaine administration patterns on dopamine receptor regulations, in different brain structures forming the two major dopaminergic pathways in the brain: the ventral tegmental area and the nucleus accumbens for the mesolimbic pathway, and the substantia sigra and the caudate putamen for the nigrostriatal pathway. These two pathways play a key role in the rewarding effects (Hyman, 1996) and the locomotor adaptations (Kalivas et al., 1992) following repeated administrations of cocaine.
The purpose of this review is to illustrate the importance of pharmacodynamic and pharmacokinetic factors in the complexity of the behavioral and neurochemical adaptations that occur following chronic treatments with drugs of abuse, with a focus on opioids and psychostimulants. As these neuroadaptations are thought to contribute to the pathogenesis and persistence of addiction, it is important to well understand how they can be modulated. The experimental results clearly show that changes observed are depending on the binding properties of the ligands, drug administration patterns, brain structures considered, and withdrawal periods. Thus, pharmacodynamic and pharmacokinetic factors play a key role, and may highly contribute to the great heterogeneity of the results reported in the literature regarding neuroadaptations observed following repeated treatments with drugs of abuse, each investigator using different protocols and/or different ligands, even if their targets/receptors are the same.
The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat
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The ability of SCH-23390 to block these effects of nicotine were not dependent on the non-specific suppression of behavioral activity since SCH-23390 did not alter the baseline response in rats previously exposed to nicotine, and data were similar to those from rats pretreated with saline. This is in agreement with previous studies showing no effect of SCH-23390 on baseline response in naïve animals (O’Neill et al., 2007; McCreary and Marsden, 1993; Daniela et al., 2004). Our findings coincide with the previous finding that SCH-23390 blocked acute nicotine-induced locomotor activity (O’Neill et al., 2007).
Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a range of psychostimulants, and other compounds, and may model neuroplastic changes seen in addictive processes and neuropsychiatric disease. The aim of the present study was to investigate the effect of dopamine D₁ receptor (D₁R) ligands on nicotine-induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically treated (5 days) with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. Following a 5 day withdrawal period, rats were pretreated with vehicle or the D₁R antagonist SCH-23390 (0.03 mg/kg; i.p.) and challenged with nicotine. Either 45 min or 24 h post-challenge, the striatum was isolated and ex vivo receptor binding and cAMP accumulation (using LC–MS/MS) were assessed. It was shown that chronic nicotine administration induced the development and expression of locomotor sensitization, of which the latter was blocked by SCH-23390. Nicotine-induced sensitization had no effect on forskolin stimulated cAMP accumulation but increased the efficacy of dopamine for the D₁R and decreased the potency of D₁R agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. No effect on D₁ receptor binding was observed. Moreover, time dependent effects were observed between tissue taken 45 min and 24 h post-challenge. The present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the D₁R. Together these data suggest that changes in D₁R signaling in the dorsal striatum may play an important role in the underlying mechanisms of nicotine-induced behavioral sensitization.
Extending therapeutic use of psychostimulants: Focus on serotonin-1A receptor
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Despite a number of medicinally important pharmacological effects, the therapeutic use of psychostimulants is limited because of abuse potential and psychosis following long term use. Development of pharmacological agents for improving and extending therapeutic use of psychostimulants in narcolepsy, attention deficit hyperactivity disorder, Parkinson's disease, obesity and as cognitive enhancer is an important research imperative. In this regard, one potential target system is the 5-hydroxytryptamine (5-HT; serotonin) neurotransmitter system. The focus of the present article is to evaluate a potential role of 5-HT-1A receptor in the alleviation of abuse potential and psychosis-induced by prescription psychostimulants amphetamines and apomorphine.
Synaptic contacts between dopamine systems and 5-HT-1A receptors are traced. Studies on serotonin-1A influences on the modulation of dopamine neurotransmission and psychostimulant-induced behavioral sensitization are accumulated.
Inhibition of amphetamine and apomorphine-induced behavioral sensitization by co administration of 5-HT-1A agonists cannot be explained in terms of direct activation of 5-HT-1A receptors, because activation of pre- as well as postsynaptic 5-HT-1A receptors tends to increase dopamine neurotransmission.
Long term use of amphetamine and apomorphine produces adaptive changes in 5-HT-1A receptor mediated functions, which are prevented by the co-use of 5-HT-1A agonists. In view of extending medicinal use of psychostimulants, it is important to evaluate the effects of co-use of 5-HT-1A agonists on potential therapeutic profile of amphetamine and apomorphine in preclinical research. It is also important to evaluate the functional significance of 5-HT-1A receptors on psychostimulant-induced behaviors in other addiction models such as drug self-administration and reinstatement of drug seeking behavior.
Serotonergic involvement in methamphetamine-induced locomotor activity: A detailed pharmacological study
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The D1 receptor antagonist SCH23390 and the D2 receptor antagonist haloperidol significantly reduced hyperlocomotion induced by METH without affecting locomotor activity alone, supporting a role for both receptors in the ability of METH to induce hyperactivity. This reflects previous studies conducted with MDMA [19], amphetamine and cocaine [30,76] and confirms those recorded with METH [12–16]. Attenuation of METH-induced locomotor activity by the DA receptor partial agonists (−)3PPP, terguride and aripiprazole further suggests the importance of DA D2 receptor activation, although caution should be elicited when interpreting terguride responses as the locomotor response induced by METH was lower than that seen in the other experiments.
The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT_1A, 5-HT_1B, 5-HT_2A and 5-HT_2C receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT_2C receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D₁ and D₂ receptor antagonists SCH23390 and haloperidol, D₂ partial agonists terguride, (−)3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT_1B antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT_1A antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED = 0.125 mg/kg), WAY163909 (MED = 3 mg/kg), Ro 60-0175 (MED = 3 mg/kg), haloperidol (MED = 0.1 mg/kg), clozapine (MED = 5 mg/kg), aripiprazole (MED = 1 mg/kg), (−)3PPP (MED = 3 mg/kg), terguride (MED = 0.2 mg/kg) and SCH23390 (MED = 0.001325 mg/kg) attenuated METH-induced locomotor activity. Administration of 20 mg/kg fluvoxamine attenuated, while SB242084 (MED = 0.25 mg/kg) potentiated METH-induced activity.
These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT_2A and 5-HT_2C receptors, but demonstrate that 5-HT_1B receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated.
Cocaine-induced hyperactivity and sensitization are dependent on GSK3
2009, Neuropharmacology
Citation Excerpt :
The mechanism by which GSK3 prevents the development of cocaine-induced sensitization is currently unknown; however there are a number of neural and anatomical substrates underlying the development of cocaine-induced sensitization, one of which involves dopamine. For example, administration of the dopamine D1 receptor antagonist SCH 23390 prior to daily cocaine prevents the development of sensitization (McCreary and Marsden, 1993), and dopamine D1 receptor knockout mice do not show locomotor sensitization to cocaine as compared to wild-type controls (Karlsson et al., 2008). The development of cocaine sensitization can also be blocked by the dopamine D2 receptor antagonist haloperidol (Karler et al., 1994).
Glycogen synthase kinase 3 (GSK3) is a critical mediator of many intracellular signaling systems. The activity of GSK3 is regulated by several kinases, with inactivation occurring via phosphorylation of the inhibitory serine-21 (α-isoform) and serine-9 (β-isoform) residues. Here, we investigated whether acute cocaine administration regulates GSK3 activity and if inhibition of GSK3 by valproate or the selective GSK3 inhibitor SB 216763 would attenuate cocaine-induced behaviors in mice. Mice injected with cocaine (20 mg/kg, i.p.) showed a reduction in the phosphorylation of GSK3β in the caudate putamen, reflecting an increase in the activity of the kinase. To assess the role of GSK3 in cocaine-induced hyperactivity, mice were pretreated with valproate (50–300 mg/kg, i.p.), SB 216763 (0.25–7.5 mg/kg, i.p.), or the appropriate vehicle prior to saline or cocaine (20 mg/kg, i.p.). Valproate or SB 216763 produced significant dose-dependent reductions in cocaine-induced ambulatory and stereotypic activity. Repeated administration of cocaine can result in an augmentation of the locomotor-stimulatory effects of the drug, a phenomenon referred to as sensitization. Mice pretreated with SB 216763 (2.5 mg/kg, i.p.) prior to daily cocaine (20 mg/kg, i.p.) for 5 days showed a significant attenuation of the development of cocaine-induced behavioral sensitization following a cocaine challenge on day 13. These results indicate that cocaine activated GSK3β in the caudate putamen and that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long-term neuroadaptations produced by repeated cocaine, therefore suggesting a role for GSK3 in the behavioral and neurochemical manifestations associated with cocaine exposure.

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^∗: Present address: Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham BN4 7ET, U.K.

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Neuropharmacology

Abstract

References (26)

Repeated atypical neuroleptic administration: effects on central dopamine metabolism monitored by in vivo voltammetry

Eur. J. Pharmac.

Cocaine-induced behavioural sensitisation and D₁ receptor function in rat nucleus accumbens and striatum

Brain Res.

Persistence of neurochemical changes in dopamine systems after repeated cocaine administration

J. Pharmac. Exp. Ther.

Sensitisation to cocaine following chronic administration in the rat

Adv. Behav. Biol.

Psychoses induced by central nervous system stimulants and related drugs

Dopaminergic neurones: effects of antipsychotic drugs and amphetamine on single cell activity

J. Pharmac. Exp. Ther.

Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding

Synapse

The effect of chronic administration of cocaine on locomotor activity and on a cognitive task: evidence for differential development of tolerance and sensitisation

Br. J. Pharmac.

Rapid tolerance to neuroleptic induced stimulation of dopamine release in freely moving rats

J. Pharmac. Exp. Ther.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the meso-limbic system of freely moving rats

The effect of repeated doses of cocaine on the rat

J. Pharmac. Exp. Ther.

Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens

Alcohol Drug Res.

Self-inhibition by dopaminergic neurones. An alternative to the “neuronal feedback loop” hypothesis for the mode of action of certain psychotropic drugs

Science

Cited by (59)

Glycogen synthase kinase-3 signaling in cellular and behavioral responses to psychostimulant drugs

Role of pharmacokinetic and pharmacodynamic parameters in neuroadaptations induced by drugs of abuse, with a focus on opioids and psychostimulants

The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat

Extending therapeutic use of psychostimulants: Focus on serotonin-1A receptor

Serotonergic involvement in methamphetamine-induced locomotor activity: A detailed pharmacological study

Cocaine-induced hyperactivity and sensitization are dependent on GSK3