Role of dopamine and glutamate receptors in cocaine-induced social effects in isolated and grouped male OF1 mice

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Abstract

Cocaine administration in paired male mice decreases social contacts as well as increases avoidance and flee elements. As dopamine (DA) and glutamate seem to be involved in some of cocaine's effects, an attempt was made to assess whether a range of associated receptors influenced the social impacts of this drug of abuse. The NMDA antagonist memantine (10 and 40 mg/kg); the AMPA antagonist CNQX (1 and 20 mg/kg); the DA release inhibitor CGS 10746b (2 and 8 mg/kg): the DA D1 antagonist SCH 23390 (0.05 and 0.5 mg/kg); and the DA D2/D3 antagonist raclopride (0.03 and 0.3 mg/kg) were administered prior to 25 mg/kg of cocaine and behaviour was evaluated during an encounter between an experimental and a standard opponent in a neutral cage for 10 min. Memantine reverts cocaine-induced social withdrawal and the increase in avoidance and flee, CNQX being effective only in these latter actions. On the other hand, SCH 23390 counteracts the social as well as the defensive action of cocaine, raclopride being effective only in blocking the cocaine-induced increase in avoidance and flee behaviours. In conclusion, although both neurotransmitter systems are involved in the effects of cocaine on social behaviour, NMDA and D1DA receptors seem to have an important role.

Introduction

Cocaine administration induces a complex series of changes in social behaviour, however, there is no agreement regarding its specific actions on aggression. Several studies report increased irritability and aggression in humans after a prolonged use of high doses of cocaine (Bukstein, 1996, Denison et al., 1997, Gordon et al., 1996, LeSage et al., 1999, McCormick and Smith, 1995, Miller et al., 1991). On the contrary, a number of authors have not found any correlation between cocaine intake or its withdrawal and an increase in aggressive behaviours (Dhossche, 1999, Moeller et al., 1997). These discrepancies are equally observed when studying the link between cocaine and aggression with animal models. In mice and rats, no changes or a reduction in threat and attack has been found after different cocaine doses (Miczek and O'Donnell, 1978, Miczek, 1979). Conversely, increases in attack have been found in other studies using mice, rats or primates (Emley and Hutchinson, 1983, Hadfield et al., 1982, Filibeck et al., 1988, Long et al., 1996). In addition to altering aggressiveness, cocaine induces other changes in interactive social behaviours. An increase in avoidance and flee has been generally reported (Blanchard and Blanchard, 1999). On the other hand, there is a general consensus regarding the reduction in social contacts with conspecifics observed after cocaine administration (Darmani et al., 1990, Rademacher et al., 2002).

In a recent work performed in our laboratory (Estelles et al., 2004), we evaluated the complex actions of cocaine on social behaviour of mice exposed to different housing situations (isolated- or group-housed) using confrontations between two male mice in a neutral area, and administering different doses of cocaine (6, 25 and 50 mg/kg) given in a single or binge pattern (three doses in 24 h). No increases in aggression were observed in any situation tested. Instead, the two highest doses of cocaine, both in a single and binge administration, decreased aggressive behaviours in isolated mice, no changes being found in grouped animals. In both types of animals, cocaine increased defensive elements (avoidance/flee) and abolished social contacts. These results suggest that cocaine, besides presenting an antiaggressive action, also exerts an anxiogenic-like effect.

Among brain neurotransmitters, dopamine (DA) is the most extensively implicated in the mechanism of drug addiction, not only as the substrate of psychostimulant reward, but more generally as a substrate of drug-related learning and neuroadaptation (Di Chiara et al., 2004). Acute or binge administration of cocaine induces a release of DA in the Nucleus Accumbens (N Acc) (Broderick et al., 1993, Zhang et al., 2001), and an increase of its turnover during cocaine self-administration in this and other brain structures, such as the ventral pallidum or lateral hypothalamus (Smith et al., 2003). Both the D1 and D2 DA family receptors seem to be involved in cocaine effects. Administration of the D1 DA receptor antagonist SCH 23390 alone or in combination with a D2 antagonist prevents cocaine-induced conditioned place preference (CPP) (Baker et al., 1998, Liao et al., 1998). Reinstatement of cocaine-induced CPP after extinction either after a priming injection of cocaine or conditioned cues is also blocked with D1 and D2 DA antagonists (Sanchez et al., 2003, Sun and Rebec, 2005). The blockade of D1 receptors also prevents the sensitised response to cocaine-conditioned rewarding effects (Shippenberg and Heidbreder, 1995). Hyperdefensiveness observed in animals chronically treated with cocaine is completely blocked after administration of the D2 DA antagonist sulpiride (Filibeck et al., 1988).

Another brain neurotransmitter, glutamate, is also implicated in psychostimulant actions. Acute and chronic administration of cocaine in rats significantly elevates glutamate levels in various limbic brain areas (Bell et al., 2000). Recent data indicate that activation of glutamatergic afferents from the amygdala and prefrontal cortex is critical in the expression of addictive behaviours. Using the reinstatement model of relapse, regardless of the stimulus modality, there is a dependence on glutamate neurotransmission in the prefrontal cortex (Capriles et al., 2003, McFarland et al., 2003, Shalev et al., 2002). Ionotropic glutamate receptors in the N Acc influence self-administration of cocaine and relapse (Cornish and Kalivas, 2000), cocaine-induced hyperlocomotion (Witkin, 1993) and behavioural sensitisation (Wolf, 1998). Cocaine-induced CPP is also abolished after the blockade of glutamatergic neurotransmission (Cervo and Samanin, 1995, Kim et al., 1996, McGeehan and Olive, 2003, Slusher et al., 2001).

The aim of the present work is to assess the role played by dopamine and glutamate neurotransmission in the social behavioural effects induced by cocaine administration in male mice. To study DA transmission, drugs acting on different DA receptors or those inhibiting its release have been used. The D1 DA receptor antagonist SCH 23390, although exerting a slight effect on the D2 receptor, is considered to be a specific D1 receptor antagonist (Hyttel, 1983). To evaluate the role of D2 DA receptors, a highly selective D2 receptor antagonist, raclopride, has been used (de Paulis et al., 1986), although it also acts as a D3 receptor antagonist. Finally, a DA release inhibitor CGS 10746B, which does not alter DA metabolism or occupy DA receptors, was additionally employed (Altar et al., 1986). Glutamate neurotransmission was studied through two of its receptors, the NMDA and the AMPA. To this purpose, memantine, a low affinity noncompetitive NMDA receptor antagonist was used and also CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), the competitive antagonist which acts on the glutamate recognition site of AMPA receptors (Witkin et al., 2003). The doses have been chosen on the basis of previous studies performed in our and other laboratories (Blanchard and Blanchard, 1999, Estelles et al., 2004, Felip et al., 2001, Itzhak and Martin, 2002, Miczek et al., 1999, Rodriguez-Arias et al., 1998, Rodriguez-Arias et al., 1999, Rodriguez-Arias et al., 2002, Sukhotina and Bespalov, 2000) except for CNQX, which were tested prior to this study. The low dose was behaviourally inactive for all the compounds and the highest presented a potent antiaggressive effect, except for CNQX, which did not have any antiaggressive action. Previous reports have shown that certain environmental conditions can alter the reinforcing effects of drugs like cocaine (LeSage et al., 1999). Many of these stimuli, such as the housing conditions of the animals, also produce changes in DA function (Bowling et al., 1983, Lapiz et al., 2001). To assess how housing conditions could affect the action of the drugs studied, animals were housed in groups or in isolation prior to the behavioural test.

Section snippets

Subjects

Four hundred and eighty male mice of the OF1 strain (CHARLES RIVER, Barcelona, Spain) were used in this study. The animals were aged 42 days on arrival at the laboratory, and were housed under standard conditions with constant temperature (21 ± 2 °C), a reversed light schedule (white lights on 19:30–07:30 h), and food and water available ad libitum (except during the behavioural test). Tests took place when animals were aged between 63 and 70 days. Half of the mice were used as experimental

Effect of dopamine and glutamate antagonists on cocaine-induced behavioural changes in group-housed animals

Time spent by mice in Non Social Exploration (Kruskal–Wallis p < 0.001) was increased in groups treated with cocaine plus memantine (p < 0.001 for Coc-Mem10 and p < 0.02 for Coc-Mem40), the high dose of CNQX (p < 0.02), CGS (p < 0.05 for Coc-CGS2 and p < 0.001 for Coc-CGS8), the low dose of SCH (p < 0.02), and raclopride (p < 0.001) in comparison with controls. Conversely, animals treated with cocaine and the high dose of SCH spent less time in this behaviour (p < 0.001). Groups treated with cocaine plus the

Discussion

Our results show that both DA and glutamate receptors are implicated in the effect of cocaine on social behaviour. To our knowledge, this is the first work evaluating the relative role of both neurotransmitter systems in the social actions of cocaine, although their influence on other effects of cocaine, such as reward, has been proved. Within the glutamate receptors, NMDA seems to play a more important role, as memantine administration reverts most of the cocaine effects, AMPA receptors being

Acknowledgements

This research was supported by the following grants: Ministerio de Educación y Ciencia, Dirección General de Investigación and FEDER (Ref BSO2002-00106); Ministerio de Sanidad y Consumo, Delegación del Gobierno para el Plan Nacional sobre Drogas (Proyectos de Investigación, 2004); and Instituto de Salud “Carlos III” (FIS), Redes Temáticas de Investigación Cooperativa (G03/005). We wish to thank Ms. Miriam Phillips for the English revision of the manuscript.

References (82)

  • D.J. Calcagnetti et al.

    Psychostimulant-induced activity is attenuated by two putative dopamine release inhibitors

    Pharmacol Biochem Behav

    (1992)
  • L. Cervo et al.

    Effects of dopaminergic and glutamatergic receptor antagonists on the acquisition and expression of cocaine conditioning place preference

    Brain Res

    (1995)
  • D.M. Dhossche

    Aggression and recent substance abuse: absence of association in psychiatric emergency room patients

    Compr Psychiatry

    (1999)
  • G. Di Chiara et al.

    Dopamine and drug addiction: the nucleus accumbens shell connection

    Neuropharmacology

    (2004)
  • G.S. Emley et al.

    Unique influences of ten drugs upon post-shock induced biting attack and pre-shock manual responding

    Pharmacol Biochem Behav

    (1983)
  • J. Estelles et al.

    Social behavioural profile of cocaine in isolated and grouped male mice

    Drug Alcohol Depend

    (2004)
  • J. Estelles et al.

    Prenatal cocaine exposure alters spontaneous and cocaine-induced motor and social behaviors

    Neurotoxicol Teratol

    (2005)
  • D. French et al.

    Effects of the dopamine release inhibitor, CGS 10746B, on the locomotor stimulant and discriminative stimulus effects of cocaine and methamphetamine

    Pharmacol Biochem Behav

    (1993)
  • M.G. Hadfield et al.

    Cocaine increases isolation-induced fighting in mice

    Pharmacol Biochem Behav

    (1982)
  • J. Hyttel

    SCH23390—the first selective dopamine D-1 antagonist

    Eur J Pharmacol

    (1983)
  • P. Hyytiä et al.

    Site-specific NMDA receptor antagonists produce differential effects on cocaine self-administration in rats

    Eur J Pharmacol

    (1999)
  • Y. Itzhak et al.

    Cocaine-induced conditioned place preference in mice: induction, extinction and reinstatement by related psychostimulants

    Neuropsychopharmacology

    (2002)
  • P.W. Kalivas

    Glutamate systems in cocaine addiction

    Curr Opin Pharmacol

    (2004)
  • H.S. Kim et al.

    Inhibition of MK-801 of cocaine-induced sensitisation, conditioned place preference and dopamine receptor supersensitivity in mice

    Brain Res Bull

    (1996)
  • M.G. LeSage et al.

    Preclinical research on cocaine self-administration: environmental determinants and their interaction with pharmacological treatment

    Neurosci Biobehav Rev

    (1999)
  • S.F. Long et al.

    The effects of cocaine and nandolone co-administration on aggression in male rats

    Prog Neuro-Psychopharmacol Biol Psychiatry

    (1996)
  • A.M. Maldonado et al.

    Handling alters cocaine-induced activity in adolescent but not adult male rats

    Physiol Behav

    (2005)
  • R.A. McCormick et al.

    Aggression and hostility in substance abusers: the relationship to abuse patterns, coping style, and relapse triggers

    Addict Behav

    (1995)
  • F.G. Moeller et al.

    Antisocial personality disorder and aggression in recently abstinent cocaine dependent subjects

    Drug Alcohol Depend

    (1997)
  • D.J. Rademacher et al.

    Effects of cocaine and putative atypical antipsychotics on rat social behavior. An ethopharmacological study

    Pharmacol Biochem Behav

    (2002)
  • M. Rodriguez-Arias et al.

    Effects of risperidone and SCH 23390 on isolation-induced aggression in male mice

    Eur Neuropsychopharmacol

    (1998)
  • M. Rodriguez-Arias et al.

    Effects of SCH 23390, Raclopride and haloperidol on morphine withdrawal-induced aggression in male mice

    Pharmacol Biochem Behav

    (1999)
  • C.J. Sanchez et al.

    Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior

    Neuroscience

    (2003)
  • M.D. Schechter

    Cocaine discrimination is attenuated by isradipine and CGS 10746B

    Pharmacol Biochem Behav

    (1993)
  • M.D. Schechter et al.

    Role of dopamine D1 receptors in cocaine lethality

    Pharmacol Biochem Behav

    (1995)
  • J.E. Smith et al.

    Brain neurotransmitter turnover rates during rat intravenous cocaine self-administration

    Neuroscience

    (2003)
  • R. Smoothy et al.

    Alcohol and social behaviour in group-housed female mice

    Physiol Behav

    (1986)
  • J.M. Witkin

    Blockade of the locomotor stimulant effects of cocaine and methamphetamine by glutamate antagonists

    Life Sci

    (1993)
  • M.E. Wolf

    The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

    Prog Neurobiol

    (1998)
  • Y. Zhang et al.

    Effect of acute binge cocaine on levels of extracellular dopamine in the caudate putamen and nucleus accumbens in male C57BL/6J and 129/J mice

    Brain Res

    (2001)
  • D.A. Baker et al.

    Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference

    Synapse

    (1998)
  • Cited by (0)

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