Role of dopamine and glutamate receptors in cocaine-induced social effects in isolated and grouped male OF1 mice
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)
- et al.
Behavioral profile of raclopride in agonistic encounters between male mice
Pharmacol Biochem Behav
(1994) - et al.
CGS 10746B: an atypical antipsychotic candidate that selectively decreases dopamine release at behaviorally effective doses
Life Sci
(1986) - et al.
Context specific enhancement of glutamate transmission by cocaine
Neuropsychopharmacology
(2000) - et al.
Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats
Eur J Pharmacol
(2000) - et al.
CGS 10746B, a novel dopamine release inhibitor, blocks the establishment of cocaine and MDMA conditioned place preferences
Pharmacol Biochem Behav
(1998) - et al.
Cocaine potentiates defensive behaviors related to fear and anxiety
Neurosci Biobehav Rev
(1999) - et al.
Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration in mice
Eur Neuropsychopharmacol
(2005) - et al.
Prevention of cocaine-induced convulsions and lethality in mice: effectiveness of targeting different sites on the NMDA receptor complex
Neuropharmacology
(2000) - et al.
The effect of the type of opponent in test of murine aggression
Behav Process
(1981) - et al.
Real time detection of acute (IP) cocaine-enhanced dopamine and serotonin release in ventrolateral nucleus accumbens of the behaving Norway rat
Pharmacol Biochem Behav
(1993)