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Repeated drug administration leading to a progressively enhanced response persisting even after long periods of withdrawal, a phenomenon termed sensitization, is suggested to be involved in the development and maintenance of drug addiction and also relapse to drug-taking behaviour in weaned addicts. Thus, sensitization is known to be induced by agents acting directly or indirectly on the dopaminergic VTA-accumbens projection and development of sensitization is reported to require transient increase in glutamatergic neurons from the prefrontal cortex to the ventral tegmental area (VTA) leading to activation of the mentioned dopaminergic pathway (Everitt and Wolf, 2002). This suggestion is supported by studies in which the development of behavioural sensitization to cocaine, amphetamine, methamphetamine and morphine as one of forms of neuronal plasticity was prevented by noncompetitive (dizocilpine, memantine) and competitive (CGS 1975) glutamate NMDA receptor antagonists (e.g. Karler et al., 1991; De Montis et al., 1992; Kalivas and Alesdatter, 1993; Stewart and Druhan, 1993; Jeziorski et al., 1994; Karler et al., 1994; Ida et al., 1995; Morrow et al., 1995; Wolf et al., 1995; Kim et al., 1996; Tolliver et al., 1996; Vecina, 2000; Moravec, 2003). From these results NMDA receptor antagonists may be suggested as drugs of choice in the pharmacotherapy of addiction. However, some other experimental evidence suggests that instead of blocking sensitization, co-administration of NMDA receptor antagonists (dizocilpine, memantine) enhances the effect of the sensitizing drug or has more complex effects on the development of sensitization (Tzschentke and Schmidt, review, 2000). In our studies repeated treatment with methamphetamine in mice led to higher levels in mouse motility scores in the open field test than acute administration of the same dose, indicating behavioural sensitization. Neither development nor expression of sensitization was significantly affected by co-administration of the drug with memantine (for further details see abstract: Landa et al.). A cross-sensitization was observed between the action of drugs of abuse and repeated stress exposure (Schmidt et al. 1999). We have shown that glutamate is involved in the control of stress hormone release (Jezova et al. 1995) and administration of drugs, such as morphine modulates not only brain but also adrenal glutamate receptor subunit gene expression (Pirnik et al. 2001). Blockade of glutamate release by treatment with phenytoin in addiction-prone Lewis rats prevented the development of compulsory wheel running, our model of non-substance addictive behavior (Schwendt et al. 2003). Hormonal changes, which can emerge in parallel with changes in glutamate neurotransmission during the development of sensitization, remain to be elucidated.
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