The mesoaccumbens dopamine system is intricately in-volved in the locomotor stimulation produced by cocaine and sensitization of this effect following repeated cocaine administration. The mechanisms responsible for the ex-pression of sensitized locomotion appear to involve alter-ations in both presynaptic (increased dopamine release) and postsynaptic (increased responsiveness of dopamine Dl receptors) aspects of dopamine neurotransmission within the nucleus accumbens. The present experiments used behavioral and single-cell electrophysiological tech-niques to determine the persistence of sensitization and of enhanced postsynaptic responses to cocaine within the nucleus accumbens following various periods of withdraw-al from repeated cocaine treatment (10 mglkg i.p., twice daily, 14 d). Behavioral sensitization to the locomotor stim-

Abstract not found

Repeated administration of stimulant drugs leads to lasting changes in their behavioral and neurochemical effects. These changes are initiated by drug actions in the somatodendritic regions of midbrain dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) and continue to develop for a period of time after termination of drug treatment. Here we show that repeated administration of amphetamine (3.0 mg/kg, i.p.; three injections, once every other day) results in sustained increases in basic fibroblast growth factor immunoreactivity (bFGF-IR) in both VTA and SNc, 200– 500 % over that seen in saline-treated animals. Increases were observed 24 hr, 72 hr, 1 week and 1 month after the last drug injection. Because glutamate participates in the development of sensitization to stimulant drugs, we assessed the effect of the glutamate antagonist, kynurenic acid (KYN), on amphetamineinduced bFGF-IR. Coadministration of KYN prevented the in-Repeated administration of stimulant drugs, such as amphetamine, cocaine, and morphine, leads to an enduring enhancement of their behavioral activating effects that is associated with changes in the functioning of the midbrain dopamine (DA) system (Robinson and Becker, 1986; Kalivas and Stewart, 1991). One frequently reported change is enhanced DA overflow in striatal regions in response to acute drug challenge. Importantly, this change is long-lasting (Robinson et al., 1988; Paulson et al.,

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca 2þ signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca 2þ signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed