Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.

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Adenosine A 1 receptor (A 1 ) protein and mRNA is increased in the nucleus accumbens following repeated cocaine treatment. In spite of this protein up-regulation, A 1 agonist-stimulated [ 35 S]GTPcS binding was attenuated in accumbens homogenates of rats withdrawn for 3 weeks from 1 week of daily cocaine injections. Cellular subfractionation revealed that the discrepancy between total A 1 protein and G protein coupling resulted from a smaller proportion of receptors in the plasma membrane. The decrease in functional receptor in the plasma membrane was further indicated by diminished formation of heteromeric receptor complex consisting of A 1 and dopamine D 1A receptors. To explore the functional significance of the altered distribution of A 1 receptors, at 3 weeks after discontinuing repeated cocaine or saline, animals were injected with cocaine and 45 min later the subcellular distribution of A 1 receptors quantified. Whereas a cocaine challenge in repeated saline-treated animals induced a marked increase in membrane localization of the A 1 receptor, the relative distribution of receptors in repeated cocaine rats was not affected by acute cocaine. These data suggest that the sorting and recycling of A 1 receptors is dysregulated in the nucleus accumbens as the consequence of repeated cocaine administration.

1 The pharmacological modulation of opioid actions by drugs acting on heterologous mechanisms could be useful to overcome some of the main problems associated with the use of opiate agonists. Based on previous ®ndings on the interactions between yohimbine and opioid drugs, we have further studied the e ects of yohimbine on the antinociceptive and positive-negative reinforcing e ects of morphine (m opioid receptor-preferring agonist), U-50,488 (k agonist) and SNC80 (d agonist). 2 Pretreatment with yohimbine completely blocked the antinociception provided by the three opioid agonists in the mouse tail-immersion test. 3 A similar blockade of SNC80 and U-50,488-induced antinociception was observed with yohimbine in the mouse hot plate test at the same doses. In this paradigm, the e ect of the k agonist was very slight and the actions of yohimbine rather variable. 4 In place conditioning experiments with SD (Sprague ± Dawley) male rats, yohimbine alone was inactive but it limited the preference induced by morphine and SNC80 and the aversive e ect of U-50,488. Impaired novelty preference was also observed with the combination of yohimbine and U-50,488. 5 It is concluded that yohimbine tends to limit opioid antinociception and the addictive potential of m and d opioid agonists. More selective drugs could help to understand the mechanisms involved in these actions.