The neurotrophic factor pleiotrophin modulates amphetamine‐seeking behaviour and amphetamine‐induced neurotoxic effects: evidence from pleiotrophin knockout mice

Abstract

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.

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation

“…We used a medium dose of amphetamine (3.0 g/kg, i.p. ) known to induce CPP in this mouse strain (Gramage et al, 2010a;Tzschentke, 2007). Thus, as expected, amphetamine caused a robust CPP in WT mice (Fig.…”

“…PTN (3 μM) limits amphetamine-and cocaine-induced decrease in PC12 and NG108-15 cell viability (Gramage et al, 2008;Gramage et al, 2010a;2010b). However, our results show that the net effect produced by PTN seems to differ in vivo, suggesting overall deleterious effects triggered by activation of PTN downstream pathways that could counteract its trophic actions on neurons.…”

“…In previous studies, it was shown that PTN-/-mice exhibit exacerbated amphetamine-induced dopaminergic damage in the nigrostriatal pathway (Gramage et al, 2010a;2010b). Thus, we hypothesized a possible neuroprotective role of PTN in response to the neurotoxic effects of amphetamine.…”

“…Interestingly, amphetamine-induced neurotoxic effects in the nigrostriatal pathway are enhanced in PTN-/-mice compared to WT mice (Gramage et al, 2010b;Soto-Montenegro et al, 2015). Also, it has to be noted that amphetamine-induced increase of GFAP-positive astrocytes, a hallmark of the neuroinflammation induced by this type of psychostimulants, was slightly increased in the striatum of PTN-/-mice (Gramage et al, 2010a). Overall, the data clearly suggest a modulatory role of PTN on amphetamine effects (Herradon and Perez-Garcia, 2014).…”

“…A single amphetamine administration causes a significant upregulation of PTN mRNA levels in the rat brain (Le Greves, 2005) suggesting that PTN takes part in a modulatory mechanism against the effects of amphetamine in the brain. Accordingly, extinction of amphetamine-induced conditioned place preference (CPP) is impaired in PTN genetically deficient (PTN-/-) mice (Gramage et al, 2010a). Furthermore, a periadolescent amphetamine treatment was found to produce transient cognitive deficits only in PTN-/-mice, not in wild type (WT) mice (Gramage et al, 2013a).…”