Amphetamine treatment during adolescence causes long-term cognitive deficits in rats. Pleiotrophin (PTN) is a cytokine with important roles in the modulation of synaptic plasticity, whose levels of expression are significantly regulated by amphetamine administration. To test the possibility that the long-term consequences of periadolescent amphetamine treatment cross species and, furthermore, to test the hypothesis that PTN could be one of the factors involved in the adult cognitive deficits observed after periadolescent amphetamine administrations, we comparatively studied the long-term consequences of periadolescent amphetamine treatment (3 mg/kg intraperitoneal, daily during 10 days) in normal wild-type (PTN+/+) and in PTN genetically deficient (PTN−/−) mice. Within the first week after cessation of treatment, significant deficits in the passive avoidance and Y-maze tests were only observed in amphetamine-pretreated PTN−/− mice. However, 13 and 26 days after the last administration, we did not find significant differences in Y-maze between amphetamine- and saline-pretreated PTN−/− mice. In addition, we did not find any genotype- or treatment-related anxiogenic- or depressive-like behaviour in adult mice. Furthermore, we observed a significantly enhanced long-term potentiation (LTP) in CA1 hippocampal slices from saline-pretreated PTN−/− mice compared with saline-pretreated PTN+/+ mice. Interestingly, amphetamine pre-treatment during adolescence significantly enhanced LTP in adult PTN+/+ mice but did not cause any effect in PTN−/− mice, suggesting LTP mechanisms saturation in naïve PTN−/− mice. The data demonstrate that periadolescent amphetamine treatment causes transient cognitive deficits and long-term alterations of hippocampal LTP depending on the endogenous expression of PTN.