The activation of the hypothalamic–pituitary–adrenal (HPA) axis, mediated by the stress response, culminates with the release, by the adrenal glands, of stress hormones: epinephrine, from the adrenal medulla, and glucocorticoids, from the adrenal cortex ( Biddie et al., 2012). It is widely recognized that emotionally arousing experiences, which activate the endogenous stress systems, are well remembered over time ( McGaugh, 2006). We recently demonstrated that the dissociative drug ketamine enhances memory performance through a mechanism that activates both the central and peripheral noradrenergic signaling ( Morena et al., 2017 Morena et al., 2020). Interestingly, it has been shown that amphetamine effects on memory consolidation are dependent on the amphetamine-induced activation of the noradrenergic system ( Lee and Ma, 1995 Colucci et al., 2019), a neurotransmitter system critically involved in the modulation of long-term memory consolidation ( Ferry et al., 1999 Roozendaal and McGaugh, 2011 McLumiere et al., 2017). While it generally enhances memory consolidation, it has been shown that it increases memory retrieval errors and alters working memory performances ( Martinez et al., 1980a Ballard et al., 2014 Bardgett et al., 2019).

Literature data demonstrated that amphetamine induces profound effects on learning and memory processes. It has been demonstrated that augmented levels of monoamines, in particular norepinephrine and dopamine, at the synaptic terminal, are responsible for euphoria, mood improvements and the general sense of wellbeing induced by amphetamine intakes ( De Wit et al., 2002 Pester et al., 2018). Such enhanced cytosolic concentration of monoamines reverts the transport direction of NET, DAT and SERT, thus increasing the amount of norepinephrine, dopamine and serotonin in the synaptic cleft ( Robertson et al., 2009). Once entered in the presynaptic neuron, amphetamine disrupts the monoamine storage vesicles and, consequently, increases monoamine levels in the neural cytosolic pool ( Teng et al., 1998). It is well known that amphetamine acts as a competitive substrate of the norepinephrine, dopamine and serotonin re-uptake transporters (NET, DAT and SERT, respectively) ( Sulzer et al., 2005). Chemical structure analogies among amphetamine and other monoamine neurotransmitters, such as norepinephrine, dopamine and serotonin, are crucial not only for the amphetamine’s mechanism of action, but also for its pharmacological properties ( Ferris and Tang, 1979). The psychostimulant amphetamine was discovered more than a century ago (see Heal et al., 2013 for a review). These dichotomic effects is dependent on stress-induced activation of the peripheral adrenergic response. Our findings showed that amphetamine enhances the consolidation of memory in rats subjected to mild stress condition, while it impairs long-term memory performance in rats exposed to strong stress. Recognition memory retention was assessed 24-h after training. Rats were thereafter exposed to a mild (1 min, 25 ± 1☌) or strong (5 min, 19 ± 1☌) forced swim stress procedure. To this aim, male adult Sprague Dawley rats were subjected to an object recognition task and intraperitoneally administered soon after training with amphetamine (0.5 or 1 mg/kg), or its corresponding vehicle. Furthermore, we evaluated whether such effects are dependent on the activation of the peripheral adrenergic system. Here, we investigated amphetamine effects on the consolidation of long-term recognition memory in rats exposed to different intensities of forced swim stress immediately after training.

Extensive evidence demonstrated that norepinephrine is crucially involved in the regulation of memory consolidation for stressful experiences. Amphetamine is a potent psychostimulant that increases brain monoamine levels.

Amphetamine effects