Substance use disorder is a chronic problem involving alterations in both reward system and memory that are altered due to prolonged drug use (Nestler, 2002; Bender and Torregrossa, 2020). Cocaine, one of the most frequently abused drugs (World Drug Report, 2023), induces euphoria by blocking monoamine reuptake transporters, particularly the dopamine uptake transporter (DAT) in presynaptic neurons (Rothman and Baumann, 2003). In part, the reinforcing and rewarding effects of cocaine are mediated by the mesocorticolimbic system, which is a pathway from the midbrain's ventral tegmental area (VTA) to the nucleus accumbens (Koob and Nestler, 1997). Substantial glutamatergic input from various corticolimbic structures, including the prefrontal cortex (PFC), amygdala, and hippocampus, is received by both the VTA in the cell body region and nucleus accumbens in the terminal region. These structures, involved in reward evaluation, conditioning, and learning, contribute to the interplay between glutamate and the dopaminergic system in addiction (Tzschentke and Schmidt, 2003). Cocaine indirectly affects glutamate transmission in the nucleus accumbens, leading to lasting changes in neuronal function in areas such as the PFC and hippocampus, which may be linked to cocaine's behavioral effects (Schmidt and Pierce, 2010).

Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts by binding to ionotropic receptors, such as N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate receptors (kainate), and metabotropic receptors (mGlu) (Reiner and Levitz, 2018). Recognizing glutamate's role in understanding the neurophysiological and behavioral outcomes of substance abuse, glutamatergic mechanisms may contribute to plastic changes in the brain, fostering addictive behavior (Rich and Torregrossa, 2018). Tetanus-induced Hebbian long-term potentiation (LTP) is a key synaptic plasticity, a fundamental molecular mechanism for learning and memory (Lynch, 2004). Initially observed in the hippocampus, this process relies on NMDA-mediated Ca2+ influx, which subsequently triggers a signaling cascade dependent on CaMKII. As a result, there is a notable increase in the expression of postsynaptic AMPA, contributing to the strengthening of synaptic connections (Bliss and Collingridge, 1993). While modulatory neurotransmitters such as dopamine can regulate LTP, these processes specifically take place at glutamatergic excitatory synapses. This process relies on glutamate release from the presynaptic neuron, synchronized with temporally coordinated postsynaptic depolarization (Bisaz et al., 2014).

Hippocampal LTP can be induced by Ca2+ entry through L-type calcium channels (LTCC) (Raymond and Redman, 2002; Sridharan et al., 2020). LTCC are multimeric proteins composed of pore-forming subunits, namely Cav1.2 or Cav1.3, along with accessory subunits (Zamponi et al., 2015). Studies with hippocampal Cav1.2 knockout mice revealed reduced LTP, impaired memory, and spatial learning (Moosmang et al., 2005). Additionally, there is evidence linking increased Cav1.3 expression in the VTA to cocaine dependence (Martínez-Rivera et al., 2017).

Preclinical evidence suggests that LTCC blockers reduce the dependence-related effects of alcohol, opioids, psychostimulants, and nicotine (Pucilowski et al., 1995; Martellotta et al., 1995; Uhrig et al., 2017). This study aimed to test if pretreating mice with the LTCC antagonist isradipine could reduce cocaine-induced behaviors. We also investigated whether isradipine's effects were linked to changes in glutamatergic neurotransmission.