Synaptic Molecules Expression in the Hippocampus After Reinstatement of Methamphetamine Conditioned Place Preference

Introduction Drug addiction treatment remains a significant challenge in addiction relapse, which is associated with brain regions including the hippocampus (Hip). The Hip is part of the limbic system and linked to memory and learning processes closely associated with relapse. Drugs alter glutamate neurotransmission and molecules such as presynaptic and postsynaptic membrane proteins and synaptic modulators. Methamphetamine (METH) is a psychostimulant and induces addictive behaviors. METH has high addiction potential. However, the specific synaptic molecules in the Hip under METH relapse conditions are unclear. Methods In the study, mice were given 2.5 mg/kg METH for 7 days, followed by extinction and reinstatement with 1.0 mg/kg METH. Western blot analysis was used to examine the expression of glutamatergic receptors, synapse‐related proteins, and other molecules. Results 1.0 mg/kg METH induced the reinstatement of conditioned place preference (CPP) in mice. The expression of Dopamine D1 receptor (D1R), Vesicular glutamate transporter 1 (VGLUT1), VGLUT2, N‐methyl‐D‐aspartate receptor 2B (NR2B), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR), synaptophysin (Syn), postsynaptic density protein 95 (PSD‐95), and brain‐derived neurotrophic factor (BDNF) was increased. The expression of Cerebellin 1 precursor (Cbln1), complement component 1q subcomponent (C1q), and Homeobox A5 (Hoxa5) was upregulated; the expression of Cbln3, neurogranin (Ng), and neurogenic differentiation 2 (NeuroD2) was decreased. Discussion The results suggest that synaptic molecules in the Hip are involved in METH relapse. SIGNIFICANCE STATEMENT Using a METH‑induced conditioned place preference reinstatement model in male C57BL/6 mice, this study systematically examined expression levels of multiple synaptic‑related proteins in the hippocampus. Our findings provide experimental evidence that may contribute to understanding the synaptic molecules underlying METH relapse. However, given the exclusive use of male animals and the whole‑hippocampus homogenate approach, these results should be interpreted with caution given these limitations. Further studies incorporating female subjects and region‑specific analyses are essential to determine the generalizability and spatial specificity of these molecular alterations, and to evaluate whether hippocampal synaptic molecules could serve as viable targets for intervention in METH addiction.