Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain MCP-1 expression in post-dependent rats

Abstract

There are no medications that target neurotoxic effects or reduce the abuse of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by binding to and downregulating the expression of CD74—a key inflammatory mediator. We reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats ( n = 20) evaluated the effects of RTL1000 on the extinction of self-administration and cue-induced reinstatement using operant behavioral methods. Rats treated with RTL1000 displayed fewer presses on the active lever as compared to vehicle treated ( p = 0.009) during the first of five extinction sessions [2-h sessions; presses on the previously active lever no longer resulted in the delivery of drug (0.06 mg methamphetamine/kg/infusion)], indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections to measure monocyte chemoattractant protein-1 (MCP-1) expression showed reduced MCP-1 in the frontal cortex ( p = 0.008) and hippocampus ( p = 0.19, n.s.) of rats treated with RTL1000, as compared to vehicle. Results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking—potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.