Genetic and pharmacological manipulation of mu opioid receptors in mice reveals a differential effect on behavioral sensitization to cocaine

Abstract

Cocaine-induced behavioral sensitization is a complex phenomenon involving a number of neuromodulator and neurotransmitter systems. To specifically investigate the role of the micro opioid receptor (MOR) in cocaine-induced behavioral sensitization in mice, both genetic and pharmacological approaches were undertaken. MOR-1 deficient mice of varying backgrounds (C57BL/6J, 129S6, F1 hybrid 129S6xC57BL/6J and 129S6xC57BL/6J) and wild-type C57BL/6J mice exposed continuously to naltrexone, an opioid receptor antagonist, received single daily injections of saline or cocaine for 10 days. All mice received a single cocaine challenge 7 days following the last saline or cocaine injection to test for the expression of sensitization. The locomotor-stimulating and sensitizing effects of cocaine observed in MOR-1 wild-type mice were absent in MOR-1 knockout mice maintained on the mixed 129S6xC57BL/6J background. In contrast, MOR-1 deficient mice developed on a C57BL/6J background showed an accentuated sensitivity to cocaine-induced locomotion. Cocaine's psychomotor activating effects were more pronounced in the MOR-1 C57BL/6J knockouts injected daily with cocaine than in the MOR-1 wild-type mice. Similar locomotor-stimulating and sensitizing effects were found in both F1 hybrid 129S6xC57BL/6J MOR-1 wild-type and MOR-1 knockout mice, while the 129S6 strain showed an overall indifference to cocaine. That is, both the locomotor-stimulating and sensitizing effects of cocaine were absent in both MOR-1 wild-type and MOR-1 knockout mice maintained on the 129S6 background. Lastly, the locomotor-stimulating and sensitizing effects of cocaine were attenuated in C57BL/6J wild-type mice exposed continuously to naltrexone. Collectively, these data support a role for opioidergic involvement in cocaine-influenced behavior in mice. Moreover, MORs appear to differentially modulate a sensitized response to cocaine in different strains of mice as delineated by MOR-1 gene deletion and pharmacological antagonism.