μ-Opioid Receptors are not Involved in Acute Cocaine-Induced Locomotor Activity nor in Development of Cocaine-Induced Behavioral Sensitization in Mice

Abstract

Although m-opioid receptors have been extensively investigated for their role in drug reinforcement, little is known about the contribution of these receptors to the acute and sensitized locomotor response to cocaine. In this study m-opioid receptor involvement in acute cocaine-induced locomotor activity and in the development of cocaine-induced behavioral sensitization was evaluated using mopioid receptor knockout mice and chronic naltrexone (NTX) pretreatment as models. In addition, co-administration of the specific mopioid receptor antagonist CTOP with repeated saline or cocaine injections was used to establish the involvement of m-opioid receptors in sensitization to the locomotor stimulant effects of cocaine. The acute locomotor response to cocaine (3, 10, 20, or 30 mg/kg i.p.) of mopioid receptor knockout or chronic NTX pretreated mice was not different from the cocaine response of their respective controls. With respect to cocaine-induced behavioral sensitization, induced by daily injections of 20 mg/kg cocaine for 11 subsequent days, mopioid receptor knockout mice developed behavioral sensitization to the locomotor stimulant effects of cocaine (challenge 10 mg/kg i.p.) comparable to wild-type littermates and the m-opioid receptor antagonist CTOP did not affect cocaine-induced sensitization either. However, mice that were pretreated with NTX exhibited augmented cocaine-induced behavioral sensitization relative to placebo pretreated controls, which may be ascribed to increased d-opioid receptor levels as has been described for chronic NTX pretreated mice. The present findings suggest that m-opioid receptors are not required for the acute locomotor response to cocaine nor are they essential for the development of cocaine-induced behavioral sensitization.

A role for mu opioid receptors in cocaine-induced activity, sensitization, and reward in the rat

“…injections of an antisense oligonucleotide directed against the mu opioid receptor failed to sensitize to cocaine (Hummel et al 2006). In contrast to these findings, Lesscher et al 2005 pretreated mice with CTOP, another selective mu receptor antagonist peptide, by peripheral (i.p.) administration before daily cocaine and failed to show an effect on behavioral sensitization.…”

“…to avoid peripheral drug metabolism and improve bioavailability at central sites. It is possible that the discrepancy between the present results and those of Lesscher et al 2005 is due to methodological issues, as this and other studies (Braida et al 1997) highlight the importance of central administration of synthetic opioid peptides when assessing the behavioral effects of psychostimulants.…”

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

“…Moreover, naloxone was found to reduce the neurochemical and behavioral effects of AMPH but not those of cocaine [41]. Several studies on the role of opioid receptors in cocaine-induced behavioral sensitization using genetic or pharmacological manipulations [11,25,56] revealed different results to ours in METH-induced behavioral sensitization. Although cocaine and METH are psychomotor stimulates that increase extracellular levels of monoamines, they differ in their mechanisms of action.…”

Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice

“…Despite these similarities, there are also distinct differences between some of the observed phenotypes in ob/ob and MOR knockout mice. MOR knockout mice do not have altered novel open field activity (Hall et al 2004), and the locomotor response to cocaine has been reported to either be elevated (Hall et al 2004; Hummel et al 2004), unchanged (Lesscher et al 2005), or reduced (Chefer et al 2004). Cocaine CPP is also reduced in MOR knockout mice (Hall et al 2004), contrary to our finding of elevated CPP at low doses of cocaine.…”