The present study established a novel mouse model of a runway drug self-administration in our laboratory. The operant runway apparatus consisted of three long runways arranged in a zig-zag manner. The methodology consisted of six distinct phases: habituation, preconditioning, conditioning, post-conditioning, extinction and reinstatement. The effects of saline were compared with escalating doses of either ethanol (0.5-4.0 g/kg, i.p), heroin (5-40 mg/kg, i.p), or nicotine (0.1-0.5mg/kg, i.p) administered in the goal box during the conditioning phase (day 1 to day 5). A significant decrease in the time of trained (conditioned) mice to reach the goal box confirmed the subjects' motivation to seek those drugs on day 6 (expression). The mice were then subjected to non-rewarded extinction trials for 5 days over which run times were significantly increased. After 5 days of abstinence, a priming dose of ethanol or heroin (1/5th of maximum dose used in conditioning) significantly reinstated the drug-seeking behavior. These results suggest that the modified runway model can serve as a powerful behavioral tool for the study of the behavioral and neurobiological bases of drug self-administration and, as such, is appropriate simple but powerful tool for investigating the drug-seeking behavior of laboratory mice.
In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75 mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100 mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75 mg/kg, p.o.) and reference drugs; acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.
In the past decade, many studies have highlighted the role of metabotropic glutamate receptor subtype 5 (mGlu5) modulators in attenuating alcohol-related biological effects such as alcohol consumption, alcohol-seeking and relapse-like behaviors. Taken together, these findings suggest that pharmacological agents acting at mGlu5 could be promising tools in curbing inebriation. mGlu5s are present abundantly in brain regions known to be involved in emotion regulation, motivation and drug administration. On a cellular level, they are primarily located at the postsynaptic part of the neuron where the receptor is functionally linked to various downstream proteins that are involved in cell signaling and gene transcription that mediate the alcohol-induced neuroplasticity. As well, the discovery of a functional link between mGlu5 and a specific isozyme, Protein Kinase C epsilon (PKCε) in mediating the attenuating effects of selective negative allosteric modulators of mGlu5 such as methyl- 6(phenylethynyl)pyridine (MPEP) and 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) has sparked interesting speculations. In this article, we shall review the following: the effects of acute and chronic alcohol intake on mGlu5 signaling; the effects of mGlu5 ligands on alcohol-related neurobehavioral changes that are currently being studied both at pre-clinical and clinical stages; and the mechanisms underlying the pharmacological effects of these drugs.