Differential involvement of opioid receptors in regulating the behavioral response to amphetamine in C57BL/6 mice

Drug addiction is recognized as a serious brain disease and with the rapid expansion in neuroscience research over the past few decades, great progress has been made in understanding the causes and effects of drug addiction and its relevance to more basic components of human behavior. It is now accepted that drugs of abuse (DOA) act on the mesolimbic dopamine (DA) brain reward system to mimic the rewards induced by more ‘natural’ stimuli such as food and sex. Acute administrations of DOA, particularly the psychostimulant amphetamine (AMPH), and the opiate heroin, lead to increases in extracellular levels of the neurotransmitter dopamine in regions comprising the brain reward system, including the nucleus accumbens (NAc), the ventral tegmental area (VTA), the striatum, and the dorsal caudate (DC). Changes in DA levels contribute to both the rewarding properties of DOA, as well as behavioral aspects of their use.; As knowledge of the molecular and behavioral effects of DOA has advanced, evidence has accumulated that opioids not only share similar rewarding properties as psychostimulants, but that the endogenous opioid system can directly modulate the mesolimbic dopaminergic system as well. However, the individual contributions of the three opioid receptors subtypes (μ, κ, and δ) in modulating the brain reward system are still unclear. In an attempt to investigate this, we developed an animal model of acute amphetamine (AMPH)-induced behaviors and studied the effect of antagonizing the individual opioid receptors (ORs) on these behaviors. Using the induction of hyperlocomotion following a low dose (2mg/kg) of AMPH as a behavioral correlate of DA levels, we found that antagonizing the δOR significantly attenuated behavior, antagonism of κORs failed to effect behavior, and antagonism of μORs had a slight, but non-significant, augmentation of DA-dependent hyperlocomotion. In contrast, utilizing the induction of stereotypic behaviors with a high dose (12mg/kg) of AMPH as our behavioral correlate, antagonism of all three ORs significantly attenuated DA-dependent stereotypy. It is assumed that these OR-dependent effects are mediated through differential regulation of target neurons within the mesolimbic reward system and indicate that the endogenous opioid system can regulate behavioral responses to rewarding stimuli.