Effect of Chronic Cocaine Treatment on μ‐ and δ‐Opioid Receptor mRNA Levels in Dopaminergically Innervated Brain Regions

Abstract

The regulation of μ‐(MOR) and δ‐opioid receptor (DOR) after chronic cocaine administration has been studied. Male Sprague‐Dawley rats were treated for 3 days with saline and cocaine (50 mg/kg/day) delivered by osmotic minipump. Expression of MOR and DOR mRNA in olfactory bulb, nucleus accumbens, and caudate‐putamen (caudal and rostral parts) was estimated using quantitative competitive PCR assays after reverse transcription. No changes in the levels of mRNA for DOR were detected after exposure to cocaine in the brain regions examined. A significant increase in the level of MOR mRNA was detected in nucleus accumbens after 3 days of cocaine treatment. In caudate‐putamen and olfactory bulb, no change in MOR mRNA was observed after cocaine administration. Both SCH 23390 and eticlopride, selective antagonists of D1‐ and D2‐dopamine receptors, respectively, blocked this cocaine‐induced up‐regulation of MOR mRNA in nucleus accumbens. We suggest that endogenous opioid systems in nucleus accumbens, the brain region specifically associated with the reinforcing properties of addictive drugs, are regulated by dopaminergic mechanisms and influenced by cocaine treatment.

High-Dose Methadone Maintenance in Rats: Effects on Cocaine Self-Administration and Behavioral Side Effects

“…In fact, we have reported that rats maintained on high-dose methadone maintenance show no cocaine-place preference and no cocaine-induced up-regulation of mu-opioid receptor mRNA in the nucleus accumbens core (Leri et al, 2006). This is notable because the effect of cocaine exposure on mu-opioid receptor density and function in mesocorticolimbic areas (Azaryan et al, 1996;Unterwald et al, 1992;Unterwald, 2001;Yuferov et al, 1999) has been associated to the intensity of cocaine cravings in humans (Gorelick et al, 2005;Zubieta et al, 1996), and to a variety of behavioral, electrophysiological and neurochemical responses to cocaine in animals (Mathon et al, 2005a(Mathon et al, , b, 2006Tang et al, 2005;Hummel et al, 2006).…”

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

“…For example, in rats administered cocaine for 14 days in a "binge" paradigm, MOR binding density increased in several regions containing terminals of the mesocorticolimbic dopaminergic system, including areas of the cingulate cortex, the nucleus accumbens, caudate-putamen, and basolateral amygdala (Unterwald et al, 1992(Unterwald et al, , 1994. A direct molecular effect of acute or 3-day cocaine administration on MOR mRNA levels has also been observed with increases in dopaminergically innervated brain regions reported (Azaryan et al, 1996;Yuferov et al, 1999). A positron emission tomography (PET) study in cocainedependent men also showed increases in MOR binding that were associated with cocaine craving (Zubieta et al, 1996).…”

Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat

“…15 mg/kg three times daily at 1 h intervals for 14 days) has been shown to increase levels of mu and kappa opioid receptors in discrete brain regions of the rat, but does not alter the density of delta opioid receptors (Unterwald et al, 1994). Other investigators have demonstrated similar changes in opioid receptor expression following cocaine (Azaryan et al, 1996;Hammer, 1989;Izenwasser et al, 1996). Although delta opioid receptor densities are unaltered, their function is modulated by cocaine and dopamine D1 receptor activation.…”