Locomotor sensitization to EtOH: contribution of β-Endorphin

Abstract

Alcohol use disorders, like all drug addictions, involve a constellation of adaptive changes throughout the brain. Neural activity underlying changes in the rewarding properties of alcohol reflect changes in dopamine transmission in mesolimbic and nigrostriatal pathways and these effects are modulated by endogenous opioids such as β-Endorphin. In order to study the role of β-Endorphin in the development of locomotor sensitization to repeated EtOH exposure, we tested transgenic mice that vary in their capacity to synthesize this peptide as a result of constitutive modification of the Pomc gene. Our results indicate that mice deficient in β-Endorphin show attenuated locomotor activation following an acute injection of EtOH (2.0 g/kg) and, in contrast to wildtype mice, fail to demonstrate locomotor sensitization after 12 days of repeated EtOH injections. These data support the idea that β-Endorphin modulates the locomotor effects of EtOH and contributes to the neuroadaptive changes associated with chronic use.

Keywords: EtOH; alcohol; knockout; mu-receptor; opioid; transgenic.

Figure 1

Locomotor activity in mice during four, 10 min test periods on Days 1–3 and 14 of a 2-week experimental protocol. On Days 1 and 2 all mice received intraperitoneal saline injections, on Day 3 the chronic saline (CS) group received saline again, but all other subjects received 2.0 g/kg EtOH. On Days 4–13, half of these were administered 2.5 g/kg EtOH (Chronic EtOH—CE) and the remainder was given equivolume saline (Acute EtOH—AE, and CS) and all were placed in their home cages immediately following injection. On Day 14, all animals were administered 2.0 g/kg EtOH and evaluated in the activity chambers. The left panel shows the horizontal distance traveled in cm (data show mean ± SE) of adult male and female C57BL/6J mice, demonstrating the development of locomotor sensitization in CE-treated subjects. The middle panel shows analogous experimental groups of heterozygote (HT) mice and the right panel shows the same data in β-E deficient (KO) mice. Neither of these latter two groups developed locomotor sensitization.

Figure 2

Horizontal distance traveled in mice of each genotype on Day 3 of the experimental protocol. Mice were either given 2.0 g/kg EtOH by intraperitoneal injection or equivolume saline immediately before 10 min evaluation (see text for experimental detail). Data represent group means ± SE.

Figure 3

The difference in horizontal locomotor activity between the first and last exposure to EtOH in chronically treated mice across the three genotypes and both sexes (see text for experimental detail). Data represent group means ± SE.