Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems

Abstract

The widespread consumption of anorectics and combined anorectic + alcohol misuse are problems in Brazil. In order to better understand the interactive effects of ethanol (EtOH) and diethylpropion (DEP) we examined the locomotion-activating effects of these drugs given alone or in combination in mice. We also determined whether this response was affected by dopamine (DA) or opioid receptor antagonists. A total of 160 male Swiss mice weighing approximately 30 g were divided into groups of 8 animals per group. The animals were treated daily for 7 consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/ kg, ip), EtOH (1.2 g/kg, ip), DEP (5.0 mg/kg, ip) or the control solution coadministered with the DA antagonist haloperidol (HAL, 0.075 mg/ kg, ip), the opioid antagonist naloxone (NAL, 1.0 mg/kg, ip), or vehicle. On days 1, 7 and 10 after the injections, mice were assessed in activity cages at different times (15, 30, 45 and 60 min) for 5 min. The acute combination of EtOH plus DEP induced a significantly higher increase in locomotor activity (day 1: 369.5 ± 34.41) when compared to either drug alone (day 1: EtOH = 232.5 ± 23.79 and DEP = 276.0 ± 12.85) and to control solution (day 1: 153.12 ± 7.64). However, the repeated administration of EtOH (day 7: 314.63 ± 26.79 and day 10: 257.62 ± 29.91) or DEP (day 7: 309.5 ± 31.65 and day 10: 321.12 ± 39.24) alone or in combination (day 7: 459.75 ± 41.28 and day 10: 427.87 ± 33.0) failed to induce a progressive increase in the locomotor response. These data demonstrate greater locomotion-activating effects of the EtOH + DEP combination, probably involving DA and/or opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH + DEP = 395.62 ± 11.92 and EtOH + DEP + HAL = 371.5 ± 6.76; day 7: EtOH + DEP = 502.5 ± 42.27 and EtOH + DEP + HAL = 281.12 ± 16.08; day 10: EtOH + DEP = 445.75 ± 16.64 and EtOH + DEP + HAL = 376.75 ± 16.4) and NAL (day 1: EtOH + DEP = 553.62 ± 38.15 and EtOH + DEP + NAL = 445.12 ± 55.67; day 7: EtOH + DEP = 617.5 ± 38.89 and EtOH + DEP + NAL = 418.25 ± 61.18; day 10: EtOH + DEP = 541.37 ± 32.86 and EtOH + DEP + NAL = 427.12 ± 51.6) reduced the locomotor response induced by combined administration of EtOH + DEP. These findings also suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by the combination.

Naloxone does not attenuate the locomotor effects of ethanol in FAST, SLOW, or two heterogeneous stocks of mice

“…Two independent reports have found that naloxone (Camarini et al 2001) and naltrexone (Pastor et al 2005) attenuated ethanol-induced locomotor stimulation in outbred Swiss mice. However, Gevaerd et al (1999) and the current study failed to find a significant effect of naloxone pretreatment in Swiss mice. Although these differences could reflect differences in procedure or apparatus, they could also reflect genetic differences in mechanisms associated with ethanol-induced stimulation.…”

“…Ethanol induced a significant increase in locomotor activity that was not attenuated by opioid receptor blockade. In another study, naloxone failed to alter the stimulant response of a low dose of ethanol (1.2 g/kg) during a 20-min test in Swiss mice (Gevaerd et al 1999). The mixed results could be associated with differences in testing procedures or with differences in the genotype of mice used in the various experiments.…”

“…The Swiss line used in this study, NIH Swiss, has been reproductively isolated for more than 70 years, and estimates of heterozygosity within this line are fairly low (Cui et al 1993;Lynch 1969). Other Swiss sublines used appear to have not been derived from the NIH colony (Pastor et al 2005) or have been derived from institutionspecific breeding colonies (Camarini et al 2001;Gevaerd et al 1999). Thus, the lines are reproductively isolated from NIH Swiss mice, and all sublines have been subject to various amounts of inbreeding throughout the years.…”

“…Most of the studies that have examined the effects of opioid receptor antagonists and fully reported experimental conditions tested ethanol-induced locomotor activity during the light phase of the light-dark cycle (Cunningham et al 1995;Pastor et al 2005;Sanchis-Segura et al 2004), and did not habituate the mice to the locomotor activity apparatus prior to locomotor activity assessment (Camarini et al 2000;Gevaerd et al 1999;Pastor et al 2005;SanchisSegura et al 2004). Under these conditions, no effect of opioid receptor blockade on ethanol-induced locomotor stimulation (Cunningham et al 1995;Gevaerd et al 1999; present studies) and blockade of ethanol-induced locomotor stimulation (Camarini et al 2000;Pastor et al 2005;Sanchis-Segura et al 2004) were both observed. Variable effects of opioid receptor blockade by naloxone or naltrexone were also observed in mice habituated to the experimental environment (Cunningham et al 1995;Kiianmaa et al 1983).…”

“…In clinical studies (King et al 1997;Swift et al 1994), naltrexone attenuated ethanol-induced increases in stimulation scores as measured by the Biphasic Alcohol Effects Scale. In addition, naltrexone and another nonspecific opioid receptor antagonist, naloxone, which both attenuate morphine-induced locomotor stimulation (Powell and Holtzman 2001;Sanchis-Segura et al 2004), were found to attenuate ethanol-induced locomotor stimulation without affecting baseline activity levels in several inbred (BALB/cJ, DBA/2J) and outbred (CD-1, Swiss) strains of mice (Camarini et al 2000;Kiianmaa et al 1983;Pastor et al 2005;SanchisSegura et al 2004; but see Cunningham et al 1995;Gevaerd et al 1999). Naltrexone did not attenuate ethanolinduced locomotor depression, however, in C57BL/6J mice (Middaugh et al 1978).…”