Haloperidol prevents ethanol-stimulated locomotor activity but fails to block sensitization

Abstract

The effect of the dopamine receptor antagonist haloperidol on the development of sensitization to ethanol-induced increases in locomotor activity was examined in DBA/2J mice. In Experiment 1, different groups of mice were given saline or ethanol (2 g/kg) immediately before each of four locomotor activity sessions (48-h intervals), and 1 h after pretreatment with saline, 0.10 or 0.15 mg/kg haloperidol. During a subsequent test, mice showed locomotor sensitization despite blockade of ethanol stimulated activity by haloperidol on the first conditioning trial. Moreover, test session activity was reduced in subjects that had previously received haloperidol, even though haloperidol was not present during testing. The second experiment examined the nature of the latter finding by comparing subjects that received equal exposure to haloperidol but differed in the pairing of its administration with the activity chambers. After four conditioning trials, each group was tested in the absence of haloperidol. Mice that had previously received haloperidol paired with the activity chambers were less active than control groups, suggesting development of a conditioned suppression of activity. Overall, these results suggest a dissociation of the neurobiological mechanisms that mediate the acute locomotor stimulant effects of ethanol and those mediating sensitization. Further, these studies illustrate the importance of antagonist-alone control groups that assess the possible influence of associative learning induced by the antagonist itself.

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

“…In contrast to some studies reporting sensitized responses following DEP or EtOH administration (6,21,22), the repeated administration of these drugs alone or in combination failed to induce a progressive increase in locomotor activity over days, i.e., sensitization. However, it is important to remember that only one dose of each treatment and one schedule of 7 consecutive days of injections were used.…”

Repeated Ethanol Intoxication Induces Behavioral Sensitization in the Absence of a Sensitized Accumbens Dopamine Response in C57BL/6J and DBA/2J Mice

“…Our data suggest that in the case of repeated ETOH intoxication and withdrawal, behavioral stimulation can occur independently of a sensitized accumbens DA response. Indeed, a dissociation between the mechanisms mediating the effects of acute and repeated ETOH on locomotor activity has been previously suggested, based on the observation that DA antagonists block the acute but not the sensitized behavioral response to ETOH (Broadbent et al, 1995). This may suggest that other brain regions or other neurotransmitter systems have a more prominent role in mediating the development and longterm expression of ETOH-induced behavioral sensitization.…”

“…The role of DA neurons, however, in mediating the development of this adaptive response has received very little attention. Although behavioral sensitization to ETOH is associated with an enhancement of electrically evoked DA release in nucleus accumbens slices (Nestby et al, 1997(Nestby et al, , 1999, systemic administration of the DA receptor antagonist haloperidol failed to modify the sensitization that develops to the locomotor-activating effects of ETOH (Broadbent et al, 1995).…”

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

“…Also, increases in DA D 2 receptor binding have been described in mice sensitized to ethanol (Souza-Formigoni et al, 1999). However, mice lacking DA D 2 receptors did not show attenuated ethanol-induced sensitization (Palmer et al, 2003) and the nonspecific DA receptor antagonist haloperidol failed at preventing sensitization to ethanol (Broadbent et al, 1995).…”

“…Sensitization to ethanol has also been associated with increases in dopamine (DA) D 2 receptor binding (Souza-Formigoni et al, 1999). Deletion of the DA D 2 receptor gene in mice, however, did not alter ethanol-induced sensitization (Palmer et al, 2003); additionally, the nonspecific DA receptor antagonist, haloperidol, has been shown to not block this effect of ethanol (Broadbent et al, 1995). The involvement of other systems in ethanol sensitization, such as g-aminobutyric acid (GABA) neurotransmission, has been additionally proposed.…”