GABAA/α1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice

Abstract

Benzodiazepine antagonists, particularly those acting preferentially at GABAA/alpha1 subunit-containing receptors, decrease alcohol-heightened and species-typical aggressive behavior, but are ineffective in attenuating the sedative effects of alcohol.

Benzodiazepines and heightened aggressive behavior in rats: reduction by GABAA/?1 receptor antagonists

“…The GABA A α 1 subunit may mediate aggressive behavior When administered in combination with midazolam, the GABA A /α 1 -preferring β-carboline, β-CCt, systematically and robustly decreased midazolam-heightened aggressive behavior, extending similar effects found in the mouse, in which β-CCt was 5 times more potent than flumazenil in antagonizing alcohol-heightened aggressive behavior (de Almeida et al 2004). Another β-carboline, 3-PBC, antagonized aggressive behavior at even lower doses than β-CCt.…”

“…Individual differences in the aggression-heightening effects of alcohol, another positive modulator of the GABA A receptor, are well documented (e.g., Miczek and Barry 1977;Blanchard et al 1987;Lister and Hilakivi 1988;Miczek et al 1992;van Erp and Miczek 1997;Miczek et al 1998;Fish et al 2001). Several BZs do not exert aggression-heightening effects at all: even at low doses, oxazepam, clorazepam, and zolpidem consistently produce anti-aggressive effects (Bond and Lader 1988;Martin-Lopez and Navarro 2002;de Almeida et al 2004), and triazolam fails to increase aggressive behavior in various experimental protocols (Cherek et al 1991;Kruk 1991;de Almeida et al 2004).…”

“…In behavioral studies, β-CCt effectively blocks several antianxiety effects of chlordiazepoxide, diazepam, and triazolam, implicating the α 1 subunit in the anxiolytic effects of BZs (Belzung et al 2000;Rowlett et al 2001). β-CCt also antagonizes alcohol-heightened and species-typical aggression in mice (de Almeida et al 2004). Though structurally similar to β-CCt, the behavioral profile of 3-PBC remains unexplored in rodents; only limited research has been conducted in squirrel monkeys (Harvey et al 2002;Lelas et al 2002;Rowlett et al 2003).…”

Neurogenetics of Aggressive Behavior: Studies in Rodents

“…The α1-containing GABA A receptors seem to play a key role in mediating the pro-aggressive effect of benzodiazepines. Antagonists such as βCCt and 3-PBC that act preferentially on α1-containing GABA A receptors reduced the aggression-heightening effects of midazolam or alcohol in mice and rats (De Almeida et al, 2004; Gourley et al, 2005). In addition, 4 weeks of SI alters the expression of GABA A receptor subunits, and male mice exposed to SI showed reduced α1 subunit expression in the hippocampus and PFC compared with group housed males (Pinna et al, 2006).…”

Heightened aggression after chronic flunitrazepam in male rats: potential links to cortical and caudate–putamen-binding sites

“…The functional importance of the α1 subunit protein for its role in aggressive behavior was investigated primarily because of the availability of α1-preferring agonists, such as zolpidem, and antagonists such as β-CCt and 3-PBC (Cox et al 1995;Huang et al 2000). Antagonist effects suggested that the α1 subunit is relevant in the aggression-heightening effects of midazolam and alcohol (de Almeida et al 2004;Gourley et al 2005). However, future studies, possibly with point-mutated animals, need to determine which subunit composition is required for flunitrazepam to heighten aggressive behavior.…”