Elsevier

Neuroscience

Volume 115, Issue 1, 15 November 2002, Pages 185-200
Neuroscience

Ventral tegmental area region governs GABAB receptor modulation of ethanol-stimulated activity in mice

https://doi.org/10.1016/S0306-4522(02)00378-0Get rights and content

Abstract

Locomotor stimulation in response to ethanol in mice may model human ethanol-induced euphoria. The associated neural substrates, possibly relevant to alcoholism, have not been fully elucidated. Systemic injection of baclofen, a GABAB receptor agonist, attenuates ethanol’s stimulant effects. GABAB receptors on dopamine cell bodies in the ventral tegmental area (VTA) may modulate ethanol-induced dopamine release, a postulated mechanism for ethanol’s stimulant effects. However, baclofen’s attenuating effects could be associated with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation, to test the hypotheses that (1) central GABAB receptors influence baclofen’s effects on ethanol-stimulated activity, and (2) VTA GABAB receptors specifically modulate ethanol’s stimulant effects. I.c.v. baclofen dose-dependently attenuated ethanol stimulation, supporting a central locus for baclofen’s effects. Anterior VTA baclofen also attenuated ethanol stimulation. However, more posterior VTA infusions unexpectedly potentiated ethanol stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice. GABAB receptor autoradiography using [3H]CGP 54626, a potent GABAB receptor antagonist, did not reveal line differences in binding density in the VTA, or in the substantia nigra pars compacta, a nearby brain structure associated with motor control. These results suggest that anterior VTA GABAB receptors play a role in baclofen’s attenuation of ethanol’s stimulant effects, and that posterior VTA GABAB receptors serve an opposite role that is normally masked. Selection for differential ethanol stimulant sensitivity has altered VTA GABAB systems that influence locomotor behavior. However, differences in GABAB receptor densities in the VTA or substantia nigra pars compacta cannot explain the selected line difference.

Section snippets

Animals

Originating from the genetically heterogeneous, HS/ibg mouse stock, FAST-1 and -2, and SLOW-1 and -2 mice, were independently produced by selective breeding for high and low sensitivity to EtOH-induced locomotor stimulation, respectively (Crabbe et al., 1987, Phillips et al., 1991, Shen et al., 1995a, Shen et al., 1995b). Selection was terminated after 37 generations when no further response had been observed across several generations (Phillips et al., 2002). These lines are now maintained at

Locomotor activity

Figure 2 shows time course data pooled on replicate and sex because these factors did not interact with the baclofen effect. When replicate effects are absent, we have argued that data for replicated selected lines most powerfully detect genetically correlated traits when combined over this factor (Crabbe et al., 1990). Inspection of the 60-min time course curves showed that the effects of i.c.v. baclofen waned after the first 30 min. When the time course data for the first 30 min of the

Discussion

Activation of GABAB receptors in the brain, in the absence of peripheral GABAB receptor activation, attenuated EtOH-induced locomotor stimulation. I.c.v. administration of the GABAB receptor agonist, baclofen, produced results almost indistinguishable from those seen after systemic baclofen (Shen et al., 1998): complete attenuation of the EtOH stimulant response. Anterior intra-VTA microinjection of baclofen also significantly attenuated or blocked EtOH’s locomotor stimulant effects in FAST

Acknowledgements

The authors thank Drs. Charlie Meshul, Amy Eshleman, and Aaron Janowsky for graciously providing expertise, assistance, and the use of laboratory space and supplies in support of the i.c.v. injection and autoradiography experiments. The authors also thank Janet Dorow and Carrie McKinnon for invaluable technical assistance. These experiments were supported by NIAAA grants F31 AA05577 and P50 AA10760, NIDA grant T32 DA07262, and the Department of Veterans Affairs.

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