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Increased acute cocaine sensitivity and decreased cocaine sensitization in GABA(A) receptor beta3 subunit knockout
A Resnick1, G E Homanics, B J Jung
1Department of Pharmacodynamics, University of Florida, Gainesville 32610, USA.
Abstract:
The role of the GABA(A) receptor beta3 subunit in determining acute cocaine sensitivity and behavioral sensitization to repeated cocaine was measured in mice missing both (-/-), one (+/-), or neither (+/+) allele of the beta3 gene. Locomotor stimulation induced by one cocaine injection (20 mg/kg, i.p.) was found to be greater in -/- mice compared with +/+ mice, whereas cocaine-induced behaviors were intermediate in +/- mice. Amphetamine did not cause greater locomotor responses in -/- mice, suggesting that the increased sensitivity of -/- mice to cocaine does not generalize to other psychomotor stimulants. GABA-stimulated chloride uptake was 51% lower in striatum of -/- mice compared with +/+ mice, but only 27% lower in cortex. After 14 daily cocaine injections, the behavioral response to cocaine was increased in +/+ and +/- mice, but was not increased further in -/- mice. Additionally, repeated cocaine exposure decreased striatal GABA(A) receptor function in +/+ and +/- mice. In -/- mice, GABA(A) receptor function was not decreased any further by repeated cocaine injections. Thus, alterations in the beta3 subunit may be responsible for determining the behavioral responses induced by acute and repeated cocaine treatment, as well as mediating the neurochemical adaptation that occurs during sensitization to repeated cocaine.
Insights
Mice lacking the GABA(A) receptor beta3 subunit showed increased cocaine sensitivity. This suggests the beta3 subunit is crucial for cocaine
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- The GABA(A) receptor is a key inhibitory neurotransmitter receptor in the brain.
- The beta3 subunit of the GABA(A) receptor plays a role in neuronal development and function.
- Cocaine addiction is a major public health concern, and understanding its neurobiological underpinnings is critical.
Purpose of the Study:
- To investigate the role of the GABA(A) receptor beta3 subunit in acute cocaine sensitivity.
- To examine the involvement of the beta3 subunit in the development of behavioral sensitization to repeated cocaine administration.
- To explore the neurochemical adaptations in GABA(A) receptor function associated with cocaine sensitization.
Main Methods:
- Generation of mice with varying numbers of functional beta3 alleles (0, 1, or 2).
- Assessment of locomotor activity and behavioral responses following acute cocaine injection.
- Measurement of GABA-stimulated chloride uptake in brain regions (striatum and cortex) after chronic cocaine exposure.
Main Results:
- Mice lacking the beta3 subunit exhibited heightened locomotor responses to acute cocaine, but not amphetamine.
- Repeated cocaine administration led to behavioral sensitization in mice with at least one beta3 allele, but not in those lacking it.
- Chronic cocaine exposure reduced GABA(A) receptor function in the striatum of mice with functional beta3 alleles, an effect not observed in beta3-deficient mice.
Conclusions:
- The GABA(A) receptor beta3 subunit is a critical determinant of acute cocaine sensitivity.
- Alterations in the beta3 subunit influence the development of behavioral sensitization to repeated cocaine exposure.
- The beta3 subunit mediates neurochemical adaptations in GABA(A) receptor function during cocaine sensitization.
