Increased Acute Cocaine Sensitivity and Decreased Cocaine Sensitization in GABAA Receptor β3 Subunit knockout Mice

: The role of the GABAA receptor β3 subunit in determining acute cocaine sensitivity and behavioral sensitization to repeated cocaine was measured in mice missing both (‐/‐), one (+/‐), or neither (+/+) allele of the β3 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 GABAA receptor function in +/+ and +/‐ mice. In ‐/‐ mice, GABAA receptor function was not decreased any further by repeated cocaine injections. Thus, alterations in the β3 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.