Neurosteroids Mediate Habituation and Tonic Inhibition in the Auditory Midbrain

Abstract

Habituation of the behavioral response to a repetitive stimulus is a well-established observation in perceptual studies and is considered a basic form of nonassociative learning. There is also a long history of physiological studies suggesting that central nervous system habituation is mediated by inhibition. At higher levels of the sensory pathways, such inhibition is mainly contributed by GABAa receptor mechanisms. Concepts of modification of synaptic efficacy that apply to excitatory amino acid synaptic transmission do not have direct parallels with these inhibitory synapses: quantal release of GABA rapidly saturates available receptors at a synapse, placing an upper limit on responsiveness to increased transmitter release. However, pharmacological modulation of GABAa-receptor efficacy with exogenous agents (e.g., benzodiazepines and β-carbolines) is known to occur through allosteric mechanisms that modulate the effectiveness (positive and negative) of GABA at this receptor. The most potent endogenous modulators are 5α-reduced steroids. Production of these steroids was attenuated in adult rats with systemic injection of Finasteride, a competitive substrate for 5α-reductase. This treatment was sufficient to block habituation of the evoked midbrain response to repetitive presentation of an acoustic click. This result confirms that simple habituation is due to an increase in active inhibition, the increase being mediated by steroid modulation of the GABAa-receptor. Finasteride treatment also brought about a 23% increase in the evoked response to a click stimulus, suggesting that 5α-reduced steroids normally contribute to tonic inhibition in the rat inferior colliculus.