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γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABAA/GABAC) and metabotropic (GABAB) receptors (R). In addition to their location on neurons, GABA and functional GABAB receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABABR has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABAB receptors to Gi in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABABR1 and GABABR2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABABR1 and GABABR2 proteins in human native and cultured airway smooth muscle. The GABABR1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABABR agonist, elicited a concentration-dependent stimulation of [35S]GTPγS binding in HASM homogenates that was abrogated by the GABABR antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABABR agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen’s effect on ERK phosphorylation, implicating Gi protein coupling. Functional GABAB receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABAB receptors coupled to the Gi protein in airway smooth muscle.

In order to assess the effects of increased central nervous system serotonergic function in humans on prolactin (PRL), growth hormone (GH) and mood, intravenous L-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more high, mellow, and drowsy following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The intravenous TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.