1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/‐ 2.8 (s.d.) ml min‐1 kg‐1 in the elderly compared with 23.4 +/‐ 4.1 ml min‐1 kg‐1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration‐time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/‐ 0.29 l kg‐1) than in the young (1.65 +/‐ 0.39 l kg‐1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/‐ 588 ng ml‐1h in the elderly compared with 1056 +/‐ 282 ng ml‐1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/‐ 0.12 compared with 0.41 +/‐ 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/‐ 0.9 ml min‐1 kg‐1 compared with 9.3 +/‐ 1.0 ml min‐1 kg‐1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, mediating fast inhibitory synaptic transmission, by activating GABAA receptors. However, these GABA-gated Cl- channels can also be excitatory, causing depolarization, and increasing Ca2+ entry via voltage-operated Ca2+ channels (VOCCs). Evidence exists for excitatory ionotropic GABA receptors in anterior pituitary cells, including gonadotropes, but these have not been directly characterized and their pharmacology remains controversial. Here we have measured the cytosolic Ca2+ concentration ([Ca2+]i) in alphaT3-1 gonadotropes, to test for expression of excitatory GABA receptors. The GABAA agonists, GABA and muscimol, both caused rapid, robust and dose-dependent increases in [Ca2+]i (EC50 values 2.7 and 1 microM), whereas the GABAB agonist, baclofen, did not. The GABAA antagonist, bicuculline, inhibited muscimol's effect, whereas the GABAB antagonist, phaclofen, did not. The neuroactive steroid 5alpha-pregnan-3alpha-ol-11,20-dione (an allosteric activator of GABAA receptors) increased [Ca2+]i, and this effect, like that of muscimol, was inhibited by picrotoxin. The muscimol effect on [Ca2+]i was blocked by the VOCC antagonist, nifedipine, or by Ca2+-free medium. When cells were pretreated with muscimol this increased the spike phase of the [Ca2+]i response to subsequent stimulation with gonadotropin-releasing hormone (GnRH). Similar amplification was seen in muscimol-pretreated cells stimulated with GnRH in Ca2+-free medium, but not when cells were pretreated with muscimol in Ca2+-free medium. The amplification was not, however, GnRH receptor-specific, because the spike response to ionomycin was also increased by muscimol pretreatment. These data provide the first direct evidence for expression of excitatory GABAA receptors, and the first demonstration of acute steroid effects, on GnRH-responsive pituitary cells. They also reveal a novel mechanism by which GABAA activation modulates GnRH action, raising the possibility that this may also influence gonadotrophin secretion from non-immortalized gonadotropes.