Gabapentin (1-(Gabapentin (1-(aminomethyl)cyclohexane acetic acid; Neurontin) is a novel antiepileptic drug that is orally active in various animal models of epilepsy, including maximal electroshock in rats and pentylenetetrazol-or audiogenically induced seizures in mice (1-3). Gabapentin has also been shown to be effective in decreasing the frequency of seizures in medically refractory patients with partial or generalized epilepsy (3, 4). Although originally synthesized as a lipophilic ␥-aminobutyric acid (GABA) 1 analogue, capable of penetrating the blood-brain barrier, gabapentin does not possess a high affinity for either GABA A or GABA B receptors, does not influence neural uptake of GABA and does not inhibit the GABA-metabolizing enzyme, GABA transaminase (EC 2.6.1.19) (3, 5). Moreover, gabapentin does not affect voltage-dependent sodium channels (the site of action of several antiepileptic drugs, including phenytoin, carbamazepine, and valproate) and is inactive in assays for a wide range of other neurotransmitter receptors, enzymes, and ion channels (5, 6).A single high affinity (K D ϭ 38 Ϯ 2.8 nM) binding site for [ 3 H]gabapentin in rat brain has been described (7). Radioligand binding to brain membranes was potently inhibited by a range of gabapentin analogues and by several 3-alkyl-substituted analogues of GABA, although GABA itself was only weakly active. Other antiepileptic drugs including phenytoin, diazepam, carbamazepine, valproate, and phenobarbitone were inactive. Gabapentin (IC 50 ϭ 80 nM) and (RS)-3-isobutyl-GABA (IC 50 ϭ 80 nM) were the most active compounds identified (7). The (Sϩ)-enantiomer of 3-isobutyl-GABA was significantly more active than the (RϪ)-enantiomer both in displacing Despite extensive research the mechanism of action of gabapentin remains unclear. In vivo behavioral studies have suggested the possible involvement of the glycine co-agonist site of the NMDA receptor complex in the anticonvulsant action of gabapentin; intracerebroventricular administration of D-serine (a glycine site agonist) reversed the protection afforded by gabapentin against chemically induced seizures in mice (9). However, radioligand binding assays have not shown gabapentin to inhibit strychnine-insensitive [ 3

Using combinations of bioluminescence resonance energy transfer, time-resolved fluorescence resonance energy transfer and the functional complementation of pairs of inactive receptor-G protein fusion proteins, the human ␣ 1A-1 -adrenoceptor was shown to form homodimeric/oligomeric complexes when expressed in human embryonic kidney (HEK) 293 cells. Saturation bioluminescence resonance energy transfer studies indicated the ␣ 1A-1 -adrenoceptor homodimer interactions to be high affinity and some 75 times greater than interactions between the ␣ 1A-1 -adrenoceptor and the ␦ opioid peptide receptor. Only a fraction of the ␣ 1A-1 -adrenoceptors was at the plasma membrane of HEK293 cells at steady state. However, dimers of ␣ 1A-1 -adrenoceptors were also present in intracellular membranes, and the dimer status of those delivered to the cell surface was unaffected by the presence of agonist. Splice variation can generate at least three forms of the human ␣ 1A-1-adrenoceptor with differences limited to the C-terminal tail. Each of the ␣ 1A-1 , ␣ 1A-2a , and ␣ 1A-3a -adrenoceptor splice variants formed homodimers/oligomers, and all combinations of these splice variants were able to generate heterodimeric/oligomeric interactions. Despite the coexpression of these splice variants in human tissues that possess the pharmacologically defined ␣ 1L -adrenoceptor binding site, coexpression of any pair in HEK293 cells failed to generate ligand binding characteristic of the ␣ 1L -adrenoceptor.

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We have investigated the effects of somatostatin (SRIF)

1 Gabapentin is a novel anticonvulsant with an unknown mechanism of action. Recent