Paolo L. Morselli

The gabaergic hypothesis of depression

UNLABELLED 1. GABAergic mechanisms have been generally ignored in the study of mood disorders and antidepressant drug (AD) action. Recently data have accumulated indicating that GABAergic mechanisms may be involved in both of these. 2. Mood disorders: GABA levels are reported to be low in the CSF and plasma of depressed patients and are related to mood changes. GABAB receptors are decreased in the frontal cortex in two rodent behavioral models of depression and GABA release is reported diminished in the hippocampus. GABAergic drugs (progabide, fengabine) reverse the behavioral deficits in the rodent models and exert clear therapeutic effects in depressed patients. 3. AD action: In behavioral models imipramine upregulates GABAB receptors only in those animals which respond behaviorally to the AD. In naive rats repeated administration of varied ADs upregulates GABAB receptors in the frontal cortex whereas non-ADs (including amphetamine) do not. Bicuculline inhibits the action of imipramine in the learned helplessness model. GABAA receptor stimulation enhances noradrenaline release in the ventral NA pathway. 4. CONCLUSIONS GABAergic mechanisms likely play a role in the modulation of mood and increasing GABAergic tone exerts and antidepressant effect. Actions at GABA synapses appear to be a fundamental facet of ADs, perhaps together with beta-adrenoceptor mediated events.

Antiepileptic Drug Therapy in Pediatrics

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Pharmacokinetics of propranolol in normal healthy volunteers

The pharmacokinetics of propranolol in blood was studied in healthy volunteers, following intravenous administration of 0.1 mg/kg and increasing oral doses of 10,20, and 40 mg, using a specific and sensitive gas Chromatographie method. The systemic availability of orally administered propranolol varied from 9% to 38% between subjects, but it was constant within each subject. A linear relationship was found between the area under the blood concentration-time curve and the oral dose. At variance with literature data, we could not observe a threshold dose.

Brain distribution of propranolol in the rat

The distribution and kinetics of D,L-propranolol in rat brain were examined after an intravenous injection of the drug. Measurements in brain areas and blood were performed by means of a sensitive and specific gas liquid chromatographic method. The disappearance rate in cortical areas paralleled that in blood. However D,L-propranolol decreased at a slower rate in hypothalamic and medullary nuclei. Since propranolol is believed to have central hypotensive effects, its retention by certain central nuclei involved in blood pressure regulation is of interest.

Betaxolol kinetics in hypertensive children with normal and abnormal renal function.

The kinetic and clinical profile of betaxolol—α β1‐selective blocker with 80% to 90% bioavailability and a 16 to 20 hr t½—were studied in ten children aged 5 to 13 yr with chronic renal hypertension and mild to severe renal failure. An IV dose of 20 mg of betaxolol per 1.73 m2 body surface area (BSA) was followed by six daily oral doses. Six patients were maintained on combination therapy and four on betaxolol alone; two of these were newly treated. After the intravenous dose, t½ (mean ± SE) was 19.9 ± 1.7 hr, total clearance 0.30 ± 0.03 l/kg/hr, and volume of distribution 8.2 ±0.7 l/kg. Clearance adjusted for BSA was 7.9 ± 0.6 l/hr. The t½ correlated linearly to serum creatinine levels. After the last dose, peak concentration was 97.4 ± 7.6 ng/ml, and t½ 19.4 ± 2.7 hr. Betaxolol 24‐hr blood levels were twice as high as after the first dose. Blood pressure was reduced in two newly treated patients and two patients on combination therapy; previous responses were maintained in the others. The maximum effect was reached after the first dose and was maintained throughout the study week. Our results indicate that betaxolol disposition in children aged 5 to 13 yr with different degrees of renal failure is of the same order as that in young healthy adults, implying that there may be a higher rate of non‐renal clearance. Renal failure‐induced modification led to a doubling of the t½ in the most severe cases, again as in adult renal patients. There is an antihypertensive effect.

GABA Receptors, Depression and Antidepressant Drug Action

The clinical demonstration of the major antidepressant action of GABAmimetic agents (Morselli et al., 1980; 1986; Musch, 1986; Weiss et al., 1986) has led to the formulation of a coherent GABA hypothesis of depression. This hypothesis in addition is supported by a large body of evidence which however, remained inconclusive in the absence of clear cut clinical data with GABAmimetics. The compounds which have stimulated this progress include two benzylidene GABAmimetics, progabide: 4- {[(4-chlorophenyl) (5-fluoro-2-hydroxy-phenyl)-methylenelamino} butanamide, and fengabine : 2-[(Butylimino) (2-chlorophenyl) methyl]-4-chlorophenyl.