Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate.

C.D. BONAVITA; V. BISAGNO; C.G. BONELLI; G.B. ACOSTA; M.C. RUBIO; S.I. WIKINSKI

NEUROPHARMACOLOGY

Elsevier

Lugar: New York; Año: 2001 p. 619 - 625

0028-3908

Benzodiazepines are anxiolytic, anticonvulsant, sedative and hypnotic compounds usually prescribed on a long-term basis. Chronic treatment with these compounds induces tolerance, which has been extensively attributed to modifications in the GABAerginc neurotransmission. However, a compensatory increase in excitatory response, named as an oppositional response, has also been put forward as a mean for explaining such tolerance. Changes in the excitatory neurotransmission have been found in withdrawn rats after a long treatment with benzodiazepines but these modifications have not been conclusively studied during tolerance. In this work we studied several parameters of glutamatergic neurotransmission in rats made tolerant to sedative effect of 3 mg/kg (i.p.) of lorazepam (LZ). We found a decrease in the ability of cortical NMDA receptor for 3H-glutamate (KD: 124.4±13.3nM in tolerant rats, 71.6± 10.4 nM in controls, P<0.05) together with a decrease in the in vitro 60  mM K+-stimulated cortical glutamate release (59±12% vs. 153±38%, tolerant vs. controls, P<0.05). We concluded that tolerance to the sedative effect of LZ correlates with a decrease sensitivity for glutamate that may in turn diminish the cortical response to a chemical stimulus. Our findings constitute an evidence against the oppositional model of pharmacodynamic tolerance in this experimental condition.