Alternate Theory of Benzo Tolerance

[Politicalchalk]

Thought this was pretty interesting. I was hoping for some general comments --> the authors make it clear that it's not full-on theory yet, but nevertheless some noteworthy findings.

So I pose to Swiy: Do you agree that the below-described postulate on benzo tolerance is justified? Or do you disagree, sticking with the traditional model of tolerance? Perhaps a synthesis?

Discuss. research purposes.
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Bonavita CD, Bisagno V, Bonelli CG, Acosta GB, Rubio MC, Wikinski SI. Instituto de Investigaciones Farmacológicas (ININFA) - CONICET. Junín 956, 5th piso. (1113), Buenos Aires, Argentina. cbonavit@ffyb.uba.ar


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 GABAergic neurotransmission. However, a compensatory increase in the excitatory response, named as an oppositional response, has also been put forward as a means 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 Changes in the excitatory neurotransmission have been found in withdrawn rats after a long treatment with benzodiazepines but these modifications have not been conclusively studied during tolerance.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 the glutamatergic neurotransmission in rats made tolerant to the sedative effect of 3 mg/kg (i.p.) of lorazepam (LZ). We found a decrease in the affinity of cortical NMDA receptors for (3)H-glutamate (K(D): 124.4 +/- 13.3 nM 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 rats vs. controls, P<0.05). We conclude that tolerance to the sedative effect of LZ correlates with a decreased 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.