Cyclic AMP Accumulation in Cerebral Cortical Slices: Effect of Carbamazepine, Phenobarbital, and Phenytoin

Abstract

Recent investigations have suggested that abnormal increases in brain cyclic 3',5'-adenosine monophosphate (cAMP) may play a role in epileptogenesis. Therefore, the effect of three commonly used antiepileptic drugs on cAMP accumulation in rat cortex slices was investigated. Ouabain, a depolarizing agent which produces seizures when applied to rat cortex, produced a five- to sevenfold increase in cAMP accumulation, and both carbamazepine and and phenytoin inhibited this increase. Ouabain stimulation may be mediated by the release of endogenous adenosine, and carbamazepine antagonized adenosine stimulation of cAMP accumulation whereas phenytoin did not. Carbamazepine had no effect on adenosine efflux. The augmentation of cAMP accumulation by norepinephrine was inhibited by carbamazepine and phenobarbital but slightly increased by phenytoin. If increases in brain cAMP are involved in epileptogenesis, the antagonism of cAMP accumulation by antiepileptic drugs may play a role in their anticonvulsant action.

Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses

“…2). Similarly, CBZ at high concentrations also attenuates the adenosine-evoked increase in the Ievel of cyclic AMP in brain slices (Lewin and Bleck, 1977;Skenitt et al, 1983a;Weir et al, 1984), which is probably also mediated by low-affinity A 2 b-receptors (Daly et al, 1983). These effects may be at Jeast partially due to ~:-.…”

“…The inhibitory effects of chronic Iithium treatment on the agonist~stimulated increase in the accumulation of cyclic AMP (Belmaker, 1981;Ebstein et al, 1988) and inositol phosphates (Casebolt and Jope, 1989;Ebstein et al, 1988;Elphick et al, 1988;Godfrey et ai., 1989;Kendall and Nahors.k!, 1987) may be involved in lithium's antimanic and prophylactic properties. CBZ iru'libits the accumulation of cyclic AMP in brain slices stimulai.ed by noradrena· line, ouabain and adenosine (Lewin and Bleck, 1977;Palmer et al, 1979;Skerritt et al, 1983a;Weir et al, 1984), although only at high concentrations. CBZ's effects on the agonist-evoked formation of inositol phos-289 phates are controversial (Elphick et al, 1988: MeDermatt andLogan, 1989).…”

A bimodal model of the mechanism of action of lithium

“…Additionally, although not yet studied by many laboratories, the effects of other anti-bipolar therapeutics, such as carbamazepine, overlap at least partially with those of lithium in modulating cyclic AMP levels. [28][29][30] Since cyclic AMP can modulate transcription factors 31 which regulate the expression of many genes, stabilization by lithium of fluctuations in cyclic AMP should contribute to stabilization of the regulated genes in affected cells. Thus the bimodal model provides a framework for apparently opposing actions of lithium to be integrated into a unifying hypothesis based on minimization of the magnitude of fluctuations in signaling system activities and the consequential regulation of gene expression.…”

Mood stabilizer psychopharmacology

“…As discussed in an earlier section, evidence suggests that carbamazepine may have direct inhibitory effects on adenylate cyclase [61], and in a number of studies has been shown to attenuate stimulated cyclic AMP signaling [54,[56][57][58][59]. This finding is especially interesting noting that lithium also attenuates stimulated cyclic AMP signaling [13].…”

“…In addition to reports suggesting that carbamazepine effects adenosine-mediated second messenger signaling [58,234,235], the drug also appears to bind to adenosine [57,[236][237][238][239]. Carbamazepine appears to act as an antagonist, with general specificity for the A 1 subtype of adenosine receptors [57] (Table 1).…”