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Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment.

Summary: Carbamazepine (CBZ) blocks the development of local anesthetic seizures kindled by cocaine and lidocaine. Cocaine and lidocaine release corticotropin-releasing hormone (CRH) in hypothalamic cell cultures, and this effect is also blocked by CBZ. Because CRH administered intracerebroventricularly (i.c.v.) can produce seizures, its potential role in the development of cocaine seizures and in the anticonvulsant effects of CBZ was studied. CRH (at doses of 5, 10, and 100 μg) potentiated cocaine-kindled seizure development and lethality in a dose-related fashion. CRH also reversed the effects of CBZ on cocaine kindling and lethality, but only at the highest doses, which also affected cocaine kindling. Thus, a selective role for CRH in the anticonvulsant effects of CBZ was not demonstrated. The findings suggest a potentially important role for CRH in exacerbating cocaine-seizure evolution and its associated lethality and confirm the inhibition of cocaine kindling and lethality by CBZ. RESUMEN La carbamacepina (CBZ) bloquea el desarrollo de ataques locales anestesicos condicionados (kindled) con cocaina y lidocaina. La cocaina y lidocaina generan la hormona liberadora de corticotropina (CRH) en cultivos de celulas hipotalamicas y este efecto tambien lo bloquea la CBZ. Puesto que la administracion intracerebroventricular (i.c.v.) de CRH puede producir ataques, se ha estudiado su posible participacion en el desarrollo de 10s ataques producidos por cocaina y 10s efectos anticonvulsivos de la CBZ. La CRH (a dosis de 5, 10 y 100 μg) potencia el desarrollo de ataques condicionados (kindled) y la mortalidad de una manera relacionada con la dosis. La CRH tambien invierte los efectos de la CBZ sobre el “kindling” de la cocaina y la mortalidad pero solamente en las dosis mas elevadas que tambien afectaron el “kindling” de la cocaina. Asi pues, no se ha demostrado un papel selectivo de la CRH sobre los efectos anticonvulsivos de la CBZ. Estos hallazgos sugieren la existencia de un papel potencialmente importante de la CRH en la exacerbacion de la evolucion de los ataques inducidos por cocaina y en la mortalidad asociada y confirman la inhibicion del “kindling” producido por la cocaina y la mortalidad producida por la CBZ. ZUSAMMENFASSUNG Carbamazepin (CBZ) blockiert die Entwicklung von Anfallen, die durch Kokain- und Lidocain-Kindling entstehen. Kokain und Lidocain setzen Corticotropin-Releasing Hormon (CRH) in hy pothalamischen Zellkulturen frei, und dieser Effekt wird ebenfalls durch CBZ blockiert. Da intraventrikular (i.c.v.) gegebenes CRH Anfalle produzieren kann, wurde seine mogliche Rolle bei der Entwicklung von Kokain-Anfallen und der antikonvulsiven Wirkung von CBZ untersucht. CRH (in Dosierungen von 5, 10 und 100 μg) verstarkte die Kokaingekindelte Anfallsentwicklung und Letalitat in einer dosisabhangigen Weise. CRH kehrte die CBZ-Wirkung auf Kokain-kindling und Letalitat um, jedoch nur in den hochsten Dosen, die ebenfalls das Kokain-Kindling beeinfluβten. Demnach wurde eine selektive Rolle von CRH bei der antikonvulsiven Wirkung von CBZ nicht gezeigt. Die Befunde demonstrieren eine moglicherweise wichtige Rolle von CRH in der Entwicklung von Kokain-Anfallen und der assoziierten Letalitat und bestatigen die Inhibition von Kokain-Kindling und Letalitat durch CBZ.

The relationship of the timing of drug administration to anticonvulsant efficacy against amygdala kindled seizures was studied. During kindling development, rats received carbamazepine (CBZ, 15mg/kg) before (CBZ-before) or after each amygdala stimulation (CBZ-after). After kindling to full seizures, when all animals were given CBZ before the stimulation, only the CBZ-after group showed a good anticonvulsant response. The rats that had received CBZ before (during development of kindled seizures) remained unresponsive to CBZ treatment (contingent inefficacy). When drug-naive or CBZ-after animals repeatedly received CBZ before electrical stimulation, they developed tolerance to its anticonvulsant effects (contingent tolerance). The tolerance could be reversed by a period of treatment with CBZ-after or by kindling the animal drug-free, but not by CBZ administration alone or by time off from both drug and seizures. These findings suggest that inefficacy and tolerance to CBZ may be affected by the temporal contingencies of drug administration and that responsiveness can be reinstated by altering these contingencies.

[3H]Nimodipine and high-affinity [125I]omega-conotoxin GVIA (CgTX) binding were investigated in membranes from rat cerebral cortex, cerebellum, and hippocampus after electrically and chemically induced seizures. Animals were decapitated 30 min after a single electroconvulsive shock (ECS) or lidocaine-induced seizure and 24 h after the last of 10 once-daily ECS or six once-daily lidocaine-induced seizures. After a single ECS, [3H]nimodipine and [125I]CgTX binding sites decreased in cerebral cortex (by 10% and 17%, respectively). A downregulation of [3H]nimodipine binding sites in hippocampus occurred after single and repeated lidocaine-induced seizures (by 24% and 11%, respectively), whereas [125I]CgTX binding remained unaltered. An earlier report on changes in [3H]nitrendipine binding after chronic ECS in cortex and hippocampus was not confirmed.

Summary: The effects of feeding a diet enriched in caffeine or carbamazepine (CBZ) were investigated in rats in a quantitative autoradiographic study of adenosine Al receptors (labeled by [3H]cyclohexyladenosine, [3H]CHA) and adenylate cyclase (labeled by pHJforskolin). Although regional distribution of [3H]CHA and [3H]-forskolin binding sites differed in some areas, chronic CBZ as well as chronic caffeine upregulated both of them. The changes in receptor densities occurred in the same brain microregions, suggesting that caffeine and CBZ act as antagonists at similar subpopulations of adenosine Al receptors and [3H]forskolin binding sites. Therefore, a selective interaction of these two drugs with distinct adenosine Al receptors (and adenylate cyclase) probably does not explain the differential effects of caffeine and CBZ on neuronal activity. RESUME Les consequences d'une alimentation enrichie en cafeine ou en carbamazepine ont ete examinees chez le rat au cours d'une etude autoradiographique quantitative des recepteurs Al de l'adenosine (marques par la cyclohexyladenosine[3H], [3H]CHA) et de l'adenylate cyclase (marquee par la forskoline[3H]). Quelque soit la distribution des sites de liaison de la CHA[3H] et de la forskoline[3H] different dans quelques structures, un traitement chronique a la carbamazepine, comme a la cafeine, augmente le nombre de ces deux types de recepteurs. Les changements de densite des sites de liaison ont ete observes dans les memes microregions cerebrales, suggerant que la cafeine et la carbamazepine agissent comme antagonistes au niveau des memes subpopulations de recepteurs Al de l'adenosine et de sites de liaison de la forskoline[3H]. Ainsi, une interaction selective de ces deux drogues avec des recepteurs distincts (Al de l'adenosine et aussi de l'adenylate cyclase) ne rend probablement pas compte des effets differents de la cafeine et de la carbamazepine sur l'activite nerveuse. RESUMEN Se nan investigado los efectos, en ratas, de la administracion de una dieta rica en cafeina o en carbamazepina, mediante un estudio autorradiagrafico cuantitativo de los receptores de ade-nosina Al (marcados mediante [3H] ciclohexiladenosina, [3H] CHA) y de la ciclasa-adenilato (marcada con [3H] forskolina). Mientras que la distribucion regional de los lugares de acoplamiento de [3H] CHA y [3H] forskolina eran diferentes en algunas areas, la presencia cronica de carboamazepina y de cafeina elevaron la regulacion de ambos tipos de receptores. Los cambios de las densidades de los receptores ocurrieron en las mismas microregiones del cerebro lo que sugiere que la cafeina y la carbamazepina actuan como antagonistas en subpoblaciones semejantes de receptores de adenosina Al y de los lugares de acoplamiento de la [3H] forskolina. Por lo tanto la existencia de una interaction selectiva de estas dos drogas con distintos receptores de adenosina Al (y ciclasa-adenilato) probablemente no explica los efectos diferenciales de la cafeina y la carbamazepina sobre la actividad neuronal. ZUSAMMENFASSUNG Die Auswirkungen einer mit Coffein oder Carbamazepin an-gereicherten Diat wurden in der Ratte in einer quantitativen au-toradiographischen Studie von Adenosin-Al Rezeptoren (mark-iert mit [3H]Cyclohexyladenosin, [3H]CHA) und Adenylat Cyclase (markiert mit [3H]Forskolin) untersucht. Es konnte gezeigt werden, dass sowohl chronische Carbamazepin als auch Coffein-Diat zentrale Adenosin-Al Rezeptoren und [3H] forskolin-bindungsstellen hochregulieren. Die Veranderungen der Rezep-tordichte ereigneten sich in denselben Hirnregionen. Dieses Ergebnis legt nahe, dass Coffein und Carbamazepin als Antago-nisten an ahnlichen Untergruppen von an Adenosin Al Rezeptoren und [3H]Forskolin-Bindungsstellen wirken. Eine selektive Interaktion dieser beiden Substanzen mit unterschiedlichen Adenosin Al Rezeptoren (und Adenylat Cyclasen) erklart daher wahrscheinlich nicht die unterschiedlichen Effekte von Coffein und Carbamazepin auf die neuronale Aktivitat.