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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.

Ro15-4513 (ethyl-8-azido-5,6-dihydro-5methyl-6-oxo-4H-imidazo-[1,5-a]-1,4-benzodiazepine-3-carboxylate), a benzodiazepine partial inverse agonist of the GABA(A) receptor, is known to protect against alcohol toxicities. The present study was designed to determine the role of Ro15-4513 in preventing anticonvulsant, toxic, and lethal effects of carbamazepine (CBZ) in amygdala-kindled rats. Acute treatment with CBZ (25 mg/kg, i.p.) produced anticonvulsant effects in fully kindled rats characterized by a significant decrease in afterdischarge and seizure duration and stage. Repeated administration of this high dose of CBZ induced sedation and high (56%) lethality. The anticonvulsant and sedative effects of CBZ were strikingly suppressed by pretreatment with Ro15-4513 (2.5 and 5 mg/kg, i.p.), and there was no mortality in animals co-administrated with Ro15-4513 during the entire experimental period. These results indicate that Ro15-4513 protects against CBZ-induced sedation and lethality, while suppressing the anticonvulsant effects of CBZ, suggesting a role for the GABA(A) receptor in CBZ efficacy and side effects. The potential clinical implications for CBZ-induced toxicity and overdose remain to be explored.

1. A variety of enzymes, peptides, neurotrophic factors and their receptors show complex cascades of alterations with amygdala-kindled seizure progression; some represent compensatory adaptations that could become new targets of therapeutics. 2. Non-convulsant brain stimulation with repetitive transcranial magnetic stimulation (rTMS) may be able to engage some of the neuro-adaptive effects of ECT without the necessity of inducing a seizure. 3. Data from preclinical and clinical studies raise the possibility that non-convulsant stimulation achieved by high or low frequency rTMS may be able to alter neurotransmitters, neuropeptides, and neurotrophic factors, leading to frequency- and region-dependent changes in neural excitability. 4. Individual depressed patients show differential responses to two weeks high vs. low frequency rTMS, as revealed by the inverse correlation of degree of improvement in depression achieved by these two frequencies. 5. Preliminary data from rTMS and positron emission tomography (PET) studies reveal moderately sustained differential effects of rTMS frequency on regional cerebral neural activity in depressed patients. 6. These data suggest the possibility that an individual's level of baseline rCBF or rCMRglu on PET would help predict which rTMS frequency might be the most appropriate treatment for their depression.

Kindling is a model of the neural plasticity that occurs following stimulation to the brain, which can result in epileptogenesis. The amygdala (Am), one of the most sensitive structures from which to induce electrical kindling, is comprised of distinct nuclei that possess differences in threshold for seizure initiation, unique cellular and molecular morphology, and specific neuroanatomical connections within the amygdala and, to other cortical and subcortical brain structures. The aim of this study was to map the spread of epileptiform activity throughout the ipsilateral and contralateral hemispheres during the transition stage between oral automatisms and generalized clonic seizures, by measuring changes in mRNA expression for c- fos, NGFI-A , and BDNF. The stimulating electrode was implanted in either the basolateral (BL) or the lateral (CeL) or medial (CeM) subdivisions of the central nucleus of the amygdala. The rats were kindled once daily using afterdischarge-threshold electrical stimulation until the first forelimb clonic seizure was induced. They were sacrificed 30 min later, and their brains were prepared for in situ hybridization to measure mRNA expression of c -fos, NGFI-A and BDNF . The results demonstrate that: (1) the threshold to elicit an afterdischarge from the BL was lower than that of either the medial (CeM) or lateral (CeL) subdivisions of the Ce, which did not differ from each other; (2) the patterns of mRNA expression for c -fos, NGFI-A and BDNF were highly similar to each other when the stimulation site was the BL or the CeL, and included mainly limbic cortical and subcortical areas ipsilateral to the electrode; (3) c- fos was the only probe to be expressed in the contralateral hemisphere following the first motor seizure, and the pattern of its expression reflected a subset of structures recruited in the ipsilateral hemisphere including the claustrum, insular and perirhinal cortices; (4) unexpectedly, stimulation of the CeM elicited seizures and afterdischarges of shorter duration than those evoked by stimulation of the BL or CeL, and failed to increase mRNA expression for any of the probes in the hippocampus or in the contralateral hemisphere. A neuroanatomical model of Am-induced seizure propagation is proposed suggesting that the Claust–Ins–PRh play a pivotal role during the transition between oral automatisms and generalized clonic convulsions.

A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation. In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of the full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly tested in the clinic, such as differential efficacy of treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance to assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence. Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses.

This study examines forms of activity-dependent synaptic plasticity in the basolateral amygdalain vitroand demonstrates that a brief high frequency stimulus (HFS) train can induce a switch in the direction of the enduring change in synaptic strength induced by subsequent low-frequency stimulation (LFS). LFS (1 Hz, 15 min) of the external capsule (EC) induced a persistent 1.7-fold enhancement in the amplitude of synaptic potentials recorded intracellularly in basolateral amygdala neurons. The enhancement occurred gradually during the stimulation and was maintained for >30 min after termination of the stimulus train. LFS-induced enduring synaptic facilitation was not affected by the NMDA receptor antagonistd(−)-2-amino-5-phosphonopentanoate (APV; 100 μm). Brief high-frequency EC stimulation (HFS; 100 Hz, 1 sec) induced APV-sensitive short-term potentiation (2.5-fold) that generally decayed within 10 min. When LFS was applied after recovery from the short-term potentiating effect of HFS (HFS/LFS), there was an initial transient (m) prevented the HFS-dependent switch from synaptic facilitation to depression. Thus, LFS in thein vitroamygdala slice can induce either enduring synaptic potentiation or depression, depending on whether a priming HFS train has been applied. This experience-dependent switch, a novel form of metaplasticity, is not dependent on NMDA receptors but may require group II metabotropic glutamate receptors. In the amygdala, experiential modification of activity-dependent long-term synaptic plasticity adds flexibility to the ways in which synaptic strength can be modified and could play a role in diverse amygdala-dependent processes, including the formation, storage, and extinction of emotional memory and the regulation of epileptogenesis.

Kindling is discussed in relation to affective illness as a nonhomologous model, which shares the feature of increasing illness severity and evolution over time following repeated exposures to certain forms of stimulation. This progressive aspect of kindling has proven useful in the study of approaches to pharmacotherapeutics, mechanisms and characteristics of drug tolerance, and, most recently, illness suppression through physiological rather than pharmacological strategies. Each of these themes is described and the mechanisms that have been uncovered using the kindling model are discussed in relation to how similar principles might apply in affective illness or epilepsy. It is hoped that some of the lessons from the kindling model will provide useful and novel insights into aspects of treatment and mechanisms of psychiatric and neurologic illnesses.

We isolated a rat orphan nuclear hormone receptor from a brain cortex cDNA library. The sequence of the cDNA insert was 2154 bp with an open reading frame of 1794 bp encoding a putative protein of 598 amino acids and predicted molecular mass of 65 kDa. The deduced amino acid sequence showed a strong homology to the mouse nurr1 and human NOT1 orphan nuclear hormone receptors of the NGFI-B/nur77/NAK1 gene subfamily. We refer to this rat clone as r-nurr1. Northern blot analysis showed that r-nurr1 mRNA was highly expressed in the brain and moderately in the lung as a 4.0 kb transcript. A smaller transcript of 2.5 kb was also detected in the testes. The level of r-nurr1 transcript in the heart, skeletal muscle, liver, kidney and spleen was marginal. In situ hybridization showed that r-nurr1 mRNA was constitutively expressed in various regions of the CNS, particularly in the deeper layers (IV to VI) of the perirhinal cortex and area 2 of parietal cortex. We further evaluated the modulation of r-nurr1 expression in CNS by an electroconvulsive seizure (ECS) and by an amgydala-kindled seizure. A single ECS administered via earclip electrodes induced a rapid and transient increase of r-nurr1 mRNA in the granule cells of the dentate gyrus, being significant at 15 min after the seizure, maximal approximately 1 h and back to baseline at 4 h. The amygdala kindled seizure revealed a less robust and restricted nurr-1 induction in the CNS, as only two of the four kindled animals showed a unilateral induction of nurr1 mRNA in the dentate gyrus. These results suggest that r-nurr1 is an immediate-early gene that is differentially induced by ECS vs. kindled seizures. In addition, as r-nurr1 is prominently expressed in the specific brain sites associated with memory acquisition and consolidation, it may play a role in memory processing.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

Cholecystokinin (CCK) can be a potent anticonvulsant neuropeptide in certain seizure models. Therefore, we examined whether seizures produced by electrical kindling of the amygdala or electroconvulsive seizures (ECS) would affect the expression of CCK mRNA in rat brain. Following a single kindled seizure, CCK mRNA expression was decreased about 20-58% in the amygdala. In contrast, after multiple consecutive kindled seizures, CCK mRNA expression was increased in the amygdala, cerebral cortex, CA1 pyramidal cell layer of the hippocampus and dentate hilus. A single ECS produced no effect on CCK mRNA expression, but multiple ECS increased expression in the interneurons of the hippocampus 24 h after the last seizure. Since seizures produced by ECS can be anticonvulsant to further ECS or kindled seizures, the CCK increases in the hippocampus may represent a compensatory anticonvulsant adaptation observed in both models. Overall, the kindling-induced alterations in CCK expression appear to be more complex involving multiple brain regions and distinct temporal properties.

We have isolated a new rat sequence containing motifs of a nuclear hormone receptor from a brain cDNA library. The deduced amino acid sequence encoded by the cDNA clone showed a strong homology to the human NUCI and the mouse peroxisome proliferator activated receptor delta (PPAR delta). We therefore refer to this new clone as rat PPAR delta (rPPAR delta). The new feature of rPPAR delta is a 14 CGG triplet repeat on the 5' untranslated region, not previously reported in either NUCI or mPPAR delta. We found that rPPAR delta was expressed as a 3.5-kb transcript which showed a wide distribution in adult rat tissues. Abundant expression was detected in brain, heart, skeletal muscle, kidney and lung. Weaker expression was noted in the liver, spleen and testis. To determine the specific brain localization of rPPAR delta we performed in situ hybridization analysis. Prominent expression was observed in the thalamus, particularly in the posterior part of the ventral medial nucleus, a site responsive to pain and cold stress. These results raise the possibility that PPAR delta might play a role in modulating response to thermal and pain sensations.

Using brain microdialysis, acetylcholine (Ach) levels were assessed in the nucleus amygdaloideus lateralis of electrically kindled rats using a cholinesterase inhibitor in the perfusion fluid to prevent Ach breakdown. During kindling development, when the animals displayed afterdischarges lasting more than 30 s but no seizures, a significant increase in Ach levels (+66%) was observed after electrical stimulation. Ach levels were also elevated after a stage 5 kindled seizure (+48%), with no additional increment compared to rats experiencing only afterdischarges. Chronic diazepam administration prevented kindling development and the increment in Ach overflow; however, diazepam itself (following acute administration) tended to decrease Ach levels in the amygdala. These findings are convergent with pharmacological data suggesting that changes in the cholinergic function may be important especially during amygdaloid kindling development.

While serotonin (5-HT) has been shown to be anticonvulsant in several types of experimentally induced seizures, 5-HT receptor binding has not been investigated in the kindling model of epilepsy. The present study examined the effects of amygdala kindling on two 5-HT receptor subtypes and on the 5-HT transporter in rat brain. Kindling induced a persistent bilateral increase in 5-HT1A binding in the dentate gyrus, while 5-HT1B receptors increased only in a delayed fashion. Binding to the 5-HT transporter was transiently decreased in dentate gyrus. In cerebral cortex, binding of the three ligands was unchanged. Alterations in 5-HT receptors and the 5-HT transporter may endogenously modulate kindled seizures. Additionally, autoradiography of adenosine A1 receptors revealed no change for these receptors in any brain region.

Repeated administration of a subconvulsant dose of a local anesthetic will eventually induce seizures, a phenomenon similar to electrical kindling. We have investigated the effect of repeated lidocaine and cocaine administration on the phosphoinositide (PI) hydrolysis induced by batrachotoxin (BTX), a specific Na channel activator. Rats were injected with cocaine or saline daily for 6 days and PI hydrolysis was assayed in sliced frontal cortex. Cocaine treatment had no effect on BTX-induced PI hydrolysis while in vitro cocaine blocked the BTX effect. In a second experiment, rats received daily injections of lidocaine or saline. After a rat developed at least two seizures, it was sacrificed together with a rat receiving lidocaine injections which had never seized and a rat receiving saline injections. Basal, BTX and ibotenic acid (IBO; a glutamate receptor agonist)-stimulated PI hydrolysis did not differ among the three groups in slices of either hippocampus (HC) or piriform cortex (PC) though IBO-stimulated PI hydrolysis was mucg greater in the HC than in the PC. Neither in vitro nor in vivo carbamazepine altered the effect of cocaine on BTX-induced PI hydrolysis. These results demonstrate that local anesthetic kindling does not alter PI hydrolysis coupled to Na channel or IBO activation.

In situ hybridization for c-fos mRNA was performed on brain sections (a) from rats after an acute cocaine-induced seizure or from saline-injected controls and (b) from rats after their first cocaine-kindled seizure, as well as from rats that had not yet developed cocaine-kindled seizures (but were exposed to the same amount of cocaine as those that did exhibit convulsions) and from saline-injected controls. Increased expression of c-fos mRNA was observed in animals demonstrating cocaine-induced seizures acutely or following pharmacological kindling. Rats that experienced acute seizures after cocaine (65 mg/kg) showed pronounced increase in expression of c-fos mRNA in the dentate gyrus of the hippocampus and olfactory bulb. Increases were also observed in several other limbic cortical regions, as well as the striatum and ventromedial hypothalamic nucleus (VMH). In rats that were injected daily with an initially subconvulsive dose of cocaine-HCl (40 mg/kg), the cocaine-kindled seizures induced elevations in c-fos mRNA in the same brain regions as with an acute cocaine-induced seizure with the single exception of the VMH. These findings not only suggest the involvement of limbic, cortical and striatal structures in the cocaine-induced seizure, but also raise the possibility that alterations in the proto-oncogene c-fos and its subsequent impact on gene expression could play a role in the changes in neural excitability associated with cocaine-induced kindling.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

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.

Rats were tested for anticonvulsant responsivity to agents active at central and peripheral-type benzodiazepine receptors before and after they were made tolerant to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. Tolerance to carbamazepine in this paradigm is a contingent process; it occurs when the drug is administered prior to, but not following the kindled seizure. In animals tolerant to carbamazepine, cross-tolerance was observed to the anticonvulsant effects of PK11195, which is active at peripheral-type benzodiazepine receptors, but not to diazepam, which affects central-type benzodiazepine receptors. In animals treated with carbamazepine after the kindled seizure (not tolerant), no alteration in the anticonvulsant effect of PK11195 was observed. These data extend previous biochemical and pharmacological findings suggesting the importance of peripheral-type benzodiazepine receptor mechanisms in the anticonvulsant effects of carbamazepine and suggest a role for this site in the process of contingent tolerance development.

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.

The failure to achieve and maintain remission is a critical problem for a high percentage of patients with epilepsy and the primary affective disorders. Early illness onset and delayed initiation of treatment may contribute to primary treatment resistance or that associated with loss of efficacy (tolerance phenomenon). Neurobiological data and principles drawn from the amygdala kindling model of seizure progression are reviewed for their heuristic value in conceptualizing molecular mechanisms of illness progression and its prevention with pharmacological agents in the epilepsies and, indirectly, the recurrent affective disorders. Caveats in the use of this model and convergences and divergences in its predictive validity for seizures and affective disorders are noted.

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.

We have reported that low frequency stimulation (1 Hz for 15 min), applied after kindling stimulation of the amygdala, inhibited the development and expression of amygdala-kindled seizures, an effect we termed quenching. Subsequently, we discovered that this effect could only be achieved when certain stimulators were used that also emitted a low-level direct current (DC). The studies reported here indicate that DC, applied once daily for 15 min at intensities of 5-15 microA, produced an intensity-related attenuation of kindling development and an increase in the afterdischarge threshold. This effect persisted in some animals for at least 1 month after discontinuation of the DC. In fully kindled animals, a robust increase in seizure threshold and persistent seizure inhibition were also observed using 10 microA of DC administered for 14 days. These results clarify and extend our original findings of a quenching effect; however, the mechanisms by which low level DC induces quenching require further elucidation.

To evaluate its potential utility in counteracting neuroleptic-induced obesity, the effects of long-term administration of tamoxifen (TAM) on body weight (BW) and food intake (FI) of gonadally intact and sulpiride-treated (SUL) female rats were assessed. In addition, estradiol and prolactin serum levels were measured in rats treated with SUL. SUL plus TAM and SUL plus bromocriptine (BR). TAM, at doses of 10, 50 and 100 micrograms, significantly decreased BW gain: FI was significantly reduced at the doses of 50 and 100 micrograms. In addition, doses of TAM ranging from 5-100 micrograms completely prevented SUL-induced BW gain and hyperphagia. BR also prevented SUL effects on BW and FI. In contrast to BR, concomitant administration of TAM did not prevent SUL-induced hyperprolactinemia. Estradiol levels were not modified by SUL alone or SUL plus BR, but they were significantly increased in the animals treated with TAM plus SUL. Neuroleptic-induced obesity in female rats might be related to an alteration in gonadal steroid balance secondary to hyperprolactinemia. While BR might counteract neuroleptic-induced weight gain by preventing hyperprolactinemia, TAM might directly interact with estrogen receptors, or indirectly increase estradiol levels. The use of TAM in preventing neuroleptic-induced obesity in humans warrants further investigation.

We examined regional cerebral metabolic rates for glucose (rCMRglc) and brain incorporation coefficients (k*) of each of three intravenously infused fatty acid radiotracers, [9,10-(3H)]palmitate ([3H]PAM), [1-(14C)]arachidonate ([14C]AA) and [1-(14C)]docosahe-xaenoate ([14C]DHA), in awake rats fully kindled by once-daily electrical stimulation of the left amygdala. Compared with sham-stimulated animals, rCMRglc was increased bilaterally during a seizure, particularly in midbrain-brain stem regions, thalamus and basolateral nucleus of the amygdala. At 24 h and 2 weeks after a seizure, there was no significant change in k* for either [14C]AA or [14C]DHA in any brain region, whereas k* for [3H]PAM at 24 h was increased significantly (by 32-53%) ipsilateral to stimulation in regions of the amygdala and thalamus. Contralateral regions showed no significant change. Two weeks after a seizure, k* for [3H]PAM was increased in the ipsilateral lateral dorsal nucleus of the thalamus. These results argue for membrane remodeling involving phosphatidylcholine in the ipsilateral amygdala and thalamus at the completed phase of amygdala kindling. Remodeling may continue for up to 2 weeks after a seizure during the completed phase.

Weight gain is an undesirable side-effect of long-term lithium administration which notably interferes with treatment compliance. The mechanisms of this weight gain remain unclear, making its management in patients difficult. In this paper, studies describing the features of this weight gain in patients and in rats treated with chronic lithium administration are reviewed. The effects of lithium on body weight differ between patients and rats in a number of ways, including the observation that excessive weight gain is observed in both male and female patients, but only in female rats. Nevertheless, an animal model of lithium-induced weight gain may be able to provide useful insights into some of the specific mechanisms involved, particularly those related to interactions with gonadal steroid function. We discuss the effects of lithium on the endocrine system, neurotransmitters, metabolism, electrolyte regulation, and feeding behavior, which might underlie lithium's effects on body weight. Finally, suggestions for the management of weight gain in the clinical setting are presented. These include, in the long term, dietary control and physical activity and, in the short term, choosing among several drugs that have been tested either in patients or in animal models of obesity. If weight gain still cannot be controlled and treatment compliance is at risk, the mood stabilizers carbamazepine or valproic acid might be substituted for lithium treatment.

Contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala kindled seizures develops when the drug is repeatedly given prior to but not after the electrical stimulation. Such tolerance can be reversed by kindling the rats for several days without drug or even by continuing to give the drug but after each seizure has occurred. Contingent tolerance can be slowed by reducing the electrical stimulus intensity and by chronic continuous (as opposed to repeated paired) drug administration. Contingent cross-tolerance has been demonstrated from carbamazepine to PK11195 (a drug active at peripheral-type benzodiazepine receptors) and valproate, but not to clonazepam and diazepam (two drugs active at central-type benzodiazepine receptors) or phenytoin. Endogenous physiological changes occur in conjunction with contingent tolerance, exemplified by the decrease in seizure threshold that returns to normal upon reversal of tolerance. We suggest that contingent tolerance is associated with a loss of seizure-induced adaptations, since many biochemical changes that occur following seizures (or in non-tolerant animals given drug after seizures) are not observed in tolerant animals. These include a loss of seizure-induced up-regulation of GABAA receptors and a loss of increases in mRNA expression for corticotropin-releasing-factor (CRF), thyrotropin-releasing-hormone (TRH), neuropeptide Y (NPY), glucocorticoid receptors and brain-derived neurotrophic factor (BDNF). Thus, several putative seizure-induced anticonvulsant adaptations, such as increases in GABAA receptors and TRH and NPY mRNA fail to occur in tolerant animals. These findings are consistent with the novel observations that, paradoxically, seizures themselves appear to facilitate the anticonvulsant effects of carbamazepine or diazepam on amygdala kindled seizures. That is, animals given a 'vacation' from seizures show a decreased response to these agents, a phenomenon we have called the 'time-off seizure' effect. Thus, seizures are postulated to induce adaptive changes that influence seizure thresholds and potentiate the anticonvulsant effects of exogenously administered drugs such as carbamazepine and diazepam. Taken together, these data suggest that seizures are associated with endogenous adaptations lasting days to weeks and that a selective failure of some of these to occur during contingent drug administration may underlie the development of contingent tolerance. These observations suggest tht endogenous illness-related mechanisms may participate both in the therapeutic responses of some agents and that their failure to occur could relate to loss of drug efficacy via tolerance; these processes may reveal new potential targets for therapeutic intervention.

Carbamazepine's effects on cocaine-induced increases in dopamine overflow in the nucleus accumbens were studied using in vivo microdialysis in anesthetized rats. Rats were chronically treated with a diet containing carbamazepine or no drug for one week prior to microdialysis procedures. The basal levels of dopamine in the nucleus accumbens did not differ between groups; however, the increases in dopamine following cocaine administration (4 mg/kg i.v.) were significantly reduced by carbamazepine. In addition, basal levels of dihydroxyphenyl acetic acid (DOPAC) were significantly diminished in the carbamazepine group and a trend in the same direction was observed for homovanilic acid (HVA). These results are consistent with reports that carbamazepine might decrease dopamine synthesis. Further studies are required to determine the mechanism of carbamazepine's inhibition of cocaine-induced dopamine overflow and its potential clinical implications.

To address the question of whether the mode of seizure induction contributes to the effects of seizures on glutamate receptor gene expression, we examined rat dorsal hippocampal slides by in situ hybridization after kindling by electrical stimulation of the amygdala, or after electrically induced tonic-clonic seizures. Levels of a glutamate receptor subtype (GluR1) mRNA were analyzed at three periods post kindled seizures and found to be decreased only in brains that were obtained 24 h after the last kindled seizure. This downregulation of GluR1 mRNA was transient and was observed only in animals that had behavioral manifestations after being electrically stimulated. It is probable that maintenance of the kindled state cannot be explained by a long-lasting change in GluR1 gene expression. Repeated electroshock-induced seizures increased GluR1 mRNA levels in the hippocampus. Our results show that mode of induction is an important determinant of the effects of seizures on the levels of expression of a glutamate receptor gene.

The present study examined changes in mRNA expression of various neuropeptides at several stages of amygdala kindled seizures. 35S-labelled oligonucleotide probes for mRNA of enkephalin (ENK), dynorphin (DYN) and thyrotropin releasing hormone (TRH) were hybridized to brain sections of rats sacrificed 24 h after a stage 1 or stage 5 seizure, or 2 weeks after a stage 5 seizure. Changes in expression developed as kindling progressed, with long-lasting changes in ENK and transient changes in DYN and TRH. ENK mRNA levels increased in pyriform and entorhinal cortices at stage 1 and 5 and remained elevated in the pyriform two weeks after a stage 5 seizure. In contrast, DYN mRNA was decreased bilaterally in the dentate gyrus 24 h after a stage 5 seizure, but returned to control levels two weeks after a stage 5 seizure. TRH mRNA was dramatically increased 24 h after a stage 1 or stage 5 seizure. After a stage 1 seizure two patterns developed. One showed increases in the pyriform, entorhinal and perirhinal cortices ipsilateral to the stimulation. The other pattern displayed bilateral increases in the dentate gyrus with or without the unilateral increases the limbic cortices. Twenty-four hours after a stage 5 seizure, large bilateral increases were found in these areas, but these returned to baseline levels by two weeks after a stage 5 seizure. The data demonstrate a constellation of alterations in several peptide systems with distinct spatiotemporal patterns, particularly in regions known to be important in kindling and epilepsy, such as the dentate gyrus and pyriform and entorhinal cortices. The relationship of these neuropeptide mRNA changes to those previously found in c-fos mRNA expression during the development of kindling is discussed.

Expression of the proto-oncogene c- fos is known to increase in rat brain following various types of seizures. Measuring c- fos mRNA or protein levels was shown to be a good cellular marker for neurons activated during central nervous system (CNS) excitation. In this study, we used in situ hybridization analysis of c- fos mRNA to determine brain regions activated by a peptide that has been closely linked to stress responsivity and kindling-like seizure activity. Corticotropin-releasing hormone (CRH) was injected into the left lateral ventricle of rats and produced the late onset of seizures between 1.5–5 h after its administration. Rats were sacrificed at various time points after the administration of CRH or sterile water, and c- fos mRNA levels were determined. In the preseizure state, CRH increased c- fos unilaterally in several cerebral cortical structures (most prominently in the dorsal endopiriform nucleus and in the piriform and insular cortices). CRH-induced seizures increased c- fos bilaterally in the same cortical regions, and in addition, in the hippocampus and olfactory bulb. The data are congruous with the hypothesis that intracerebroventricularly (i.c.v.) administered CRH elicits a rapid kindling-like response.

The effects of carbamazepine (CBZ) treatment on local anesthetic-kindled seizures and lethality were evaluated in different stages of the kindling process and under different methods of CBZ administration. Chronic oral CBZ inhibited the development of both lidocaine- and cocaine-inducedseizures, but had little effect on the fully developed local anesthetic seizures. Chronic CBZ also decreased the incidence of seizure-related mortality in the cocaine-injected rats. Acute CBZ over a range of doses (15–50 mg/kg) had no effect on completed lidocaine-kindled or acute cocaine-induced seizures. Repeated i.p. injection of CBZ (15 mg/kg) also was without effect on the development of lidocaine- or cocaine-kindled seizures. The differential effects of CBZ depending upon stage of seizure development suggest that distinct mechanisms underlie the development versus maintenance of local anesthetic-kindled seizures. The effectiveness of chronic but not repeated, intermittent injections of CBZ sugests that different biochemical consequences result from the different treatment regimens. The possible utility of chronic CBZ in preventing the development of toxic side effects in human cocaine users is suggested by these data, but remains to be directly evaluated.

Nervous pointer dogs have been extensively characterized as an animal model for some human pathological anxiety states. During our work with these animals suspicion developed that some of these dogs had a hearing deficit. We decided to systematically evaluate this observation and to study the relation between hearing status and fear-related behaviors in the nervous pointer dogs. Our results revealed that a majority of the nervous dogs in our colony (75%) suffer from bilateral deafness as demonstrated by complete absence of brain stem auditory evoked response. Furthermore, behavioral ratings revealed that hearing and deaf dogs do not differ in their pathological response to the characteristic fear-provoking stimuli (e.g., human interaction) and that both hearing and deaf nervous dogs markedly differ from normal dogs in that respect. The relation between these abnormalities and their implications for research involving breeding of animals for selected traits are further discussed in this report.

The finding that the development of lidocaine-kindled seizures is blocked by carbamazepine suggests an interaction of carbamazepine with local anesthetic mechanisms. To study the site of interaction, the effects of lidocaine, carbamazepine and another anticonvulsant drug, phenytoin on scorpion venom-enhanced specific binding of [ 3 H]batrachotoxinin A 20-α-benzoate to the sodium channel gating complex were examined in vitro in a rat brain hippocampus preparation. Lidocaine shifted the concentration inhibition curve of carbamazepine to the right and vice versa. Carbamazepine shifted the concentration inhibition curve of phenytoin to the right and vice versa. The experimentally determined apparent dissociation constants were in a good agreement with the dissociation constants calculated for a one-site model, suggesting that the interaction occurs because lidocaine shares a common binding site with carbamazepine and phenytoin in the voltage-dependent sodium channels.

Chronic carbamazepine treatment for a period of 2 weeks caused a highly significant increase in brain adenosine receptors in the rat. The carbamazepine was administered in food pellets in a diet that achieved clinically relevant total plasma concentrations of carbamazepine and its active-10,11-epoxide metabolite. Of the several brain areas examined, the cerebral cortex and hippocampus exhibited the most robust increases in [3H]cyclohexyladenosine (CHA) binding. Increases of 35-40% were observed in these brain regions whereas an 8-10% increase was seen in the cerebellum. The carbamazepine induced increase in brain adenosine receptors in all these areas persisted unabated at 1 and 5 days as well as 2, 4, and 8 weeks following termination of carbamazepine treatment, suggesting a relatively permanent alteration of the adenosine receptor by this drug.

Intracerebroventricular (i.c.v.) administration of ovine corticotropin-releasing factor (CRF) in doses varying from 10 to 100 micrograms has been reported to produce the late onset of seizures that resemble those observed during electrical kindling of the amygdala. We assessed the effects of repeated CRF administration on seizure development and on subsequent electrical kindling of the amygdala. Rats were administered vehicle or CRF (100 micrograms in 10 microliter of sterile water, i.c.v.) once daily for 5 consecutive days and were rated for seizures and aggressive behavior. On days 1 or 2, all animals receiving CRF developed major motor seizures of late onset (1-5 h post-injection), accompanied by spiking in the amygdala. By day 5, however, no rats had seizures, suggesting the development of tolerance. Defensive biting attacks were also observed following latencies of several hours and tolerance appeared to develop to these as well. After the CRF regimen, treated rats developed amygdala-kindled seizures following electrical stimulation approximately twice as fast as vehicle-injected controls (P less than 0.03). In a second experiment, rats were electrically kindled or sham-kindled prior to receiving i.c.v. CRF (100 micrograms). Kindled animals were significantly less sensitive to the seizure-inducing effects of CRF (P less than 0.03), but were more intensely aggressive than sham-kindled animals or naive rats receiving CRF for the first time.

Normative data are reported for the visual acuity, luminance-difference threshold and size-difference threshold of pigeons (Columba livia). The mean visual acuity was 12.66 c/deg or 2.53 min (N = 54), the mean log luminance-difference threshold was 0.11 (N = 105) and the mean size-difference threshold was 0.94 mm (N = 20).

Summary: The effect of carbamazepine on adenosine receptors in vitro has been well documented, with findings from several groups showing that therapeutic doses of this drug are sufficient to inhibit binding to the major portion of adenosine receptors in brain. In this study, we describe the effects of chronic carbamazepine on central adenosine receptors from several areas of rat brain using [3H]diethylphenylxanthine ([3H]DPX) and [3H]cyclohexyladenosine ([3H]CHA) as ligands. Carbamazepine was administered to rats orally in the diet at doses of 2.25 g/kg of diet and 5.0 g/kg of diet for periods of 3 and 11 days, respectively. Carbamazepine-treated animals displayed higher levels of adenosine receptors in virtually all brain areas tested, most of which reached significance in the 11-day treatment group. Scatchard analysis revealed increases in the number of receptors. There was no change in peripheral and central type benzodiazepine receptors or β-adrenergic receptors in the carbamazepine-treated animals. Therefore, carbamazepine treatment in vivo appears to upregulate adenosine receptors, suggesting that this drug may act as an adenosine antagonist. RESUME L'effet de la carbamazepine sur les recepteurs de l'adenosine a ete bien etudie in vitro et les constatations de plusieurs groupes d'investigateurs montrent que des doses therapeutiques de ce produit sont suffisantes pour inhiber la majorite des recepteurs d'adenosine du cerveau. Cette etude decrit les effets de l'administration chronique de carbamazepine sur les recepteurs de l'adenosine de diverses aires cerebrales du rat en utilisant les (3H) DPX et (3H) CHA comme ligands. La carbamazepine a ete administree par voie orale dans l'alimentation des rats a des doses de 2,25 g/kg d'aliments et de 5,0 g/kg d'aliments pour des periodes de 3 et 11 jours. Les animaux traites par la carbamazepine ont un taux plus eleve de recepteurs de l'adenosine dans a peu pres toutes les zones cerebrales etudiees, dont la plupart a un taux atteignant la significativite statistique dans le groupe ayant ete traite 11 jours. L'analyse du scatchard montrait une augmentation du nombre de recepteurs. II n'y a pas de modification des recepteurs de type cerebral ou peripherique pour les benzodiazepines, ni des recepteurs B. adrenergiques chez les animaux traites par la carbamazepine. Le traitement par la carbamazepine in vivo, semble done hypersensibiliser les recepteurs pour l'adenosine suggerant que cette substance peut agir comme un antagoniste de l'adenosine. RESUMEN Los efectos de la carbamazepina sobre los receptores de adenosina in vitro han sido bien documentados en estudios de diversos grupos que muestran que las dosis terapeuticas de esta medicacion son suficientes para inhibir la mayor parte de los receptores de adenosina en el cerebro. En este estudio describimos los efectos de la carbamazepina cronica sobre los receptores centrales de adenosina en diversas regiones del cerebro de rata utilizando 3H DPX y 3H CHA como ligandos. La carbamazepina se administro a las ratas por via oral en sudieta habitual a dosis de 2.25 g/kg de su dieta y 5.0 g/kg de dieta durante periodos de 3 y 11 dias. Los animales tratados con carbamazepina mostraron niveles mas altos de receptores de adenosina virtualmente en todas las areas cerebrales examinadas mostrando, en su mayor parte, resultados significativos en el dia 11 del grupo tratado. Los “Scatchard analisis” han revelado incremento del numero de receptores. No se observo ningun cambio en los receptores perifericos o centrales de la benzo-diazepina o en los receptores B adrenergicos en los animales tratados con carbamazepina. Por lo tanto, el tratamiento de carbamazepina in vivo, parece que incrementa la regulacion de los receptores de adenosina, lo que sugiere que esta medicacion puede actuar como un antagonista de la adenosina. ZUSAMMENFASSUNG Die Wirkung des Carbamazepins auf die Adenosin-Rezeptoren ist in vitro durch Befunde von verschiedenen Gruppen gut dokumentiert, die gezeigt haben, das therapeutische Dosen dieses Medikaments aus-reichen, einen grosen Anteil der Adenosin-Rezeptoren des Gehirns zu inhibieren. In dieser Untersuchung beschreiben wir die Wirkungen der chronischen Carbamazepin-Anwendung auf die zentralen Adenosin-Rezeptoren in verschiedenen Gegenden des Rattenhirns; sie wurden mit (3H) DPX und (3H) CHA als Liganden durchgefuhrt. Carbamazepin wurde den Ratten oral in einer Diat mit Dosen von 2,25 g/kg Diat und 5,0g/kg wahrend 3 bis 11 Tagen verabfolgt. Die mit Carbamazepin behandelten Tiere zeigten hohere Spiegel von Adenosinrezeptoren in praktisch allen untersuchten Hirnarealen; die meisten von ihnen erreichten eine Signifikanz am 11. Behandlungstag. Scatchard-Analyse zeigte eine Vermehrung in der Anzahl der Rezeptoren. Bei den mit Carbamazepin behandelten Tieren gab es keine Veranderungen in den peripheren und zentralen Rezeptoren vom Benzodiazepin-Typ oder den B-adrenergen Rezeptoren. Carbamazepin-Behandlung in vivo scheint die Adenosin-Rezeptoren hochzuregeln und last vermuten, das dieses Medikament als Adenosin-Antagonist wirkt.

The effect of alteration in thyroid status on beta adrenergic receptors in the cortex of the rat was assessed. Normal animals were treated with large doses of thyroxine (T4) and triiodothyronine (T3) and thyroidectomized animals were treated with physiological replacement doses of T4 and T3 in order to assess the possible differential effects of these hormones. In addition, a group of rats was treated with a diet of carbamazepine (an anticonvulsant also used in the treatment of manic-depressive illness), which has been shown to reduce peripheral levels of thyroid hormone in humans. The intended manipulations of the thyroid were achieved by the various treatments with thyroid hormone, and carbamazepine-diet-treated animals had significantly lower plasma T4 levels as compared with controls. No significant alteration in the density or affinity of beta-adrenergic receptors in the cortex was noted with major, short-term alterations in thyroid status or with treatment with carbamazepine. It is concluded that even marked, but relatively short-term, changes in thyroid status do not necessarily affect beta-receptors in the cerebral cortex and that carbamazepine may represent an exception to the general proposition that antidepressant agents decrease the number of beta-receptors.

Possible mechanisms of action of carbamazepine and diazepam on amygdala-kindled seizures were studied using compounds acting at the central and “peripheral-type” benzodiazepine binding sites. Ro-15-1788, a selective antagonist at the central benzodiazepine site, blocked the anticonvulsant effect of diazepam, but not of carbamazepine. In contrast, Ro5-4864, which acts at the “peripheral-type” benzodiazepine site, blocked the anticonvulsant effect of carbamazepine, but not of diazepam. The effect of Ro5-4864 was itself reversed by PK-11195, a compound that displaces Ro5-4864 binding in vitro and in vivo . These data indicate that the anticonvulsant effects of carbamazepine and diazepam on amygdala-kindled seizures are differentially mediated and suggest that the “peripheral-type” benzodiazepine binding site is functionally involved in the anticonvulsant effect of carbamazepine.

We investigated the effects of chronic carbamazepine treatment in rats on brain somatostatin. Following 12 days of carbamazepine treatment, no changes in somatostatin levels were found in any of the brain areas examined which included: amygdala, hippocampus, caudate-putamen, median eminence, arcuate nucleus, nucleus accumbens, nucleus interstitialis of the stria terminalis, nucleus periventricularis, parietal cortex, and occipital cortex. Thus, carbamazepine in low doses does not affect basal levels of brain somatostatin in the rat, in contrast to the previous reports of decreased somatostatin in the cerebrospinal fluid of affectively ill patients.

Summary: The effect of carbamazepine and its −10,11-epoxide on the development of amygdala-kindled seizures and on completed kindled seizures in the rat was evaluated. Neither carbamazepine (15 mg/kg) nor the −10,11-epoxide (15 mg/kg) was capable of preventing the development of amygdala-kindled seizures, although both drugs, at these doses, exerted marked anticonvulsant effects on completed kindled seizures. These data suggest that different phases of kindling are differentially responsive to pharmacological intervention. They also support the conclusion that different mechanisms underlie the acquisition and maintenance of kindled seizures.

Nine pigeons were trained to perform a simultaneous discrimination task with stimuli that were lateral mirror images, vertical mirror images and nonmirror images. All subjects acquired the discriminations rapidly and at approximately equal rates. Following training, bilateral stereotaxic lesions were made in either the visual wulst or ectostriatum, which are telencephalic components of the thalamofugal and tectofugal visual pathways, respectively. After surgery both groups were retrained to their preoperative performance levels or for a maximum of 140 sessions. The performance of the four subjects that received visual wulst lesions was only mildly and transiently impaired and was equally disrupted on each pattern discrimination. The performance of the five subjects that received ectostriatal lesions, however, was markedly and persistently impaired on all pattern discriminations. The impairment was most severe and sustained on the lateral mirror-image discrimination problem in all subjects. Only three of the five subjects with ectostriatal lesions reached their preoperative performance levels on the lateral mirror-image problem, whereas all subjects returned to their preoperative performance levels on the other problems. Possible reasons for this selective deficit in lateral mirror-image pattern discrimination are discussed in relation to interhemispheric pathways and the relative importance of the thalamofugal and tectofugal visual pathways in birds and in mammals.

Seven pigeons were trained to perform in a psychophysical procedure to determine the smallest difference in luminous intensity (intensity difference threshold) that they could discriminate. When their performance stabilized, lesions were made in the ectostriatum in 4 birds and in the neostriatum in the remaining 3 birds. After surgery, the pigeons with ectostriatum lesions showed markedly elevated thresholds. The neostriatum control cases showed only trivial threshold changes as a consequence of the surgery. A psychophysical scaling analysis showed that the ectostriatum-lesioned pigeons had lost from 50% to 83% of their preoperative capacity to discriminate differences in the intensity of visual stimuli. A multiple-regression analysis based on quantitative reconstructions of the lesions revealed that only damage to the core region of the ectostriatum contributed to the postoperative threshold changes.

Fifteen pigeons were tested in a psychophysical procedure that determined the limits of their ability to detect differences in the sizes of stimuli. The results indicated that intact pigeons can reliably discriminate an annulus 3.0 mm in diameter from one that is 3.9 mm in diameter. In the first experiment, pigeons with lesions of the ectostriatum that spared the medial 15% were unimpaired in their size-discrimination ability. Those cases in which the lesions involved both the medial and lateral regions of the ectostriatum were greatly impaired. In a second experiment, these findings were replicated. In some cases, the electrode trajectory was varied to rule out possible effects from non-ectostriatal structures. In addition, the second study indicated that destruction of the medial ectostriatum with the lateral regions intact had no measurable effect on size-difference thresholds. The medial region of ectostriatum is part of the termination field of a second tectofugal pathway to the telencephalon. This pathway passes from the optic tectum to nucleus dorsolateralis posterior thalami and then to the neostriatum intermedium, including the medial ectostriatum. An examination of the data of the present experiment and those of other behavioral studies of the ectostriatum suggest that the medial ectostriatum may be involved in the processing of visual information with low spatial-frequency components and the lateral ectostriatum may be processing information about the high-frequency composition of stimuli.

Amygdala-kindled seizure thresholds were studied in animals which were or were not tolerant to the anticonvulsant effects of carbamazepine. The seizure threshold was defined as the lowest current that elicited a major motor seizure (stage 3 or greater). Amygdala-kindled rats received carbamazepine, once daily, either before each electrical stimulation (carba-before) or after each stimulation (carba-after). The rats given carbamazepine before, but not after, each once-daily kindling stimulation became tolerant to its anticonvulsant effects. Following this manipulation, seizure thresholds were redetermined in both groups of animals while medication-free. The carba-before (i.e., tolerant) animals showed a decreased seizure threshold, while the carba-after (i.e., nontolerant) animals showed no change. Tolerance to carbamazepine was reversed by giving the rats kindled seizures for a period of 7 days without drug; nontolerant animals received the same stimulation and seizures. When seizure thresholds were reevaluated, the carba-before animals (now not tolerant) had returned to their pretolerance values, while the carba-after group again showed no change. This effect of carbamazepine tolerance and its reversal being associated with respective decreases and increases in basal seizure threshold was replicated two more times. In each case the change in the generalized seizure threshold mirrored the change in responsivity of the animals to carbamazepine. These findings, consistent with the formulations of Siegel regarding conditioned compensatory response mechanisms mediating contingent drug tolerance, may have important clinical and theoretical implications.