Search

Anxiety is prevalent in asthma, and is associated with disease severity and poor quality of life. However, no study to date provides direct experimental evidence for the effect of allergic inflammation on the structure and function of medial prefrontal cortex (mPFC) and amygdala, which are essential regions for modulating anxiety and its behavioral expression. We assessed the impact of ovalbumin (OVA)-induced allergic inflammation on the appearance of anxiety-like behavior, mPFC and amygdala volumes using MRI, and the mPFC-amygdala circuit activity in sensitized rats. Our findings exhibited that the OVA challenge in sensitized rats induced anxiety-like behavior, and led to more activated microglia and astrocytes in the mPFC and amygdala. We also found a negative correlation between anxiety-like behavior and amygdala volume. Moreover, OVA challenge in sensitized rats was associated with increases in mPFC and amygdala activity, elevation of amygdala delta-gamma coupling, and the enhancement of functional connectivity within mPFC-amygdala circuit - accompanied by an inverted direction of information transferred from the amygdala to the mPFC. We indicated that disrupting the dynamic interactions of the mPFC-amygdala circuit may contribute to the induction of anxiety-related behaviors with asthma. These findings could provide new insight to clarify the underlying mechanisms of allergic inflammation-induced psychiatric disorders related to asthma.

Low-frequency stimulation (LFS) is a potential therapy utilized in patients who do not achieve satisfactory control of seizures with pharmacological treatments. Here, we investigated the interaction between anticonvulsant effects of LFS and phenobarbital (a commonly used medicine) on amygdala-kindled seizures in rats. Animals were kindled by electrical stimulation of basolateral amygdala in a rapid manner (12 stimulations/day). Fully kindled animals randomly received one of the three treatment choices: phenobarbital (1, 2, 3, 4 and 8 mg/kg; i.p.; 30 min before kindling stimulation), LFS (one or 4 packages contained 100 or 200 monophasic square wave pulses, 0.1-ms pulse duration at 1 Hz, immediately before kindling stimulation) or a combination of both (phenobarbital at 3 mg/kg and LFS). Phenobarbital alone at the doses of 1, 2 and 3 mg/kg had no significant effect on the main seizure parameters. LFS application always produced anticonvulsant effects unless applied with the pattern of one package of 100 pulses, which is considered as non-effective. All the seizure parameters were significantly reduced when phenobarbital (3 mg/kg) was administered prior to the application of the non-effective pattern of LFS. Phenobarbital (3 mg/kg) also increased the anticonvulsant actions of the effective LFS pattern. Our results provide an evidence of a positive cumulative anticonvulsant effect of LFS and phenobarbital, suggesting a potential combination therapy at sub-threshold dosages of phenobarbital and LFS to achieve a satisfactory clinical effect.

Adenosine exerts its anticonvulsants effect through different brain regions including piriform cortex. In this study, the effect of amygdala kindled seizures on adenosine A1 receptor-mediated neuromodulation in piriform cortex pyramidal neurons was tested at 24 h and 1 month after kindling. Animals were kindled by daily electrical stimulation of amygdala. Field potentials were recorded from layer II of piriform cortex pyramidal cells following stimulation of the lateral olfactory tract. Obtained results showed that N6-cyclohexyladenosine (CHA), a selective adenosine A1 receptor agonist (1, 10 and 100 microM; i.c.v.), reduced A1 slope and B1 amplitude of field potentials in both kindled and non-kindled (control) rats. However, its effects on kindled animals were more potent at 24 h, but not 1 month post-kindling. 8 cyclopenthyl-1,3-dimethylxanthine (CPT), a selective adenosine A1 receptor antagonist (50 microM, i.c.v.), had no significant effect on the field potential parameters. However, CPT (50 microM, i.c.v.) pretreatment eliminated effects of CHA (10 microM; i.c.v.) on the field potentials. These results indicate that activation of adenosine A1 receptors has an inhibitory effect on the field potentials of piriform cortex pyramidal neurons and the efficiency of adenosine A1 receptor neuromodulation in piriform cortex is increased at short-term (24 h) but return to normal at long-term (1 month) after kindling implementation.

In this study, the effect of A1 and A2A adenosine receptor activity of the piriform cortex (PC) on amygdala-kindled seizures was investigated in rats. Animals were kindled by daily electrical stimulation of the amygdala. In fully kindled rats, N6-cyclohexyladenosine (CHA, a selective A1 agonist), 8-cyclopentyl-1,3-dimethylxanthine (CPT, a selective A1 antagonist), CGS21,680 hydrochloride (CGS, a selective A2A agonist), and ZM241,385 (ZM, a selective A2A antagonist) were microinjected bilaterally into the PC. Rats were stimulated 5 min post-drug microinjection and seizure parameters were measured. Results showed that intra-PC CHA (10 and 100 micromol/L) decreased the duration of both afterdischarge and stage 5 seizure and significantly increased the latency to stage 4 seizure. Intra-PC CPT increased afterdischarge and stage 5 seizure duration at the dose of 20 micromol/L. The anticonvulsant effect of CHA (100 micromol/L) was eliminated by CPT (10 micromol/L) pretreatment. On the other hand, neither intra-PC CGS nor ZM had a significant effect on kindled seizures. These results suggest that activity of A1, but not A2A, receptors of the PC have anticonvulsant effects on kindled seizures elicited from electrical stimulation of the amygdala.

Adenosine is an endogenous anticonvulsant that exerts its effects through A1 receptors. As the piriform/amygdala is a critical circuit for limbic seizure propagation, in this study, the role of basolateral amygdala A1 receptors on piriform cortex (PC)-kindled seizures was investigated. Rats were kindled by daily electrical stimulation of PC. In fully kindled animals, bilateral intra-amygdala N6-cyclohexyladenosine (CHA; 10-500 micromol/L, a selective A1 receptor agonist) had no effect on kindled-seizure parameters. However, bilateral intra-amygdala 2% lidocaine (reversal neuronal inhibitor) reduced the kindled seizure severity. There was significant increase in stage 4 latency and decrease in stage 5 duration. Bilateral lesion of basolateral amygdala of kindled animals (by electrical DC current) reduced the kindled seizure severity more dramatically. Our results showed afterdischarge duration, stage 5 duration, and seizure duration were decreased and stage 4 latency increased significantly. In addition, daily intra-amygdala CHA had no significant effect on PC kindling acquisition. Therefore, it may be concluded that although the basolateral amygdala neuronal activity has a critical role in the propagation of epileptic seizures from PC, the amygdala A1 receptors have no role in this regard. On the other hand, amygdala A1 receptors have no anticonvulsant or antiepileptogenic effect on PC-kindled seizures.

In this study the effect of adenosine A(1) receptors of the entorhinal cortex (EC) and amygdala on kindled seizures was investigated. Animals were kindled by daily electrical stimulation of amygdala (group 1) or EC (group 2). In the fully kindled animals, N(6)-cyclohexyladenosine (CHA), a selective A(1) receptor agonist, and 1,3-dimethyl-8-cyclopenthylxanthine (CPT), a selective A(1) receptor antagonist, were microinjected bilaterally into the EC (group 1) or amygdala (group 2). The seizure parameters were measured at 5, 15, 60 and 120 min post injection. Obtained data showed that in group 1, intra-EC microinjection of CHA at concentration of 10 microM reduced amygdala- and, EC-afterdischarge duration and stage 5 seizure duration at 5, 15, 60 and 120 min post drug injection. It also increased the latency to stage 4 seizure but no alteration was observed in seizure stage. At concentrations of 0.1 and 1 microM, CHA reduced only EC-afterdischarge duration at 5 and 15 min post drug infusion. Bilateral microinjection CPT at concentrations of 5 and 10 microM into the EC did not alter seizure parameters. Intra-EC microinjection of CPT (5 microM), 5 min before CHA (10 microM), blocked the anticonvulsant effects of CHA. On the other hand, in group 2 animals, intra-amygdala CHA (10, 50 and 100 microM) or CPT (5 and 10 microM) had no significant effect on seizure parameters of EC-kindled rats. These results suggest that adenosine A(1) receptors activation of the EC may have an inhibitory effect on amygdala-kindled seizures. But, despite of reciprocal interconnections between these two regions, activation of the A(1) receptors of the amygdala has no effect on EC-kindled seizures.

In this study the effect of transient inhibition of the CA1 region of the dorsal hippocampus by lidocaine on amygdala kindling rate and amygdaloid kindled seizures was investigated. In experiment 1, rats were divided into four groups. In group 1, animals were implanted only with a tripolar electrode into the amygdala but in groups 2-4, two guide cannulae were also implanted into the CA1 regions of the dorsal hippocampi. Animals were stimulated daily to be kindled. In groups 3 and 4, saline or 2% lidocaine (1 microl/2 min) was also injected respectively into the hippocampus, 5 min before each stimulation. Results obtained showed that amygdala kindling rate and the number of stimulations to receive from stage 4 to stage 5 seizure were significantly increased in group 4. In experiment 2, lidocaine (1% and 2%) was infused (1 microl/2 min) into the hippocampus of amygdala kindled rats bilaterally and animals were stimulated at 5, 15 and 30 min after drug injection. Twenty four h before lidocaine injection, saline was also infused (1 microl/2 min) into the hippocampus as control. Obtained results showed that afterdischarge duration was reduced 5 min after lidocaine (1% and 2%) injection. Stage 5 seizure duration was also decreased 5 and 15 min after 2% lidocaine. Thus, it may be suggested that in amygdala kindling, activation of the hippocampal CA1 region has a role in seizure acquisition and seizure severity so that inhibition of this region results in decreasing of seizure severity and retards amygdala kindling rate., (Copyright 2002 Elsevier Science B.V.)

Background & Objectives: The amygdala and hippocampus are recognized as the two important structures in the brain involved in the development and control of kindled seizures. The study on the precise interconnection between these two regions can provide important insights into the functional anatomy of complex partial seizures. In this study the effect of an experimentally increased excitability in hippocampal neurons, via hippocampal kindling, on the amygdala kindling rate was investigated in rats., Methods: Animals were divided into four groups. Tripolar electrodes were implanted in the amygdala and CA1 region of the dorsal hippocampus of animals of Groups 1, 3 and 4. In Group 2 animals, tripolar electrodes were only implanted in the amygdala. In Group 1, one week after surgery, the rats were kindled first from the hippocampus and the next day kindled by amygdala stimulation. In Groups 2 and 3, one week after surgery, rats were kindled from the amygdala. Group 4 animals had a recovery period of one week plus 32 days, which was the mean of the hippocampal kindling rate in Group 1, and then were kindled from the amygdala., Results: In Group 1, the amygdala kindling rate (n; number of days for which animals were stimulated before a stage 5 motor convulsion is triggered) and seizure stage at day n/2 were significantly facilitated and increased respectively. There was also a significant positive correlation between hippocampal and amygdala kindling rates., Interpretation & Conclusion: Results obtained show that an increase in hippocampal excitability can facilitate kindling from the amygdala. Thus, it is suggested that the hippocampus has an important role in the development and propagation of seizures from the amygdala.

In this study the role of adenosine A(1) receptors of CA1 region of the hippocampus on amygdala-kindled seizures was investigated in rats. Results obtained showed that in kindled animals, bilateral injection of N(6)-cyclohexyladenosine (CHA), an adenosine A(1) receptor agonist, at doses of 0.1, 1 and 10 microM into the CA1 region of the hippocampus significantly decreased the afterdischarge duration and stage 5 seizure duration and increased the latency to stage 4 seizure, but there were no changes in seizure stage. Also, bilateral injection of 1,3-dimethyl-8-cyclopenthylxanthine (CPT), an adenosine A(1) receptor antagonist, at doses of 0.5 and 1 microM into the CA1 region of the hippocampus could not produce any changes in the seizure parameters. Intrahippocampal pretreatment of CPT (1 microM) before CHA (0.1 and 1 microM), reduced the effects of CHA on seizure parameters significantly. Thus, it may be suggested that CA1 region of the hippocampus plays an important role in spreading seizure spikes from the amygdala to other brain regions and activation of adenosine A(1) receptors in this region, participates in anticonvulsant effects of adenosine agonists.

Effects of intraperitoneal and intraamygdala N(6)-cyclohexyladenosine (CHA), a selective adenosine A(1) receptor agonist, and 1,3-dimethyl-8-cyclopentylxanthine (CPT), a selective adenosine A(1) receptor antagonist, were examined in fully hippocampal kindled rats. Intraperitoneal administration of CHA (0. 25, 0.5 and 1 mg/kg) decreased hippocampal secondary afterdischarge duration (SAD) and amygdala afterdischarge duration (ADD). Only the 1 mg/kg dose induced a significant increase in latency to stage 4. Intraperitoneal administration of CPT (0.25, 0.5 and 1 mg/kg) induced a significant increase in stage 5 duration, hippocampal SAD and ADD. Pretreatment of animals with CPT (1 mg/kg), antagonized effects of CHA on seizure parameters. Intraamygdala microinfusion (1 microl over 2 min) of CHA (5 nM-1 mM) significantly reduced hippocampal SAD and amygdala ADD. These effects were antagonized by intraamygdala CPT (1 microM). Results obtained suggest that in hippocampal kindled rats, amygdala may be regarded as a relay point for AD propagation specially in recruit activity of the hippocampus.

Possible anticonvulsant effects of 2-chloroadenosine injected focally into the perirhinal cortex of amygdala kindled rats were investigated over a 2 h period. Animals were microinfused (1 microl) with 2-chloroadenosine (2-CLA; 5, 10, 15, 25 and 100 nM) or artificial cerebrospinal fluid applied through a cannula located in the perirhinal cortex. At the doses employed, 2-CLA significantly reduced afterdischarge duration and stage 5 seizure duration. The latency to stage 4 seizure was increased only at the highest dose of 2-CLA (100 nM), while even at this dose no significant change in seizure stage could be seen. The maximum effect of 2-CLA was obtained 30 min after microinfusion of the drug. Pre-treatment (intraperirhinal cortex) of animals with the nonselective adenosine antagonist, caffeine (50 microM; 1 microl), blocked the anticonvulsant activity of 2-CLA. These results suggest that adenosine receptors located in the perirhinal cortex may play an important role in the suppression of seizure activity elicited from the amygdala.

The seizure-modulating effects of 2-chloroadenosine (2-CLA) infused directly into the amygdala were investigated. Different groups of amygdala-kindled rats were infused (1 microliter) with 2-CLA (0.25, 1, 10 and 25 nM), caffeine (200 microM and 2 mM), a combination of the two or artificial cerebrospinal fluid (ACSF) applied directly through a cannula located in the amygdala. Infusion of 2-CLA dramatically suppressed seizure stage (SS), after discharge duration (ADD) and stage 5 seizure duration (S5D), while the latency to bilateral forelimb clonus (S4L) was significantly prolonged. These anticonvulsant effects were evident after 5 min, reached a maximum at the 60 min time point and were still detectable 360 min post-2-CLA infusion. Pretreatment with caffeine blocked the anticonvulsant effects of 2-CLA dose-dependently. These results may suggest that in amygdaloid-kindled rats, adenosine receptors located in the amygdala play a major role in the expression of the anticonvulsant activity of 2-CLA.

Effects of intraperitoneal and intrahippocampal 2-chloroadenosine and caffeine were examined in fully kindled amygdaloid rats. Intraperitoneal administration of 2-chloroadenosine (5 and 10 mg/kg) decreased afterdischarge duration, stage 5 seizure duration and prolonged time taken to reach stage 4 seizure. Only the 10 mg/kg dose induced a significant reduction in seizure stage. Intraperitoneal administration of caffeine (50 mg/kg) increased both afterdischarge duration and stage 5 seizure duration but did not significantly alter other parameters. Intrahippocampal microinfusion of 2-chloroadenosine (1 mM) or caffeine (2 mM) did not alter any of the measured seizure parameters. Intraperitoneal but not intrahippocampal pretreatment of animals with caffeine (50 mg/kg and 2 mM, respectively) blocked the anticonvulsant effects induced by intraperitoneal administration of 2-chloroadenosine. It may therefore be concluded that the adenosine A1 receptors of the CA1 region of the hippocampus do not play a role in mediating the anticonvulsant effects of intraperitoneally administered 2-chloroadenosine in amygdaloid kindled rats.