Desmethylimipramine pretreatment prevents 6-hydroxydopamine induced somatostatin receptor reduction in the rat hippocampus.

Several studies have shown anatomical and functional interconnections between catecholaminergic and somatostatinergic systems. To assess whether somatostatin (SS) may act presynaptically on catecholamine neurons, SS receptors were measured using radioligand test-tube binding assays on synaptosomes from hippocampus and frontoparietal cortex--areas that are innervated by catecholaminergic neurons with different densities and that have a high number of SS receptors--from control and 6-hydroxydopamine (6-OHDA)-treated rats. Intracerebroventricular (i.c.v.) injection of the catecholamine neurotoxin 6-OHDA (0.78 mg free base/kg of body weight in saline with 0.1% ascorbic acid) lowered hippocampal and frontoparietal cortical noradrenaline (NA) and dopamine (DA) levels at 1 week following the injection. Pretreatment of rats with desmethylimipramine (DMI) (40 mg/kg, intraperitoneal) prevented the drop in NA levels, but was not effective in attenuating DA depletion in the two brain areas studied. Treatment with 6-OHDA lowered the number of 125I-Tyr11-SS receptors in the hippocampus (130 +/- 19 vs. 266 +/- 16 fmol/mg protein, P < 0.001), whereas in the frontoparietal cortex a non significant 20% reduction in receptor number was found. The dissociation constants of 125I-Tyr11-SS binding to synaptosomes from frontoparietal cortex (0.65 +/- 0.06 vs. 0.60 +/- 0.04, P not significant) and hippocampus (0.44 +/- 0.04 vs. 0.63 +/- 0.14, P not significant) were similar in control and treated groups. Pretreatment with DMI reversed up to 80% of the effect of 6-OHDA on hippocampus SS receptors. DMI alone had no observable effect on the number and affinity of SS receptors. The 6-OHDA and the DMI treatment did not affect SLI levels in the brain areas studied. These results suggest that a portion of the hippocampal SS receptors may be localized presynaptically on the noradrenergic and dopaminergic nerve terminals.     

Effect of haloperidol withdrawal on somatostatin level and binding in rat brain

The effects of withdrawal on the level and specific binding of somatostatin in the frontoparietal cortex and hippocampus of the rat after chronic haloperidol treatment were examined using¹²⁵I-Tyr¹¹ somatostatin as tracer. One week after haloperiodol withdrawal the number of specific somatostatin receptors in both brain areas returned to control values, after having decreased as the result of chronic administration. Neither administration of haloperidol nor withdrawal of it affected the levels of somatostatin-like immunoreactivity (SLI) in the two brain areas studied. The return of the somatostatin receptor number to control values after haloperidol withdrawal may be related to the motor side-effects that are clinically observed when the haloperidol treatment is terminated.     

Involvement of nitric oxide in pentylenetetrazole-induced kindling in rats

We investigated the role of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) in the pentylenetetrazole (PTZ)-induced kindling in rats. Seizures were induced by single administration of PTZ, which was associated with an increase in levels of NO metabolites (NOx) in the hippocampus. Pretreatment with a neuronal NO synthase inhibitor, 7-nitroindazole (7-NI), diminished the PTZ-induced increase in NOx levels without affecting the seizure intensity. Repeated administration of PTZ produced a gradual increase in the seizure intensity, leading to the development of kindling. In the kindled rats, PTZ at a dose of 40 mg/kg increased NOx levels in the hippocampus, whereas it had no effect in control animals. Cotreatment of 7-NI with PTZ blocked the development of kindling and attenuated the PTZ-induced increase in NOx levels. A significant increase in BDNF levels was observed in the hippocampus of the kindled rats, which returned to the control levels following seizures induced by PTZ. 7-NI reduced the hippocampal BDNF levels in control rats and suppressed the increase of BDNF levels in the kindled rats. Our findings suggest that NO plays a role in the development of PTZ-induced kindling and that BDNF may contribute to the NO-dependent plastic changes in neuronal excitability.     

Effects of alloxan-induced diabetes on somatostatin binding to cytosolic components of rabbit gastric fundic mucosa

Diabetes was induced by administration of alloxan (150 mg/Kg) to 24 h-fasted rabbits. Somatostatinlike immunoreactivity (SLI) and cytosolic binding sites for somatostatin in gastric fundic mucosa were studied using radiolabelled Tyr¹¹-somatostatin. Three months after the onset of the disease, the specific binding of somatostatin to these sites was seen to be significantly lower, due to a reduction in the number (but not the affinity) of specific somatostatin binding sites of high-affinity and a disappearance of the specific, somatostatin binding sites of low-affinity. These changes were associated with an increase in the SLI concentration in both gastric fundic mucosa and plasma.     

Effect of Pentylenetetrazole-Induced Kindling on Acetylcholine Release in the Hippocampus of Freely Moving Rats

Abstract: The role of γ-aminobutyric acid (GABA) modulation of septohippocampal cholinergic neurons in kindling was investigated. Hippocampal acetylcholine release was evaluated with the microdialysis technique in freely moving rats either after acute administration of isoniazid (an inhibitor of GABA synthesis) or pentylenetetrazole (PTZ)(a blocker of the GABA_A receptor-associated Cl⁻ channel) or after chronic administration of PTZ. Short-term treatment with PTZ (5–50 mg/kg, i.p.) or isoniazid (150–250 mg/kg, s.c.) increased hippocampal acetylcholine release in a dose-dependent manner. In contrast, the basal concentration of acetylcholine in the dialysate from the hippocampus of rats chronically treated with PTZ (kindled animals) was significantly reduced relative to that of vehicle-treated rats (2.39 ± 0.21 vs. 4.2 ± 0.31 pmol per 20-min sample; p < 0.01). Moreover, the release of acetylcholine was markedly more sensitive to the effect of a challenge injection of PTZ (10 or 20 mg/kg, i.p.) in kindled rats than in naive rats or rats chronically treated with vehicle. Abecarnil, a selective benzodiazepine receptor agonist with marked anticonvulsant activity, was administered together with chronic PTZ to evaluate whether persistent activation of GABA_A receptors and suppression of seizures during kindling might affect the sensitivity of septohippocampal cholinergic neurons to a challenge dose of PTZ. Abecarnil (1 mg/kg, i.p.) administered 40 min before each PTZ injection neither antagonized the decrease in basal acetylcholine release (2.26 ± 0.19 pmol per 20-min sample) nor prevented the development of kindling. In contrast, abecarnil prevented the chronic PTZ-induced increase in the sensitivity of acetylcholine release to a challenge dose of PTZ. These results provide novel in vivo data concerning the role of hippocampal acetylcholine function in the development of kindling and potentially in the learning and memory deficits associated with this phenomenon.     

The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with beta-amyloid 1-40

Intraventricular infusion of rats with beta-amyloid for 14 days resulted in memory deficit in the water maze as well as decreases in choline acetyltransferase activities and somatostatin levels in the cerebral cortex and hippocampus. These changes were not altered by daily intraperitoneal injection of 20 mg/Kg melatonin. Orally administered Ginkgo biloba extract, however, partially reversed the memory deficit and the decrease in choline actyltransferase activities in the hippocampus. The latter treatment failed to reverse the decrease in somatostatin levels. The results indicate that orally administered Ginkgo biloba extract can protect the brain against beta-amyloid from changes leading to memory deficit through its effect on the cholinergic system.     

Antiepileptic effects of nifedipine]

In experiments on freely moving male Wistar rats it was shown that nifedipine in a dose 10 mg/kg (i.p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. A similar suppressing effect of nifedipine was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg, i.p.). Nifedipine in the same dose was not effective on chronic PTZ administration (PTZ-kindling, 30 mg/kg i.p. during 28 days): when injected 30 min before each PTZ administration it didn't delay the development of kindling induced seizure susceptibility and had no effect on the severity of seizures. The administration of nifedipine in a dose of 10 or 30 mg/kg to control kindled animals which had not been treated with nifedipine had no influence on the severity of seizures provoked by a testing dose of PTZ (30 mg/kg i.p.): its intensity was similar to that of caused by PTZ injection along.     

A Study of Somatostatin Receptors in Amygdaloid-Kindled Rat Brain

Abstract: Kindling is an animal model of epilepsy. Previously somatostatin (SRIF) was implicated in seizure activity in the brain. Recently we reported a significant increase in brain SRIF content in the temporal cortices and cortices of kindled rats. Since the interaction between the neurotransmitter and the receptor eventually is responsible for the biological response, the present study was undertaken to examine evidence for the participation of SRIF receptor in the kindled state. In this study we present a procedure for detection of SRIF receptors using radiolabeled (D-Tyr⁸)-SRIF as a tracer. The present study indicates that in kindled rats there are no differences in the total number or affinity of the binding sites in the temporal cortex and a slight increase in the total number of binding sites in the cortex when compared with controls. These results, in view of our other observations, suggest that in kindled rat brain there may be an increased release of SRIF but no down-regulation of SRIF receptors in temporal cortex and cortex. There appears to be a significant decrease in the number of SRIF receptors in kindled hippocampus. The mechanism by which this occurs remains unclear.     

Histamine H1-Receptors Modulate Somatostatin Receptors Coupled to the Inhibition of Adenylyl Cyclase in the Rat Frontoparietal Cortex

Puebla, L., A. OcaÑa and E. Arilla. Histamine H₁-receptors modulate somatostatin receptors coupled to the inhibition of adenylyl cyclase in the rat frontoparietal cortex. Peptides 18(10) 1569–1576, 1997.—Since exogenous histamine has been previously shown to increase the somatostatin (SS) receptor-effector system in the rat frontoparietal cortex and both histamine H₁-receptor agonists and SS modulate higher nervous activity and have anticonvulsive properties, it was of interest to determine the participation of the H₁-histaminergic system in this response. The intracerebroventricular (i.c.v.) administration of the specific histamine H₁-receptor agonist 2-pyridylethylamine (PEA) (10 μg) to rats 2 h before decapitation increased the number of SS receptors (599 ± 40 vs 401 ± 31 femtomoles/mg protein, p< 0.01) and decreased their apparent affinity for SS (0.41 ± 0.03 vs 0.26 ± 0.02 nM, p < 0.01) in rat frontoparietal cortical membranes. No significant differences were seen for the basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activities in the frontoparietal cortex of PEA-treated rats when compared to the control group. In the PEA group, however, the capacity of SS (10⁻⁴ M) to inhibit basal and FK (10⁻⁵ M)-stimulated AC activity in frontoparietal cortical membranes was significantly higher than in the control group (34 ± 1% vs 20 ± 2%, p < 0.001). The ability of low concentrations of the stable GTP analogue 5′-guanylylimidodiphosphate [Gpp(NH)p] to inhibit FK-stimulated AC activity in frontoparietal cortical membranes was similar in the PEA-treated and control animals. These results suggest that the increased SS-mediated inhibition of AC activity in the frontoparietal cortex of PEA-treated rats may be due to the increase of the number of SS receptors induced by PEA. Pretreatment with the H₁-receptor antagonist mepyramine (30 mg/kg, intraperitoneally (IP) prevented the PEA-induced changes in SS binding and SS-mediated inhibition of AC activity. Mepyramine (30 mg/kg, IP) alone had no observable effect on the somatostatinergic system. The in vitro addition of PEA or mepyramine to frontoparietal cortical membranes obtained from untreated rats did not affect the SS binding parameters. Altogether, these results suggest that the H₁-histaminergic system modulates the somatostatinergic system in the rat frontoparietal cortex.     

Age dependence of somatostatin levels and somatostatin binding in the rat brain

1. Somatostatin-like immunoreactivity (SLI) and 125I-Tyrl-somatostatin binding were measured from the brains of rats aged 1, 8 and 18 months. 2. Somatostatin binding was reduced in the striatum, frontal cortex, hypothalamus and hippocampus of the 8-month-old rats compared to the 1-month-old group. 3. Somatostatin binding was reduced in the striatum, frontal cortex and hippocampus of the 18-month-old rats compared to the 1-month-old group. 4. The reduction (40%) was most striking in the frontal cortex. 5. In no area of the brain did changes in SLI differ significantly between the different age groups.     

Modulation of somatostatin receptors,somatostatin content and Gi proteins by substance P in the rat frontoparietal cortex and hippocampus

Substance P (SP) and somatostatin (SRIF) are widely spread throughout the CNS where they play a role as neurotransmitters and/or neuromodulators. A colocalization of both neuropeptides has been demonstrated in several rat brain areas and SP receptors have been detected in rat cortical and hippocampal somatostatinergic cells. The present study was thus undertaken to determine whether SP could modulate SRIF signaling pathways in the rat frontoparietal cortex and hippocampus. A single intraperitoneal injection of SP (50, 250 or 500 micro g/kg) induced an increase in the density of SRIF receptors in membranes from the rat frontoparietal cortex at 24 h of its administration, with no change in the hippocampus. The functionality of the SRIF receptors was next investigated. Western blot analysis of Gi proteins demonstrated a significant decrease in Gialpha1 levels in frontoparietal cortical membranes from rats treated acutely (24 h) with 250 micro g/kg of SP, which correlated with a decrease in functional Gi activity, as assessed by use of the non-hydrolyzable GTP analog 5'-guanylylimidodiphosphate. SRIF-mediated inhibition of basal or forskolin-stimulated adenylyl cyclase activity was also significantly lower in the frontoparietal cortex of the SP-treated group, with no alterations in the catalytic subunit of the enzyme. SRIF-like immunoreactivity content was increased in the frontoparietal cortex after acute (24 h) SP administration (250 or 500 micro g/kg) as well as in the hippocampus in response to 7 days of SP (250 micro g/kg) administration. All these SP-mediated effects were prevented by pretreatment with the NK1 receptor antagonist RP-67580. Although the physiologic significance of these results are unknown, the increase in SRIF receptor density together with the desensitization of the SRIF inhibitory signaling pathway might be a mechanism to potentiate the stimulatory pathway of SRIF, inducing a preferential coupling of the receptors to PLC.     

Effect of prenatal and postnatal cocaine exposure on somatostatin content and binding in frontoparietal cortex and hippocampus of developing rat pups.

The effects of cocaine administration to pregnant and/or nursing rats on somatostatin (SS) concentration and receptors in offspring brains at birth and 15 days of age were studied. SS was measured by radioimmunoassay and SS receptors by radio receptor assay in frontoparietal cortex and hippocampus. In newborn and 15-day-old animals the exposure to cocaine produced an increase in SS concentration in the frontoparietal cortex and a decrease of this parameter in the hippocampus. Administration of cocaine only during lactation did not induce such changes. Exposure during pregnancy or nursing induced in 0- or 15-day-old offspring an increase in the total number of SS receptors and a decrease in the affinity constant only in the cortex.     

Topiramate modulates hippocampus NMDA receptors via brain Ca2+ homeostasis in pentylentetrazol-induced epilepsy of rats

Background: Increase in neuronal Ca²⁺, activation of hippocampus N-methyl-D-aspartate receptor (NMDAR) and defects in enzymes such as brain cortex microsomal membrane Ca²⁺-ATPase (MMCA) are thought to play a role in epilepsy. Topiramate (TOP) is a novel drug with broad antiepileptic effect, and its effect on brain cortex MMCA is not known. We investigated effects of TOP on pentylentetrazol (PTZ)-induced MMCA activity and NMDAR subunits in rat brain.

Materials and methods: Thirty-two rats were randomly divided into four equal groups. The first group and second groups were used for the control and PTZ groups, respectively. 50 and 100?mg TOP were administered to rats constituting the third (TOP50) and fourth (TOP100) groups for 7 days, respectively. At the end of 7 days, all groups except the first received a single dose PTZ. Brain and hippocampus samples were taken at 3?hrs after PTZ administration.

Results: The microsomal MMCA activity was lower in the PTZ group than in control although the MMCA activities were higher in the treatment group than in PTZ group. Brain cortex total calcium levels, the hippocampus NMDAR 2A and 2B subunit concentrations were higher in the PTZ group than in control although their concentrations were decreased by TOP50 and TOP100 administration. Total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations were higher in TOP100 group than in TOP50 group.

Conclusion: The two doses of TOP modulated MMCA activity, total brain cortex calcium and hippocampus NMDAR 2A and 2B subunit concentrations in the epileptic rats.     

Effects of Nigella sativa on apoptosis and GABAA receptor density in cerebral cortical and hippocampal neurons in pentylenetetrazol induced kindling in rats

We investigated the effects of Nigella sativa on apoptosis and gamma-aminobutyric acid (GABA_A) receptor density in cerebral cortical and hippocampal neurons in a pentylenetetrazol (PTZ)-induced kindling model in rats. The PTZ kindling model was produced by injecting PTZ in subconvulsive doses to rats on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22 and 24 of the study into animals of PTZ treated (PTZ) and PTZ + N. sativa treated (PTZ + NS) groups. Clonic and tonic seizures were induced by injecting a convulsive dose of PTZ on day 26 of the study. Rats in the PTZ + NS group were treated also with a 10 mg/kg methanolic extract of N. sativa 2 h before each PTZ injection. Rats in the control group were treated with 4 ml/kg saline. The number of neurons that expressed GABA_A receptors in the hippocampus and cerebral cortex of rats in the PTZ and PTZ + NS groups increased significantly. There was no significant difference in the number of GABA_A receptors between the PTZ and PTZ + NS groups. GABA_A receptor density of the neurons in the cerebral cortex, but not hippocampus, was increased in PTZ group compared to controls. We observed a significant increase in the number of apoptotic neurons in the cerebral cortex of rats of both the PTZ and PTZ + NS groups compared to controls. We observed a significant decrease in the number of the apoptotic neurons in the cerebral cortex of rats in the PTZ + NS group compared to the PTZ group. N. sativa treatment ameliorated the PTZ induced neurodegeneration in the cerebral cortex as reflected by neuronal apoptosis and neuronal GABA_A receptor frequency.     

Benzodiazepine Receptor Binding Following Amygdala-Kindled Convulsions: Differing Results in Washed and Unwashed Brain Membranes

The binding of [3H]flunitrazepam and [3H]RO5-4864 was measured in unwashed brain homogenates and in extensively washed brain membranes from amygdala-kindled and "yoked" control rats sacrificed 2 weeks following the sixth stage 5 convulsion. In unwashed homogenates, [3H]flunitrazepam binding was reduced in both the hypothalamus and ipsilateral right cortex of kindled rats (unchanged in other areas). In washed brain membranes, [3H]flunitrazepam binding was unaltered in these regions; it was bilaterally elevated, however, in both the amygdala and hippocampus (unchanged in other areas). In washed membranes, the in vitro addition of gamma-aminobutyric acid enhanced [3H]flunitrazepam binding to a similar extent in kindled and control membranes. These data indicate that the type of benzodiazepine binding abnormality observed after kindling depends on the type of tissue preparation employed in the assay procedure.     

Role of Glutamate and GABA Transporters in Development of Pentylenetetrazol-Kindling

Kindling is a form of epileptogenesis that can be induced with pentylenetetrazol (PTZ). We undertook this study to evaluate the contribution of glutamate and GABA transporters to the process of PTZ kindling. Rats were injected i.p. three times per week with PTZ (40 mg/kg) until they were fully kindled. In rats who achieved full kindling, measurement of hippocampal glutamate and GABA transporters within 24 h by western blot showed that GLAST, GLT-1, and EAAC1 were elevated significantly. However, fully kindled rats at 30 days after their last seizure had no change in either glutamate or GABA transporters proteins. These sequential observations suggest that glutamate transporters may contribute to the occurrence of seizures, but were not associated with maintenance of epileptogenesis. During this experiment, we collected data from animals that had kindled easily and animals who were resistant to kindling. Easily-kindled rats reached full kindling with less than five injections of PTZ. Kindling resistant animals failed to achieve full kindling even after administration of 12 consecutive injections of PTZ. Levels of EAAC1 and GAT-1 in easily-kindled rats were decreased by 30% when compared to kindling resistant animals at 30 days after the last PTZ injection. Since decreased EAAC1 and GAT-1 would diminish GABA function, less quantity of these proteins would appear to be associated with the convulsive threshold at the beginning of kindling development. We wonder if glutamate and GABA transporters might be operant in a convulsion threshold set factor or as a pace factor for kindling.     

Involvement of Presynaptic Histamine H3 Receptors in the Modulation of Somatostatin Binding and Its Effects on Adenylyl Cyclase Activity in the Rat Frontoparietal Cortex

Abstract: Thioperamide (2 mg/kg, i.p.), a histamine H₃-receptor antagonist, increased the number of somatostatin (SS) receptors, with no change in the affinity constant, in the rat frontoparietal cortex. This effect was prevented by treatment with ( R )-α-methylhistamine (3.2 mg/kg, i.p.), a histamine H₃-receptor agonist. Thioperamide also induced an increase in SS binding in rats pretreated with mepyramine, a histamine H₁-receptor antagonist, or cimetidine, a histamine H₂-receptor antagonist. Pretreatment with mepyramine plus cimetidine administered simultaneously antagonized the thioperamide effect on SS binding. The increase in the number of SS receptors was accompanied by a greater SS-mediated inhibition of basal and forskolin-stimulated adenylyl cyclase (AC) activity in frontoparietal cortical membranes in the thioperamide group. Furthermore, the functional activity of the guanine nucleotide-binding inhibitory protein (G_i protein) was not altered by thioperamide or ( R )-α-methylhistamine administration in frontoparietal cortical membranes. In rats treated with mepyramine plus thioperamide or cimetidine plus thioperamide, the increase in the number of SS receptors was also accompanied by an increased SS inhibition of AC activity. Thioperamide induced a significant increase in SS-like immunoreactivity content in the frontoparietal cortex. Altogether, these results suggest that frontoparietal cortical histamine may play, at least in part, a role in the regulation of the somatostatinergic system.     

戊四氮点燃癫痫大鼠海马P75NTR及NF-κB的表达变化

目的探讨戊四氮点燃癫痫大鼠海马神经营养因子受体P75NTR及核转录因子NF-κB表达的变化,以探讨癫痫的发病机制。方法戊四氮腹腔注射诱导大鼠癫痫持续状态（SE）,观察大鼠行为学改变,分别选取1,6,24,72h四个时间点运用反转录多聚酶链反应（RT-PCR）方法检测SE大鼠和对照组海马P75NTR mRNA及NF-κB mRNA的表达。结果SE后6h,P75NTR和NF-κB表达开始增高,24h达高峰（P〈0.01）,72h略有下降,但仍高于对照组水平（P〈0.05）。各组间两两比较差异有统计学意义（P〈0.05）。结论癫痫SE时,P75NTR高表达同时伴NF-κB活性增强,二者变化具有相关性,可能为SE致痫的共同途径。     

Somatostatin Binding Sites in Human and Monkey Brain: Localization and Characterization

A radioiodinated analogue of somatostatin 28, 125I [Leu8,D-Trp22,Tyr25] SS-28, was used to localize and characterize somatostatin binding sites in both human and monkey brain. High-affinity binding sites (approximately 1 nM) were found in cerebral cortex. The highest binding was in cerebral cortex with intermediate binding found in hippocampus, striatum, and amygdala and low binding in hypothalamus and brainstem. There was a rough correlation between somatostatin receptor binding and concentrations of somatostatin-like immunoreactivity (SLI) in human brain. Somatostatin receptors were stable for up to 24 h in an animal model simulating human autopsy conditions and there was no correlation between postmortem interval and receptor binding in human brain. Pharmacologic characterization in human cortex showed that there was a correlation between the inhibition of receptor binding by somatostatin analogues and their known abilities to inhibit growth hormone secretion. These findings demonstrate that a highly specific membrane-associated receptor for somatostatin is present in both monkey and human brain. Examination of somatostatin receptor binding in Alzheimer's disease and Huntington's disease may improve understanding of the role of somatostatin in both these illnesses.     

Alterations in 5-HT(1A) receptors and adenylyl cyclase response by trazodone in regions of rat brain

The in vivo effect of trazodone on the density of [(3)H]5-HT binding sites and 5-HT(1A) receptors and adenylyl cyclase (AC) response was studied in regions of rat brain. The chronic administration of trazodone (10 mg/Kg body wt, 40 days) resulted in a significant downregulation of [(3)H]5-HT binding sites and 5-HT(1A) receptors in cortex and hippocampus. Trazodone significantly (p < 0.0001) decreased the density of [(3)H]5-HT binding sites in cortex (42.6 +/- 3.6 fmol/mg protein, 65%) and hippocampus (12.6 +/- 1.6 fmol/mg protein, 87%) when compared to control values of 121.9 +/- 5.4 and 99.3 +/- 7.5 fmol/mg protein in these regions, respectively. Similarly there was a significant (p < 0.0001) decrease in the density of 5-HT(1A) receptors in both cortex (7.2 +/- 0.5 fmol/mg protein, 70%) and hippocampus (6.3 +/- 1.2 fmol/mg protein, 79%) when compared to control values of 24.2 +/- 2.1 and 30.6 +/- 3.7 fmol/mg protein, in these regions respectively. However, the affinity of [(3)H]5-HT to 5-HT binding sites (1.83 +/- 0.26 nM, p < 0.0001) and [(3)H]8-OH-DPAT to 5-HT(1A) receptors (0.60 +/- 0.06 nM, p < 0.05) was significantly decreased only in cortex when compared to the control K(d) values of 0.88 +/- 0.04 nM and 0.47 +/- 0.02 nM in these regions, respectively.The basal AC activity did not alter in treated rats, where as, the inhibition of forskolin-stimulated AC activity by 5-HT (10 microM) was significantly (p < 0.0001) decreased both in cortex (43%) and hippocampus (40%) when compared to control levels. In conclusion, chronic treatment with trazodone results in downregulation of 5-HT(1A) receptors in cortex and hippocampus along with concomitant increased AC response, suggesting the involvement of 5-HT(1A) receptor-mediated AC response in the mechanism of action of trazodone.