Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

The anaerobic bacterial flora of the mouse cecum.

Refinements of the anaerobic technique such as the utilization of prereduced media and the removal of traces of oxygen from the gases used by passage through a hot copper oven resulted in quantitative and qualitative improvements in the recovery of anaerobic bacteria from the cecum of SPF mice. The commonest morphologic types of bacteria in the mouse cecum were tapered rods. These characteristically gave "speckled" colonies on agar plates. Those identified were species of the genera Fusobacterium, Eubacterium, and Clostridium. Several of the morphologic types seen with phase microscopy still could not be cultivated. The implications of these findings for the study of the intestinal flora are discussed.

Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium.

Sixty-two patients with metastatic disease were treated with continuous infusion folinic acid (leucovorin calcium; Lv) and 2-deoxy-5-fluorouridine (floxuridine; FUDR). Lv was given by constant intravenous (IV) infusion at 500 mg/m2/d, days 1 to 6, while FUDR was given by IV push, days 2 to 6, at 3:00 PM daily with doses ranging from 294 to 1,214 mg/m2/d. This program was well tolerated with dose-limiting toxicities of diarrhea and stomatitis, while hematologic toxicity was minimal. Eighty-two percent of the assessable patients (46 of 56) had failed at least one chemotherapy regimen. One complete remission lasting 9 months and 10 partial remissions ranging from 5 to 10 months were observed in this heavily pretreated patient population for an overall response rate of 20%. These data suggest that the combination therapy with Lv and FUDR may have clinical use. Because of differing patient sensitivity to this drug combination, the recommended dose of FUDR for the initial therapy cycle is 500 mg/m2/d, days 2 to 6, with subsequent escalation to 900 mg/m2/d in those patients without extreme sensitivity. Phase II studies are now in progress with these doses.

Iodination and the structure of human thyroglobulin.

We have studied human thyroglobulin of extremely low iodine content obtained from a goitrous cretin who had no measurable peroxidase activity in his thyroid gland. Thyroglobulin from these patients is of interest because of the possibility that poorly iodinated thyroglobulin is particularly susceptible to dissociation and proteolysis. In the present study our data indicated that poorly iodinated thyroglobin isolated under conditions inhibiting proteolysis possessed properties similar to normal human thyroglobulin in its secondary, tertiary, and quaternary structures.

Antagonism of dopamine supersensitivity by estrogen: neurochemical studies in an animal model of tardive dyskinesia.

The withdrawal from chronic haloperidol or estradiol benzoate (EB) treatment results in a behavioral supersensitivity to dopamine agonists in ovariectomized rats. On the other hand, the administration of EB during the withdrawal from haloperidol or the continuous treatment with EB will attenuate or prevent the development of a supersensitivity to dopamine agonists. The enhanced behavioral sensitivity to dopamine agonists is correlated with an increase in 3H-dopamine binding sites in striatal membranes. The administration of EB during the withdrawal from chronic haloperidol treatment or the continuous administration of EB decreases or prevents the proliferation of dopamine binding sites in the striatum that normally orccur upon withdrawal of these two substances. These results indicate that exogenous estrogens may modulate the number of dopamine receptors in the central nervous system and, as such, may decreasse the incidence and/or relieve the symptoms of tardive dyskinesia.

Modulation of dopamine receptor sensitivity by estrogen.

Postmenopausal females have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose them to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in an animal model of tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol (Haldol, 0.5 mg/kg) or Haldol + estradiol benzoate (EB, 10 micrograms/kg). Rats were then challenged with d-amphetamine or apomorphine 1 week following cessation of the chronic treatments. Chronic treatments with either Haldol or EB alone produced an enhanced response to both d-amphetamine and apomorphine, while the combined treatment produced a synergistic response. Rats treated chronically with Holdol, and treated daily with EB following the Haldol treatment, showed an attenuation of drug-induced stereotypy. These preliminary data indicate that estrogen can attenuate the development or mask the display of the supersensitive dopamine receptor.

In situ binding of a photo-affinity GTP analog to synaptic membrane G-proteins. Distribution of bound GTP analog reflects the status of adenylate cyclase.

Regulation of synaptic membrane adenylate cyclase is likely to involve interaction between neurotransmitter receptors, G-proteins and the adenylate cyclase catalytic unit as well as several other membrane proteins and lipids. Despite intensive study of this system, regulation of guanine nucleotide binding by the G-proteins which stimulate [Gs] or inhibit [Gi] adenylate cyclase has been examined only when those proteins have been purified and removed from the influence of the membrane environment. The hydrolysis-resistant photoaffinity GTP-analog, P3-(4-azidoanilido)-P1 5'-GTP (AAGTP) is able to bind specifically to the G-proteins in rat cerebral cortex synaptic membranes and, in this study, we have used this probe to examine the specificity and selectivity of guanine nucleotide binding to each G-protein without removing those proteins from the synaptic membrane. Marked differences were noted between guanine nucleotide binding data obtained with detergent-soluble G-proteins and data from this in situ approach. In these studies it was found that the affinity of the G-proteins binding AAGTP correlated well with the expression of adenylate cyclase activity, the affinity of both forms of Gs increasing under conditions favoring the stimulation of that enzyme.

Estrogen in experimental tardive dyskinesia.

Postmenopausal women have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol alone (0.5 mg per kilogram) or haloperidol plus estradiol benzoate (EB; 8 microgram per kilogram). Rats were then challenged with apomorphine (0.25 mg per kilogram) 4 and 10 days after cessation of the chronic treatments. Chronic treatment with haloperidol alone enhanced the response to apomorphine, whereas the combined treatment produced a synergistic response. Rats treated chronically with haloperidol and then treated daily with EB after the haloperidol treatment showed an attenuation of drug-induced stereotypy. These data indicate that estrogen may mask development of tardive dyskinesia.

Evaluation of ciladopa hydrochloride as a potential anti-Parkinson drug.

The effects of the putative dopamine agonist, ciladopa hydrochloride (AY 27,110) a non-ergot compound, were investigated in animal models of dopaminergic activity to evaluate its possible role in the treatment of Parkinson's disease. Ciladopa induced stereotyped behavior in both rats and guinea pigs. Unlike apomorphine, however, ciladopa did not produce a maximum behavioral response, i.e. stereotyped gnawing. Pretreatment with haloperidol and sulpiride blocked the effects induced by ciladopa. Pretreatment with reserpine and alpha-methyl-p-tyrosine did not alter the behavioral effects of ciladopa. Ciladopa caused contralateral rotation in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine. Ciladopa induced vomiting in dogs. Small doses of ciladopa decreased locomotor activity in rats, an effect presumably mediated by presynaptic autoreceptors. The chronic injection of both subthreshold and suprathreshold doses of ciladopa failed to induce behavioral supersensitivity. Ciladopa binds to D-2 dopamine receptors in the mammalian caudate nucleus. These data indicate that ciladopa can cause stimulation of central dopaminergic receptors and that the drug is a partial dopamine agonist with direct-acting properties. Ciladopa differs from other available dopaminergic drugs and may possess therapeutic advantages for the treatment of Parkinson's disease.

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Traumatic avulsion of the trachea associated with cricoid fracture.

A 15-year-old girl sustained a cricoid fracture, avulsion of the trachea, and bilateral cord paralysis in a automobile injury. An airway was established by intubation, and primary repair was performed on the day of injury. A postoperative stricture was successfully managed by endoscopic dilatation and injection of triamcinolone into the stricture. Function of one vocal cord appears to be returning 6 months after the injury, and the patient is leading an active life.

The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity--inhibition of apomorphine-induced climbing.

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.

The possible role of 2-hydroxyestradiol in the development of estrogen-induced striatal dopamine receptor hypersensitivity.

In the present study, we have confirmed the existence of a biphasic response in striatal dopamine receptor sensitivity following the administration of estradiol benzoate (EB). This biphasic response consists of a hyposensitive phase 24 h after the last injection of EB, followed by a hypersensitive phase 72 h after the last injection of EB. In contrast to this, the administration of 2-hydroxyestradiol (2-OHE2), a catechol metabolite of estrogen, resulted in a striatal dopamine receptor hypersensitivity at both 24 and 72 h after the last injection of 2-OHE2. Studies on the in vivo metabolism of [3H]estradiol to its [3H]catechol metabolites indicated that the administration of piperonyl butoxide (PBO; a microsomal enzyme inhibitor) significantly decreased the level of [3H]catechol metabolites of [3H]estradiol in the striatum and in the medial basal hypothalamus. In addition, PBO administration resulted in about a 7-fold decrease in the ability of estradiol to induce a striatal dopamine receptor hypersensitivity. These data indicate that the biphasic response in striatal dopamine receptor sensitivity following estrogen, may be mediated by separate molecular mechanisms. The association of the hypersensitive phase with pharmacological doses and/or treatment paradigms, the development of a similar hypersensitivity following the administration of the 2-OHE2 metabolite of estrogen and the attenuation of the estrogen-induced striatal dopamine receptor hypersensitivity in PBO pretreated animals all suggest that this striatal dopamine receptor hypersensitivity may be mediated, at least in part, by the catecholestrogens.

Influence of gamma-aminobutyric acid on lordosis behavior and dopamine activity in estrogen primed spayed female rats.

In the first experiment the role of gamma-aminobutyric acid (GABA) in the display of lordosis behavior was examined in septal-lesioned and sham-operated ovariectomized rats. Following estradiol benzoate (EB) priming, septal-lesioned rats were tested for lordosis behavior before and after bilateral infusion of picrotoxin or saline directly into the substantia nigra (SN). Sham animals were given the same behavioral tests but received intranigral infusion of either hydrazinopropionic acid (HPA) or saline. Picrotoxin, which blocks GABA receptors, was effective in suppressing the high levels of lordosis behavior seen in the EB-primed septal-lesioned female rat 30 min after infusion, but not at 120 min. Conversely, HPA, which elevates endogenous GABA levels, was effective in facilitating lordosis behavior in sham-operated rats treated with EB only. The lordosis quotient was moderately increased 30 min after HPA infusion, reached high levels at 120 min, and returned to low levels by 360 min post-infusion, demonstating the reversibility of the drug effect. Saline infusions in lesioned and sham-operated controls were without effect. In the second experiment sepal-lesioned and sham-operated rats were primed with EB and infused with the drugs as in the first experiment, but were sacrificed at the time the macimal behavioral effect had been observed in the first experiment. Tyrosine hydroxylase (TH) activity and dopamine (DA) and homovanillic acid (HVA) levels were measured. No effect on TH activity was found. However, sham-operated rats receiving HPA infusions had lower DA and HVA levels compared to those of saline-injected controls, and septal-lesioned rats receiving picrotoxin infusions had higher DA and HVA levels than those of lesioned saline-injected controls. Septal-lesioned saline-infused rats also showed decreased DA and HVA levels relative to sham-operated saline-infused animals. These results support the concept of a GABA inhibitory neuronal feedback system which modulates DA turnover and perhaps plays a critical role in the neural control of lordosis behavior.

Hypophysectomy induced hypersensitivity to dopamine: antagonism by estrogen.

Hypophysectomized (HYPOX) or sham HYPOX (SHAM) and ovariectomized rats were injected with either estradiol benzoate (EB, 10 microgram/kg/day x 3) or sesame oil (0.25 ml/kg/day x 3). Twenty hours after the last dose of EB or oil all animals were injected with apomorphine and the resulting stereotypy scored. The HYPOX + oil group was more sensitive to the apomorphine than the SHAM + oil group (ED50 = 0.24 and 0.45 mg/kg, respectively). Treatment with EB resulted in a shift to the right of the dose response curves for both the HYPOX and SHAM groups. The ED50 for the HYPOX group was increased to 0.62 mg/kg, while the SHAM group increased to 0.93 mg/kg. The Bmax values for [3H]spiroperidol binding to striatal membranes were not significantly different for the HYPOX + EB, SHAM + EB, or SHAM + oil groups. However, the HYPOX + oil group was significantly increased (54%) at 7 days post-HYPOX. By 28 days post-HYPOX, the Bmax for the HYPOX animals had increased by 94% relative to SHAM animals. The HYPOX induced increase in dopamine sensitivity could be increased by chronic treatment and withdrawal of haloperidol. The haloperidol induced increase in apomorphine induced stereotypy and [3H]spiroperidol binding could be antagonized by EB treatment during the withdrawal phase of the haloperidol treatment. These data indicate that the pituitary has a modulating effect on striatal spiroperidol binding and apomorphine induced stereotypy, but that its presence is not required for estrogen to suppress the efficacy of dopamine or dopamine agonists.

Evidence for a morphological sex difference within the medial preoptic area of the rat brain.

The present report demonstrates the existence of a marked sexual difference in the volume of an intensely staining cellular component of the medial preoptic nucleus (MPON) of the rat. Moreover, this sexual dimorphism is shown to be independent of several specific hormonal conditions in the adult, but significantly influenced, perhaps determined, by the perinatal hormone environment. Adult rats were gonadectomized and sacrificed 2 or 5-6 weeks later, or sacrificed after gonadectomy and priming with estradiol benzoate (2 microgram/day x 3) and 500 microgram progesterone, or testosterone propionate (TP, 500 microgram/day x 14), or the ingestion of propylthiouracil (0.15% of the diet) for one month, or following water deprivation for 24 h. These treatments did not affect the sexual dimorphism in the MPON and, in all groups, nuclear volume in the male animals was significantly greater than that of females whether nuclear volume was expressed in absolute terms or relative to brain weight. On the other hand, the volume of the MPON of the adult male castrated neonatally was significantly reduced when compared to that of the male castrated at the time of weaning, i.e. after the period of sexual differentiation of the brain. Consistent with the view that this nuclear region undergoes sexual differentiation is the fact that the volume of the MPON was significantly greater in female rats injected with 1 mg TP on day 4 of life than in oil-treated females. More subtle sex differences in the volume of the suprachiasmatic nucleus were also detected, as were several treatment effects. Although these differences may fall within the error of the analytical procedure, it is possible that hormone- or sex-dependent morphological differences exist elsewhere in the brain. Nevertheless, the gross sexual dimorphism in the MPON clearly demonstrates a possible morphological basis for the sexual differentiation of brain function.

Modulation of apomorphine-induced stereotypy by estrogen: time course and dose response.

Previous data have indicated that estrogen may either suppress or enhance the potency of dopamine and/or dopamine agonists. The effects of estrogen (estradiol benzoate; EB) in ovariectomized rats were indicative of a dose related suppression of apomorphine-induced stereotypy at 24 hours after the last dose of EB. HOwever, at 48 hours after the last dose of EB, the apomorphine-induced stereotypy was enhanced in those animals that received EB at 100 microgram/kg x 3 days. Ninety-six hours after the last injection of EB, all animals that received either the 100 or 50 microgram/kg dose of EB displayed an enhanced behavioral response to apomorphine. Animals pretreated with a low dose of EB (10 microgram/kg x 3 days) displayed a suppressed apomorphine stereotypy score at 24 hours, after the last dose, but were indistinguishable from Oil injected ovariectomized controls in all subsequent behavioral tests. These data indicate that estrogen can suppress dopamine and/or dopamine agonist potency 24 hours after the last dose of estrogen. However, an enhanced behavioral response to dopamine agonists can been seen at 48 hours (or more) after the last dose of estrogen. The time delay and the dose dependence of the enhanced response to dopamine agonists are indicative of a "withdrawal" phenomenon, suggesting the possibility that the role of endogenous estrogen is to suppress dopaminergic function.

Permanent haloperidol-induced dopamine receptor up-regulation in the ovariectomized rat.

One of the confounding problems associated with the study of tardive dyskinesia in rodent models has been the inability to produce a permanent supersensitivity to dopamine (DA) following neuroleptic drugs. We recently observed that ovariectomy (OVX) results in a permanent dopamine receptor (DA-R) up-regulation in the striatum of the rat. This permanent up-regulation of striatal D2 DA-R required three months to fully develop and lasted for at least 12 months post-OVX. In the present study we further characterized this model by examining the development of both apomorphine-induced stereotypy and D2 DA-R density in the striatum of OVX and Sham-operated rats following haloperidol (16 days at 1.0 mg/kg/day, IP). Following the chronic haloperidol treatment, both the OVX and the Sham-operated animals increased both their behavioral responses (stereotypic sniffing) to apomorphine, and the density of striatal D2 DA-R. However, by 30 days posthaloperidol, the Sham animals had reverted to normal behavioral responses to apomorphine and normal levels of striatal DA-R, while both the behavioral responses and the density of D2 DA-R in the OVX animals treated with haloperidol remained up-regulated. These data indicate that 1) the time required to develop this unique animal model of a permanent DA-R up-regulation in the ovariectomized (OVX) rat can be considerably shortened; 2) there is probably a unique neurochemical change induced by haloperidol in the OVX but not in Sham rats that leads to the DA-R up-regulation becoming permanent.

Pre- and postsynaptic neurochemical alterations following estrogen-induced striatal dopamine hypo- and hypersensitivity.

The administration of pharmacologic doses of estrogen results in a biphasic response in striatal dopamine sensitivity, as measured by apomorphine-induced stereotypy. At 24 hr after the last dose of estradiol benzoate (EB) there is a suppression of apomorphine-induced stereotypy, which is followed by an increased sensitivity to apomorphine at 48 hr. The dopamine hyposensitivity is reflected postsynaptically by an increased KD (i.e., decreased affinity) for 3H-spiroperidol binding to striatal membranes, while the hypersensitive phase is reflected by an increased Bmax for 3H-spiroperidol binding to striatal membranes. Presynaptically during the hyposensitive phase the tyrosine hydroxylase displayed a decreased KM for the pterine cofactor. The decreased KM for the cofactor was retained in the hypersensitive animals, however the Vmax for tyrosine hydroxylase was decreased during the hypersensitive phase of the EB-induced changes in dopamine sensitivity. The presynaptic or autoreceptor sensitivity of the dopamine neurons projecting to the striatum was assessed by determining the apomorphine IC50 value for the inhibition of synaptosomal tyrosine hydroxylase activity. Utilizing this assay the animals that were hyposensitive to dopamine showed a normal presynaptic sensitivity, while those animals that had developed a hypersensitivity to dopamine following EB were also hypersensitive to dopamine presynaptically.

Effects of septal lesions and chronic estrogen treatment on dopamine, GABA and lordosis behavior in male rats.

Septal lesions (SL) in female rats result in an increased sensitivity to the behavioral effects of acute estradiol benzoate (ACUTE-EB; 2 microgram/day X 3) treatment as measured by the lordosis quotient (LQ: number of lordotic responses X 100/number of mounts). Male rats, intact or castrated, do not show this enhanced behavioral response to ACUTE-EB unless they are treated with EB (2 microgram/day) for 2--4 weeks immediately following the production of SL. The present study was undertaken to examine possible neurochemical alterations which could account for the enhanced behavioral sensitivity to ACUTE-EB seen in the SL male rat treated chronically with EB during the postlesion period (SL-EB). Three groups, normal males, SL-EB and SL males chronically treated with oil (SL-oil), were subdivided and treated with ACUTE-EB or oil and decapitated. The brains were removed, frozen and stored at -50 degrees C prior to dissection and assay. Tyrosine hydroxylase (TH) activity was assayed in the dopamine (DA) rich areas of the forebrain (striatum, STR, nucleus accumbens septi, ACB; and olfactory tubercle). The TH activity was significantly suppressed in both the STR and ACB of the SL-EB males treated with ACUTE-EB. The glutamic acid decarboxylase (GAD) activity in both the substantia nigra and ventral tegmentum was significantly increased in the SL-EB males given ACUTE-EB relative to that of all other groups. In summary, SL-EB males given ACUTE-EB show (1) an enhanced LQ, (2) decreased TH activity in the region of DA terminals, and (3) increased GAD activity in the region of DA cell bodies. The increase in GAD activity is suggested to be a result of an altered neuronal feedback because of plastic changes that occur during chronic EB treatment following production of SL. This probable increase in inhibitory tone in the region of the DA cell bodies may explain the observation that the SL-EB male exhibits decreased DA turnover following ACUTE-EB treatment. Moreover, since DA may be inhibitory to the display of lordosis behavior, the SL-EB males may show an enhanced LQ, at least partially, because of this reduction in DA activity.