Chronic haloperidol treatment potentiates apomorphine- and ethanol-induced hypothermia in the rat

Supersensitivity developed in the central dopaminergic system of the rat after 21 days of chronic haloperidol injection. This was indicated by a higher level of apomorphine-elicited stereotypic behavior and by higher concentrations of striatal ³H-spiroperidol binding sites in haloperidol-treated rats compared to saline-treated controls. The chronic haloperidol treatment did not affect the baseline body temperature but potentiated both apomorphine- and ethanol-induced falls in core temperature. Such potentiation may also be related to dopamine supersensitivity. However, no significant correlation was found between apomorphine- or ethanol-induced hypothermia and apomorphine-elicited stereotypic behavior or the concentration of striatal ³H-spiroperidol binding sites. Hence, the nigrostriatal dopamine system does not appear to be involved in the development of hypothermic responses to these agents.     

Dopamine agonists reverse the elevated 3H-neuroleptic binding in neuroleptic-pretreated rats.

Chronic administration of large doses of haloperidol (10 mg/kg/day for 21 days) resulted in a 37–45% increase in the specific binding of ³H-spiperone and a 28% increase in the specific binding of ³H-apomorphine in rat striatal homogenates. The increase in ³H-spiperone binding in neuroleptic-pretreated rats could be reversed significantly by a five day administration of either bromocryptine (35 mg/kg p.o.) or L-DOPA (200 mg/kg p.o.)+ Carbidopa (20 mg/kg p.o.). Treatment of normal rats for 5 days with either L-DOPA or bromocryptine alone had no effect on ³H-spiperone binding.These results indicate that dopamine agonists can reverse the neuroleptic-induced elevation of brain neuroleptic binding, suggesting that short-term high-dose therapy with dopamine agonists might be of some value in alleviating neuroleptic-induced tardive dyskinesia clinically.     

Effect of chronically administered methylxanthines on ethanol-induced motor incoordination in mice

The effect of chronic (10 days) administration of methylxanthines, caffeine, IBMX and theophylline on acute ethanol-induced motor incoordination has been investigated in the mice. In animals that received caffeine, 45 and 90 mg/kg/24 h, ethanol, 1.5 g/kg, produced motor incoordination significantly greater compared to that in the control groups. Significantly greater ethanol-induced motor incoordination was seen in animals fed IBMX, 30 and 60 mg/kg/24 h, compared to controls. Ethanol-induced increased motor incoordination in caffeine and IBMX-fed animals was also associated with significantly greater 3H-R-PIA binding in whole brains compared to tap water controls indicating an increase in brain adenosine binding sites. However neither motor incoordination nor 3H-R-PIA binding was altered in theophylline 75 and 150 mg/kg/24 h, fed animals. The increased motor incoordination associated with increased adenosine binding sites in the brains of caffeine and IBMX-fed animals suggests an involvement of central adenosine mechanisms in the motor incoordinating effect of ethanol and further supports our earlier suggestion for the role of adenosine in some of the central effects of ethanol.     

Effects of chronic administration of phencyclidine on stereotyped and ataxic behaviors in the rat

After chronic administration of Phencyclidine (PCP) to rats, a high test dose (15 mg/kg) of PCP produced increases in stereotypic and ataxic behaviors, and a lower test dose of PCP (5 mg/kg) produced decreases in these behaviors, compared to behavioral responses of control rats. Rearing behavior in rats chronically administered PCP was increased at all test doses of the drug. Rats treated chronically with 15 mg/kg PCP for 9 days showed marked increases in most of these behaviors, whereas, rats receiving 5 mg/kg PCP for 9 days showed less change in several stereotypic and ataxic behaviors. Rats receiving 10 mg/kg PCP on a once-weekly schedule also exhibited more rearing and ataxic behavioral responses after the 3rd or 4th weekly PCP injection. Chronic PCP rats did not show more stereotypic or ataxic behavior after administration of apomorphine or amphetamine than control rats. These results suggest that chronic administration of PCP augments sensitivity to the stereotypic inducing effects of high doses, and decreases sensitivity to low doses of PCP.     

Effects of bicuculline on [3H]SR 95531 binding in discrete regions of rat brains

Effects of bicuculline in vitro, and acute and chronic treatment of a subconvulsive dose of bicuculline on [³H]SR 95531 binding to discrete regions of rat brains were studied in Sprague-Dawley rats. Scatchard analysis of the binding isotherms exhibited two populations of binding sites for [³H]SR 95531 in frontal cortex, cerebellum, striatum and substantia nigra. The apparent K_D for high-affinity sites was significantly increased in the frontal cortex and cerebellum in the presence of bicuculline (1 M) with no change in B_max. In contrast, the apparent affinity for low-affinity sites was not altered in the presence of bicuculline in these regions, whereas the B_max was significantly decreased in the cerebellum. Following acute (2 mg/kg, i.p.) or chronic (2 mg/kg, i.p. for 10 days) bicuculline treatment, [³H]SR 95531 binding was also investigated in various regions of brains. The acute bicuculline treatment did not affect the [³H]SR 95531 binding in any of the regions studied. In contrast, apparent affinity for [³H]SR 95531 was significantly decreased in low-affinity sites of all regions studied in rats treated chronically with bicuculline. The B_max values of high and low-affinity sites were significantly increased in the cerebellum with no change in the frontal cortex, striatum and substantia nigra. The present study demonstrates that chronic bicuculline treatment decreases apparent affinity of [³H]SR 95531 binding whereas the treatment increases apparent affinity of [³H]SR 95531 and [³H]muscimol binding in the cerebellum may be due to true up-regulation of GABA binding sites, involving increased de novo synthesis of receptor protein. These results also suggest that properties of cerebellar GABA_A receptors are different from those in other regions.Abbreviations used GABA -aminobutyric acid - FC frontal cortex - CB cerebellum - ST striatum - SN substantia nigra     

MDL-646, a new synthetic E1-prostaglandin with local protective effects on the gastric mucosa

The gastric protection, diarrheogenic and arterial hypotensive effects of MDL-646, a PGE₁ derivative, have been studied in rats. The compound administered p.o. or i.v. was able to inhibit the maroscopic damage to gastric mucosa produced by noxious stimuli (ethanol and indomethacin). In the stomach perfusion test with the anesthetized rat, intravenously administered MDL-646 reduced histamine- or pentagastrin-stimulated gastric secretion. After intraduodenal administration (i.d.) doses at least 40–50 times greater were necessary for an antisecretory effect. In conscious rats with chronic gastric fistulas, intragastrically administered (i.g.) MDL-646 affected both acid concentration and volume of unstimulated gastric secretion. In experimental models for gastric lesions, DML-646 was much more potent after oral (p.o.) (15–30 times) than after i.v. administration. (ED₅₀ μg/kg: vs. alcohol lesions, 0.05 p.o. and 0.7 i.v.; vs. indomethacin ulcers, 7.0 p.o. and 195 i.v.). Our data would fit the hypothesis that it was a local effect on the gastric mucosa. The mechanism of this effect is not known. The supposed local activity coupled with the antisecretory effects and the good tolerability make it interesting to test MDL-646 as an anti-ulcer agent in man.     

Effects of Chronic Administration of Interferon α A/D on Serotonergic Receptors in Rat Brain

The effects of chronic administration of interferon (IFN; recombinant human IFN -A/D) on serotonergic binding sites in rat brain were investigated. IFN was injected daily for 2 weeks at a dose of 100000 I.U./kg, (i.p.) in male Wistar rats. IFN did not alter either [³H]ketanserin binding to 5-HT_2A receptors or [³H]paroxetine binding to 5-HT transporters. Scatchard analysis of [³H]8-hydroxy-dipropylaminotetraline (8-OH-DPAT) binding to 5-HT_1A receptors demonstrated the presence of high- and low-affinity binding sites in both treatment and control groups. IFN significantly increased both Kd and Bmax measures of [³H]8-OH-DPAT binding at low-affinity binding sites, but not at the high-affinity sites. These results suggest that IFN affects the low-affinity 5-HT_1A receptors sites and may be involved in the development of IFN-induced psychiatric disturbances.     

Changes in Histamine Metabolism in the Mouse Hypothalamus Induced by Acute Administration of Ethanol

The effect of acute ethanol administration on histamine (HA) dynamics was examined in the mouse hypothalamus. The steady-state level of HA did not change after intraperitoneal administration of ethanol (0.5-5 g/kg), whereas the level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, increased when 3 and 5 g/kg of ethanol was given. Pargyline hydrochloride (80 mg/kg, i.p.) increased the level of t-MH by 72.2% 90 min after the treatment. Ethanol at any dose given did not significantly affect the t-MH level in the pargyline-pretreated mice. Decrease in the t-MH level induced by metoprine (10 mg/kg, i.p.), an inhibitor of HA-N-methyltransferase, was suppressed by ethanol (5 g/kg), thereby suggesting inhibition of the elimination of brain t-MH. Ethanol (5 g/kg) significantly delayed the depletion of HA induced by (S)-alpha-fluoromethylhistidine (50 mg/kg, i.v.), a specific inhibitor of histidine decarboxylase. Therefore, a large dose of ethanol apparently decreases HA turnover in the mouse hypothalamus.     

Effects of ethanol and haloperidol on plasma levels of hepatic enzymes, lipid profile, and apolipoprotein in rats.

This work studied the effects of ethanol in the absence and presence of haloperidol under two experimental conditions. In protocol 1, rats were treated daily with ethanol (4 g/kg, p.o.) for 7 days, and received only haloperidol (1 mg/kg, i.p.) from the 8th day to the 14th day. In protocol 2, animals received ethanol, and the treatment continued with ethanol and haloperidol from the 8th day to the 14th day. Results show increases in alanine transaminase (ALT; 48% and 55%) and aspartate transaminase (AST; 32% and 22%) levels after ethanol or haloperidol (14 days) treatments, as compared with controls. Apolipoprotein A-1 (APO A1) levels were increased by haloperidol, after 7- (148%) but not after 14-day treatments, as compared with controls. Levels of lipoprotein (high-density lipoprotein (HDL-C)) tended to be increased only by ethanol treatment for 14 days. ALT (80%) and AST (43%) levels were increased in the haloperidol plus ethanol group (protocol 2), as compared with controls. However, an increase in APO A1 levels was observed in the haloperidol group pretreated with ethanol (protocol 1), as compared with controls and ethanol 7-day treatments. Triglyceride (TG) levels were increased in the combination of ethanol and haloperidol in protocol 1 (234%) and 2 (106%), as compared with controls. Except for a small decrease in haloperidol groups, with or without ethanol, as related to ethanol alone, no other effect was observed in HDL-C levels. In conclusion, we showed that haloperidol might be effective in moderating lipid alterations caused by chronic alcohol intake.     

Effects of acute and chronic administration of ethanol on rat brain arylsulphatase A and B

Acute (4g/kg i.p.) and chronic (Sustacal^TM diet containing 10% ethanol for 20 days) administration of ethanol to male Sprague-Dawley rats produced no change in the content or enzyme activity of brain arylsulphatase A. In contrast to the lack of effect on arylsulphatase A, the acute and chronic administration of ethanol resulted in an increase in the activity of brain arylsulphatase B (15.8% and 18.4%, respectively). However, the enhancement of the activity of arylsulphatase B was observed only in the brain homogenates which were subjected to osmotic shock. No enhancement of the arylsulphatase B activity was found in the supernatant soluble fraction after the acute and chronic administration of ethanol. Furthermore, acute and chronic ethanol administration did not alter the activities of arylsulphatase A and B in microsomes which have been suggested as sites of the synthesis of lysosomal hydrolases. In addition, 80 mM ethanol, in vitro, did not affect the activity of arylsulphatase A and B. The results of the present study suggest that the acute or chronic administration of ethanol might enhance the activity of lysosomal membrane bound arylsulphatase B via altering the lipid metabolism of lysosomal membranes.     

Inhibition by 16, 16-dimethyl PGE2 of ethanol-induced gastric mucosal damage and leukotriene B4 and C4 formation

The effects of PGE₂ and its stable analogue, 16, 16 dimethyl PGE₂ (dmPGE₂) were investigated on ethanol-induced gastric mucosal haemorrhagic lesions and leukotriene formation in the rat. Exposure of the rat gastric mucosa to ethanol , produced a concentration-related increase in the mucosal formation of leukotriene B₄ (LTB₄) which was correlated with macroscopically-apparent haemorrhagic damage to the mucosa. Challenge with absolute ethanol likewise enhanced the mucosal formation of LTC₄ whereas the mucosal formation of 6-keto-PGF_1α was unaffected. Challenge of the rat gastric mucosa with ethanol induced a concentration-dependent increase in the formation of LTB₄ and LTC₄, but not 6-keto PGF_1α. Pretreatment with PGE₂ (200–500μg/kg p.o.) prevented the haemorrhagic mucosal damage induced by oral administration of absolute ethanol but not the increased formation of leukotrienes by the mucosa. In contrast, pretreatment with a high dose of dmPGE₂ (20μg/kg p.o.) prevented both the gastric mucosal lesions and the increase mucosal leukotriene formation. The differences in the effects of these prostaglandins may be related to the nature or degree of protection of the gastric mucosa. Thus, high doses of dmPGE₂ but not PGE₂ may protect the cells close the luminal surface of the mucosa and hence reduce the stimulation of leukotriene synthesis by these cells.     

Evaluation of the co-mutagenicity of ethanol and delta 9-tetrahydrocannabinol with Trenimon.

The mutagenic potential of chronic treatments of male CF-1 mice with ethanol and delta 9-tetrahydrocannibinol (THC), and their comutagenic potential with a known mutagenic agent, Trenimon, were examined. This was accomplished by measuring the frequency of dominant lethal mutations arising from mating of treated males with nontreated females. Adult male mice were treated with 5% (v/v) ethanol as part of a liquid diet (28% ethanol-derived calories) for five weeks; 10 mg/kg body weight (p.o.) THC every two days for five weeks; a single injection of Trenimon (0.125 mg/kg, i.p.) on day 28 of diet treatment; and all combinations of treatments. The control group was pair-fed a liquid diet in which isocaloric sucrose replaced ethanol; these males were also given sesame oil (vehicle for THC) and saline (vehicle for Trenimon) on the same schedule as that for the treated males. Neither body weights nor hematocrits were adversely affected by any treatment. Both ethanol and Trenimon treatments resulted in a small (8-9%; p less than 0.05) decrease in testicular weight. The effect of combined treatment with ethanol and Trenimon was roughly additive. Treatment with THC had no effect on testicular weight. Seminal vesicle weights were not affected by any treatment. Treatments were without significant effect on fertility, as measured by the frequency of males producing pregnancies. Ethanol and Trenimon treatments produced approximately 3- and 7-fold increases, respectively in the frequencies of preimplantational loss over that seen for the control group (7.3%), resulting in significant ethanol and Trenimon effects (p less than 0.001). No interactive effects of ethanol and Trenimon treatments were noted. Frequencies of dead fetuses per pregnancy in the ethanol- and Trenimon-treated groups were increased approximately 2.5- and 4-fold, respectively, over the control value of approximately 16%. However, the effect of combined treatments was not greater than that due to Trenimon alone, resulting in Trenimon and ethanol effects (p less than 0.001) and ethanol-Trenimon interaction (p less than 0.001). The calculated mutation index resulting from each treatment yielded significant (p less than 0.001) ethanol- and Trenimon-induced effects. In contrast to effects of ethanol and Trenimon treatments, THC, given alone, or in combination with ethanol and/or Trenimon, had no effect on either preimplantational loss, fetal mortality or the resulting mutation index. The data suggest that chronic ethanol treatment, at levels resulting in minimal fertility impairment, increases the frequency of dominant lethal mutations. In contrast, chronic treatment with THC, as administered in the present study, appears to be without effect.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ethanol dissociates thiopental and GABA-receptor interaction

The effect of ethanol on thiopental and GABA-receptor interaction was studied in hippocampal slice preparations and membrane fractions. The field potentials evoked in pyramidal neurons by stratum radiatum stimulation are inhibited by GABA 10⁻⁴–10⁻³ M. Thiopental, 10⁻⁵ M, enhanced the inhibitory effect. When ethanol, 35 mM, was included, no enhancement of GABA inhibition of the field potentials by thiopental was observed. This effect of ethanol was reversible. The dissociative effect of ethanol on thiopental and GABA-receptor interaction was observed also in [³H]GABA binding experiments. In slices from rats chronically administered ethanol (2 g/kg, b.i.d., 30 days), thiopental was without effect on GABA inhibition of the field potentials. The results are discussed in relation to phenomena underlying chronic barbiturate or ethanol intoxication.     

State of the opioid system in rats with different sensitivity to ethanol

In this work we investigated the content of opioids in plasma blood and the changes caused by ethanol (1.5 g/kg, i.p.) in midbrain opioid receptors of rats with different sensitivity to ethanol, as determined according to the duration of ethanol-induced sleep (DEIS). A receptor binding technique with selective delta-DADLE and mu-DAGO radioligands were used. Ethanol even at low dose produced changes in the midbrain opioid receptors which appeared after 6 hours. The response of the receptors and the content of opioids in plasma blood of rats with different DEIS were not identical.     

Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol

Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up‐regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN^?/?) mice and in mice with cortex‐ and hippocampus‐specific transgenic PTN over‐expression (PTN‐Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN^?/? compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN‐Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN‐Tg mice, suggesting that up‐regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.

     

Yokukansan,a traditional Japanese herbal medicine,alleviates the emotional abnormality induced by maladaptation to stress in mice

The aim of the present study was to examine the effect of yokukansan, a traditional Japanese herbal medicine that is composed of Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 60 or 240 min/day for 14 days. From the 3rd day of stress exposure, mice were given yokukansan orally (p.o.) or the 5-HT_1A receptor agonist flesinoxan intraperitoneally (i.p.) immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using an automatic hole-board apparatus. A single exposure to restraint stress for 60 min induced a decrease in head-dipping behavior in the hole-board test. This emotional stress response disappeared in mice that had been exposed to repeated restraint stress for 60 min/day for 14 days, which confirmed the development of stress adaptation. In contrast, mice that were exposed to restraint stress for 240 min/day for 14 days did not develop this stress adaptation, and still showed a decrease in head-dipping behavior. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with yokukansan (1000 mg/kg, p.o.) as well as flesinoxan (0.25 and 0.5 mg/kg, i.p.) immediately after daily exposure to stress. These findings suggest that yokukansan may have a beneficial effect on stress adaptation and alleviate the emotional abnormality under conditions of excessive stress.     

Opposite effects of acute and repeated administration of desmethylimipramine on adrenergic responsiveness in rat pineal gland.

The effect of acute and repeated desmethylimipramine (DMI) treatment on catecholamine-stimulated production of adenosine 3', 5'-monophosphate (cyclic AMP) in rat pineal gland was studied $\text{in}$$\text{vivo}$. In rats exposed to continuous illumination, the administration of isoproterenol (2μmol/kg) to control animals produced a marked increase in the concentration of cyclic AMP in pineal gland. In contrast, norepinephrine (2μmol/kg) failed to increase the levels of cyclic AMP. After acute treatment with DMI (single injection, 38μmol/kg, i. p.), the isoproterenol-induced rise in cyclic AMP was not significantly different from that measured in control animals. However, acute DMI treatment did allow a significant elevation in the concentration of cyclic AMP in pineal gland in response to norepinephrine. In rats given nine injections of DMI (38μmol/kg, i.p., twice daily) neither isoproterenol nor norepinephrine caused a significant increase in the concentration of cyclic AMP in pineal glands. Although acute treatment with DMI had no significant effect on [³H] dihydroalprenolol binding, chronic treatment with DMI significantly reduced [³H] dihydroalprenolol binding in the pineal gland. The results of this study suggest that while a single administration of DMI can enhance adrenergic responses elicited by norepinephrine, chronic administration of DMI leads to compensatory decreases in receptor density and adrenergic responsiveness.     

Dopamine antagonist binding: a significant decrease with morphine dependence in the rat striatum

(³H)-Spiroperidol specific binding was determined in striatal tissue of rats which received a single dose of, or made dependent on morphine. Acute morphine (30 mg/kg i.p.) did not alter (³H)-spiroperidol specific binding. However, morphine-dependent rats with two 50 mg pellets when withdrawn for 24 or 48 hours, significantly decreased the binding and increased K_d. Binding sites were reduced with a decrease in K_d in rats implanted with four-50 mg pellets or receiving high doses of morphine. These results indicate that binding characteristics of (³H)-spiroperidol depend on the relative dose of morphine used to induce dependence. Low dose dependence (2 pellets) results in a decrease in binding affinity while high dose dependence (4 pellets or chronic injection) results in an increase of (³H)-spiroperidol affinity in the presence of fewer binding sites.     

Effects of acute and chronic ethanol administration on thromboxane and prostacyclin levels and release in rat brain cortex

The effects of acute (3 g/kg i.p. two jours before sacrifice) and chronic (6% in drinking water and libitum for 15 days) ethanol administration to male rats (200 g body weight) on basal levels and release of TxB_2n2 and 6-keto-PGF_1α in brain cortex were studied. Also the effects of chronic ethanol (30 days) on the fatty acid composition of brain cortical tissue and liver phospholipids were investigated. Acute treatment reduced basal levels of 6-keto-PGF_1α in brain cortical tissue (rats sacrificed by microwave radiation) and decreased the accumulation of 6-keto-PGF_1α in brain cortex after post-decapitation ischemia (PDI). Basal TxB₂ levels were also reduced in brain cortex, but TxB₂ release during PDI was enhanced. Chronic treatment (15 days) induced changes of TxB₂ and 6-ketoPGF_1α levels and release during PDI in brain cortex less pronounced than those observed after acute treatment. The reduced effectiveness of chronic ethanol on brain vasoactive eicosanoids suggest adaptation processes. After chronic treatment (30 days), the fatty acid composition of brain cortex total phospholipids were not significantly modified. Changes of eicosanoid production after ethanol were thus independent from modifications of the fatty acid precursor pool(s). Ethanol-induced changes in the production of vascular eicosanoids in the CNS may be of relevance to the action of the compound on the CNS and may also have implications for the clinic.     

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

Kinin B1 receptor (B1R) is virtually absent under physiological condition, yet it is highly expressed in models of diabetes mellitus. This study aims at determining: (1) whether B1R is induced in the brain of insulin-resistant rat through the oxidative stress; (2) the consequence of B1R activation on stereotypic nocifensive behavior; (3) the role of downstream putative mediators in B1R-induced behavioral activity. Sprague-Dawley rats were fed with 10% d-glucose in their drinking water or tap water (controls) for 4 or 12 weeks, combined either with a standard chow diet or a diet enriched with α-lipoic acid (1 g/kg feed) for 4 weeks. The distribution and density of brain B1R binding sites were assessed by autoradiography. Behavioral activity evoked by i.c.v. injection of the B1R agonist Sar-[D-Phe⁸]-des-Arg⁹-BK (10 μg) was measured before and after i.c.v. treatments with selective antagonists (10 μg) for kinin B1 (R-715, SSR240612), tachykinin NK1 (RP-67580) and glutamate NMDA (DL-AP5) receptors or with the inhibitor of NOS (L-NNA). Results showed significant increases of B1R binding sites in various brain areas of glucose-fed rats that could be prevented by the diet containing α-lipoic acid. The B1R agonist elicited head scratching, grooming, sniffing, rearing, digging, licking, face washing, wet dog shake, teeth chattering and biting in glucose-fed rats, which were absent after treatment with α-lipoic acid or antagonists/inhibitors. Data suggest that kinin B1R is upregulated by the oxidative stress in the brain of insulin-resistant rats and its activation causes stereotypic nocifensive behavior through the release of substance P, glutamate and NO.