Thiokynurenates prevent excitotoxic neuronal death in vitro and in vivo by acting as glycine antagonists and as inhibitors of lipid peroxidation.

Several derivatives of kynurenic and thiokynurenic acids were synthesized and tested for their ability to protect primary cultures of cerebellar granule cells against excitotoxic damage, and to affect the binding of [3H]glycine ([3H]Gly), [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA), [3H]3-(2-carboxypiperazine-4-yl-)propyl-1-phosphonic acid ([3H]CPP), [3H]kainic acid and [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) to rat cortical membranes. Kynurenic and thiokynurenic acid derivatives with one or two halogens in position 5 or 7 were selective glycine antagonists, failing to affect N-methyl-D-aspartate (NMDA), kainate or AMPA sites at micromolar concentrations. 7-Cl-kynurenic, 7-Cl-thiokynurenic, 5,7-diCl-kynurenic and 5,7-diCl-thiokynurenic acids had similar IC50s for displacing [3H]Gly from its strychnine-insensitive site and for reducing the stimulated (0.5 microM NMDA and 1 microM glycine) [3H]TCP binding to cortical membranes. However, 7-Cl-thiokynurenic acid was particularly potent to prevent excitotoxic neuronal death in cultured cerebellar granule cells. This action may be ascribed to inhibition of lipid peroxidation, a property which was demonstrated for the 5- or 7-Cl derivatives of thiokynurenic acid. Furthermore, 7-Cl-thiokynurenic acid reduced excitotoxic damage caused by the injection of quinolinic acid in the rat striatum. Thus, 7-Cl-thiokynurenic acid appears to be a new compound with interesting antiexcitotoxic properties both in vitro and in vivo.     

Effects of neonatal antithyroid treatment on brain [3H]-imipramine binding sites.

The action of the antithyroid, sulphydryl reagent methimazole (MMI) on the specific binding of [3H]-imipramine in the cerebral cortex and corpus striatum of immature and mature rats has been examined. Chronic administration of MMI through the first 30 days of life decreased the number of imipramine binding sites in cortical but not striatal membranes, as assessed 48 h after the last injection of goitrogen. A similar treatment did not affect the binding profile of [3H]-imipramine in mature rats. Acute administration of MMI to 30 day-old rats increased the number of imipramine binding sites shortly after the injection, an effect no longer evident 48 h later. MMI in vitro increased the binding of [3H]-imipramine. It is concluded that maturational impairment of the hypothyroid cortex, rather than any alteration of membrane bound thiol groups, was a major cause for the diminished binding of [3H]-imipramine in MMI-treated, immature rats.     

3H]-imipramine binding sites in fawn-hooded rats

The existence of high-affinity [3H]-imipramine recognition sites was demonstrated in membranes prepared from the cerebral cortex, hypothalamus and platelets obtained from fawn-hooded rats. The Bmax and Kd values for [3H]-imipramine binding to cerebral cortical membranes were virtually identical to those obtained with cortical membrane preparations of Sprague-Dawley rats. An NBR strain of rats, genetically related to fawn-hooded rats, was found to have significantly higher levels of [3H]-imipramine binding sites in cerebral cortical membranes when compared to fawn-hooded and Sprague-Dawley rats. All four strains of rats examined possessed extremely high densities of [3H]-imipramine binding sites in a purified platelet membrane fraction. These results do not support the finding of others that the cerebral cortex and platelets of fawn-hooded rats are virtually devoid of [3H]-imipramine binding sites.     

Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats chronically treated with haloperidol

Chronic treatment of rats with haloperidol decanoate (30 mg/kg and 100 mg/kg IM every 4 weeks for 52 weeks) increased [³H] SCH 23390 binding in striatal membranes by 25% and 50% and in frontal cortical membranes by 56% and 125% in 30 and 100 mg/kg haloperidol treatment groups, respectively. These increases in [³H] SCH 23390 binding to the membranes were restored to control levels after ceruletide treatment (100 µg/kg IP twice a day for 5 days). [³H] Spiperone binding to the rat striatal and cortical membranes also increased after chronic haloperidol treatment (by 66% and 99% in striatal membranes and by 27% and 62% in cortical membranes in the 30 and 100 mg/kg haloperidol treatment groups, respectively). Administration of ceruletide to haloperidol-treated rats reduced the increased [³H] spiperone binding to the cortical membranes toward the control level, but ceruletide was not effective in reducing the haloperidol-induced increase of [³H] spiperone binding to the striatal membranes. Activation of adenylate cyclase by dopamine (1 µM or 100 µM) or Gpp(NH)p (1 µM) was reduced in striatal and cortical membranes from haloperidol-treated rats. Ceruletide restored the lowered level of dopamine-stimulated or Gpp(NH)p-stimulated adenylate cyclase activity in the membranes from haloperidol-treated rats to control levels. These findings indicate that systemically administered ceruletide is capable of reversing alterations in D₁ dopamine receptor/D₁ dopamine receptor coupling to adenylate cyclase in striatum and frontal cortex induced by chronic treatment of rats with haloperidol decanoate.     

[3H]Ketanserin labels 5-HT2 receptors and α1-adrenoceptors in human and pig brain membranes

The binding characteristics of [3H]ketanserin (a reported selective radioligand for serotonin 5-HT2 receptors) and [125I]BE 2254 (which labels selectively alpha 1-adrenoceptors) were characterized in brain frontal cortex membranes of pig and man. Saturation experiments indicated that both radioligands label apparently a homogeneous class of binding sites in human and pig fontal cortex membranes. Competition experiments with [125I]BE 2254 using 17 agonists and antagonists showed monophasic and steep curves in human and pig frontal cortex membranes. The pharmacological profile of these sites is typical of alpha 1-adrenoceptors. In competition experiments with [3H]ketanserin, most of the tested compounds displayed shallow or biphasic curves. In particular, alpha 1-adrenoceptor-selective antagonists (prazosin, WB 4101, BE 2254...) displaced with nanomolar affinity about 15 and 40% of the specific [3H]ketanserin binding in human and pig frontal cortex membranes, respectively. The minor component of [3H]ketanserin binding correlated highly significantly with [125I]BE 2254 binding in both membrane preparations. The major component of [3H]ketanserin binding to pig and human frontal cortex membranes correlated significantly with [3H]ketanserin binding in rat brain cortex membranes (which is essentially to 5-HT2 receptors). The present data demonstrate that [3H]ketanserin in nanomolar concentrations binds significantly to alpha 1-adrenoceptors in human and pig frontal cortex membranes; this suggests a rather limited degree of selectivity of ketanserin for 5-HT2 receptors in pig and human tissues.     

Rapid-eye-movement sleep deprivation inhibits clonidine-induced sedation in rats

The effects of 24 and 48 h of rapid-eye-movement sleep deprivation (REMD) on clonidine-induced sedation and [³H]clonidine binding to cortical membranes were studied in rats. REMD did not affect the exploratory behaviour (ambulation, rearing + peeping) of normal rats. The sedative effect of clonidine (0.2 mg/kg s.c.) on the rearing + peeping behaviour of rats was inhibited by REMD. [³H]Clonidine binding in the cerebral frontal cortex remained unaffected. The results are discussed in terms of changes in the noradrenegic system.     

Biochemical changes in the brain consequent to dietary exposure of developing and mature rats to chlordecone (kepone)

Adult male rats receiving 10 or 30 ppm chlordecone (Kepone) in the diet for 90 days exhibited decreased binding of [³H]spiroperidol in membranes prepared from the striatum. [³H]Muscimol and [³H]quinuclidinyl benzilate binding in the cerebellum were also depressed. The binding of [³H]diazepam and [³H]serotonin to cortical membranes was unaltered in treated animals. The areas of brain of exposed animals which exhibited a reduced ability to bind several ligands for specific neurotransmitter-receptor sites also possessed an increased amount of membrane protein. The frontal cortex of chlordecone-dosed rats where ligand binding was not altered, showed no significant change in membrane protein content. Thus chlordecone-induced alterations in receptor properties could be accounted for in terms of a region-specific hyperplastic increase in nonreceptor proteins. Thirty days after cessation of dosing ligand-binding properties and membrane protein from regions of treated animals did not differ significantly from controls, suggesting that these effects were reversible at the dose levels used. Male and female rats exposed indirectly throughout gestation and lactation showed no abnormal concentrations of membrane protein at 30 days of age after a maternal diet of 1 or 6 ppm chlordecone. No decrease in cerebellar binding of muscimol or quinuclidinyl benzilate, in frontal cortical binding of serotonin, or in striatal binding of spiroperidol was observed. At the 6-ppm dose level, male rats had an elevation of striatal dopamine binding. These data illustrate that gestational exposure to chlordecone can have effects that are in an opposite direction than those observed after exposure of adults to a higher dose level.     

Up-regulation of cortical AMPA receptor binding in the fawn-hooded rat following ethanol withdrawal

The present study has employed quantitative receptor autoradiography to compare the binding of (S)-[3H]5-fluorowillardiine to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the brains of alcohol-preferring Fawn-Hooded (FH) rats, alcohol non-preferring Wistar-Kyoto (WKY) rats, and FH rats following a 28-day period of 5% ethanol consumption with or without ethanol withdrawal. Significantly higher binding of [3H]5-fluorowillardiine was found in the cingulate cortex (+12%) and claustrum (+13%) in alcohol na?ve FH rats compared to WKY rats. Chronic ethanol consumption decreased binding of (S)-[3H]5-fluorowillardiine in four cortical regions (frontal, parietal, occipital and temporal cortex), hippocampus and septohippocampal nucleus. In contrast, ethanol withdrawal induced a significant "rebound" increase in binding by +22% in frontal and parietal cortex, by +17% in cingulate cortex and +13% in claustrum, and by +14% in the septohippocampal nucleus compared to chronic ethanol-exposed FH rats. The findings suggest that AMPA receptors in frontal cortical regions are sensitive to ethanol and therefore may be implicated in the predisposition of alcohol preference in FH rats.     

Responses of dopaminergic and serotonergic systems to triethyllead intoxication

Rats treated with triethyllead (TEL) exhibit a behavioral supersensitivity to challenge with dopamine agonists at 7 days following administration of TEL. In the present series of experiments, some neurochemical mechanisms which may affect this behavioral supersensitivity were detected. Administration of a single dose of TEL chloride (7.88 mg/kg, SC) to male Fischer-344 rats decreased the concentrations of dopamine in hippocampus, and of serotonin in olfactory tubercle, at Day 7 posttreatment. The ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine (one estimate of serotonin turnover) was increased in nucleus accumbens (p less than 0.05), with a similar trend in olfactory tubercle and striatum (p less than 0.10). No changes were detected in binding of [3H]spiperone to D2 dopamine receptors in striatum or olfactory tubercle. However, although basal adenylate cyclase activity was unaltered in TEL-treated rats, the Vmax for dopamine-stimulated adenylate cyclase activity was significantly elevated in olfactory tubercle. Conversely, TEL at micromolar concentrations markedly attenuated both basal and dopamine-stimulated adenylate cyclase activity in vitro in striatal homogenates. These data suggest the hypothesis that administration of TEL to rats results in an up-regulation of D1 dopamine receptors in olfactory tubercle, and that the behavioral supersensitivity of TEL-treated animals to dopamine agonists may, in part, be a result of this receptor supersensitivity.     

Alteration of cerebral neurotransmitter receptor function by exposure of rats to manganese

Adult male rats were treated on 15 successive days with i.p. injection of manganese chloride at 10 or 15 mg/kg body weight. 24 h after the last dose, the binding of the dopaminergic antagonist [3H]spiroperidol to striatal membranes was elevated significantly. At the lower dose, no other high-affinity binding site measured was altered. However, at the 15 mg/kg body weight dose, cerebellar GABA, frontal cortical serotonin, and striatal muscarinic binding were all depressed. Neither dose level altered striatal levels of enkephalin, substance P, dopamine, serotonin, or dihydroxyphenylacetic acid (DOPAC). Receptor binding measurements may be a sensitive means of detecting disturbances of specific neural circuits.     

Effect of 3,4-methylenedioxymethamphetamine on [3H]paroxetine binding in the frontal cortex and blood platelets of rats.

The effects of single or repeated administration of the racemic mixture of 3,4-methylenedioxymethamphetamine (MDMA; 20 mg/kg, s.c.) on the number (Bmax) of serotonin (5-HT) uptake sites as determined by [3H]paroxetine binding and the concentration of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the frontal cortex and blood platelets of rats 1 and 7 days following its administration. A single injection of MDMA significantly (P less than 0.05) decreased the number of [3H]paroxetine binding sites as well as the concentrations of 5-HT and 5-HIAA in the frontal cortex but not in platelets 7 days following administration. Repeated injections of MDMA (twice daily for 4 days) significantly (P less than 0.05) decreased the number of 5-HT uptake sites and the concentration of 5-HT and 5-HIAA in the frontal cortex but not in platelets 7 days following administration. Pretreatment with the 5-HT2/5-HT1C antagonist, ketanserin, inhibited the MDMA-induced decrease in 5-HT and 5-HIAA concentrations and the number of [3H]paroxetine binding sites in the frontal cortex 7 days following a single administration. These data are suggestive that blood platelets are less sensitive than brain tissue to the 5-HT-depleting effects of MDMA. The ability of ketanserin pretreatment to block MDMA-induced decreases in [3H]paroxetine binding sites in the frontal cortex is suggestive that 5-HT2/5-HT1C receptors may be involved in the neurotoxic effects of MDMA.     

Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla

Binding sites labeled by [3H]p-aminoclonidine ([3H]PAC) were characterized in bovine brain membranes prepared from the ventrolateral medulla, the probable site of the antihypertensive action of clonidine and analogs. Comparison was made with [3H]PAC binding to membranes prepared from frontal cortex, which has been studied extensively. Saturation binding isotherms for [3H]PAC were similar in the two regions, although Bmax values were approximately two-fold lower in ventrolateral medulla relative to frontal cortex. Norepinephrine and other phenylethylamines displaced [3H]PAC from a maximum of 70% of the total sites in the ventrolateral medulla. The remaining 30% were norepinephrine-insensitive, non-adrenoceptor sites which displayed high affinity for imidazole compounds. Ligand selectivity differed markedly between ventrolateral medulla and frontal cortex, since some imidazole compounds which potently inhibited [3H]PAC binding in the ventrolateral medulla had no effect in frontal cortex. Imidazole binding sites may mediate, in part, the hypotensive action of clonidine and other imidazole compounds in the ventrolateral medulla. These sites may also participate in the functions of a putative endogenous clonidine-like substance.     

Relationship between up-regulation of nicotine binding sites in rat brain and delayed cognitive enhancement observed after chronic or acute nicotinic receptor stimulation

(–)-Nicotine tartrate (2 mg/kg), and a nicotinic agonist, RJR 2403 (1.4 mg/kg), and antagonist, mecamylamine (1 mg/kg), were administered to separate groups of rats SC twice daily for 10 days. Two other groups received the same doses of nicotine or RJR 2403 for 1 day followed by saline for 9 days. Twenty-four hours after the final injection, the rats were compared to a 10-day saline-injected group on acquisition of a hidden platform position in the Morris water maze (20 trials, 30-min inter-trial interval). The rats were killed 48 h after the last drug injection and frontal, entorhinal and posterior cingulate cortex and dorsal and ventral hippocampus assayed for [³H]-nicotine binding density. Chronic nicotine significantly increased the number of frontal and entorhinal cortical and dorsal hippocampal, but not posterior cingulate cortical or ventral hippocampal, nicotinic receptors, and improved rate of learning. Chronic mecamylamine and RJR 2403 also significantly increased the number of nicotinic receptors in frontal cortex, though not other regions, but retarded rate of learning. Nicotine given for 1 day 11 days earlier marginally increased nicotinic receptors in entorhinal cortex (but not other regions) and significantly increased rate of learning, though significantly less than 10-day nicotine. Entorhinal cortical and dorsal hippocampal nicotinic receptor numbers were positively associated with rate of learning but not performance at asymptote. Thus cognitive enhancement after chronic nicotine is in part a delayed consequence of nicotine administration 11 days earlier, and may reflect regional changes in nicotinic receptor up-regulation.     

Effect of chronic desmethylimipramine or electroconvulsive shock on selected brain and platelet neurotransmitter recognition sites

Rats were treated with electroconvulsive shock (ECS), desmethylimipramine (DMI), ECS plus DMI, or diazepam. In vitro analyses showed that chronic ECS produced an elevated density of recognition sites for [3H]imipramine (IMI) in platelet membranes, but had no effect on membrane preparations derived from cortical tissue. A similar elevation in receptor binding was seen exclusively in platelets after chronic ECS plus DMI, whereas no effect was observed with DMI alone. Equilibrium dissociation constant (KD) values for [3H]IMI were also increased in platelet membranes from rats given chronic ECS or ECS plus DMI treatment. Chronic ECS or DMI administration produced a decreased density of beta-adrenergic recognition sites in frontal cortex and cerebellum as assessed by [3H]dihydroalprenolol (DHA) binding. The combination of ECS plus DMI produced a similar decrease. In addition, chronic diazepam administration produced a down-regulation of the beta-adrenergic receptor only in the cerebellum. These data provide evidence for the differential regulation of brain and peripheral neurotransmitter recognition sites.     

Effect of chronic treatment with selective monoamine oxidase inhibitors and specific 5-hydroxytryptamine uptake inhibitors on [3H]paroxetine binding to cerebral cortical membranes of the rat

[3H]Paroxetine is a highly selective ligand for the 5-hydroxytryptamine transporter complex and the specific binding of this ligand to membrane fractions from cerebral cortex or hippocampus was studied in rats treated with specific inhibitors of the uptake of 5-hydroxytryptamine and monoamine oxidase inhibitors. The Kd and Bmax of the binding of [3H]paroxetine to cerebral cortical membranes of the rat was unaffected, compared to sham controls, by either acute or chronic administration with citalopram or chlorimipramine. Also, chronic treatment with chlorimipramine did not alter the parameters of the binding of [3H]paroxetine to hippocampal membranes from the rat compared to sham controls. Furthermore, chronic and acute treatments with clorgyline or deprenyl did not produce any significant changes in the Kd and Bmax of the binding of [3H]paroxetine to cerebral cortical membranes in the rat. These findings on the binding of [3H]paroxetine are discussed in light of previous equivocal results on the plasticity of neuronal binding sites for [3H]imipramine after various pharmacological treatments.     

Mesulergine, a selective serotonin-2 ligand in the rat cortex, does not label these receptors in porcine and human cortex: evidence for species differences in brain serotonin-2 receptors

The kinetic and pharmacological characteristics of the binding of [3H]ketanserin and [3H]mesulergine to frontal cortical brain membranes from rat, pig and human were studied. In the 3 species [3H]ketanserin labeled sites with the characteristics of the 5-HT2 receptors previously described in the rat. In contrast, [3H]mesulergine labeled 5-HT2 receptors in rat, but not in pig and human cortices. The characteristics of the sites labeled by [3H]mesulergine in pig cortex were similar to those of sites in the choroid plexus of rats, pigs and humans. While several reputed 5-HT2 ligands presented a similar affinity for the [3H]ketanserin binding sites in the 3 species, other such ligands, e.g. mesulergine, methysergide, cinanserin and LSD which displaced these sites with high affinity in rat brain, had lower affinities in pig and human brain. These results indicate that 5-HT2 receptors show different pharmacological profiles in different species. Caution should thus be exerted in extrapolating data from laboratory animals to humans.     

Effect of nifedipine on the shuttlebox escape deficit induced by inescapable shock in the rat

The behavioural effect of subchronic treatment with calcium channel antagonists (nifedipine, verapamil) and with imipramine was assessed in rats subjected to inescapable shock (IS). The effect of subchronic treatment with nifedipine and imipramine on specific [3H]nitrendipine ([3H]NDP) binding was investigated in frontal cortex of naive rats and in rats given IS then tested for shuttlebox escape. The rats showed a severe impairment in escape behaviour after IS. Imipramine and nifedipine significantly reduced FR1 and FR2 escape deficits. Verapamil had no effect. A small but significant increase in the number of [3H]NDP binding sites (Bmax) was seen in rats exposed to the shuttlebox escape test independent of a previous exposure to IS. Imipramine had no influence on Bmax in any of the groups. Nifedipine did not affect [3H]NDP binding in naive rats but decreased Bmax in rats subjected to IS and the shuttlebox escape test. The comparable ability of nifedipine and imipramine to reverse the shuttlebox escape deficit induced by IS argues for a possible antidepressant activity of nifedipine. The biochemical data indicate that cortical [3H]NDP binding sites are not correlated to performance in the shuttlebox escape test.     

Differences in the binding of [3H][D-Ser2,Thr6]leucine-enkephalin and [3H][D-Pen2,D-Pen5]enkephalin to brain membranes of morphine tolerant-dependent rats.

The effect of morphine tolerance-dependence and abstinence on the characteristics of delta-opiate receptors was determined in male Sprague-Dawley rats. Two ligands used for characterizing the receptors were [3H][D-Ser2,Thr6]leucine-enkephalin ([3H]DSTLE) and [3H][D-Pen2,D-Pen5]enkephalin ([3H]DPDPE). Rats were implanted s.c. under light ether anesthesia with six morphine pellets (each containing 75 mg of morphine free base). Rats which served as controls were implanted similarly with placebo pellets. Two sets of rats were used. In one group of rats, the pellets were left intact (tolerant-dependent) at the time of sacrificing and in the other the pellets had been removed 18 h earlier (abstinent). The spinal cord and brain regions (amygdala, hippocampus, hypothalamus, corpus striatum, mid-brain, pons and medulla and cortex) were dissected for binding studies. The binding of [3H]DSTLE to membranes of cerebral cortex of morphine-tolerant-dependent rats was decreased in comparison to control rats, and was due to a decrease in Bmax rather than Kd value. The binding of [3H]DSTLE to other brain regions or spinal cord of morphine-tolerant-dependent and abstinent rats did not differ from their respective controls. On the other hand, the binding of [3H]DPDPE was unaffected in any brain region or the spinal cord of morphine-tolerant-dependent and abstinent rats when compared to their controls. The decrease in binding of [3H]DSTLE to cortical membranes of morphine-tolerant-dependent rats amounted to 15%. Since DSTLE also binds to mu-opiate receptors, which have earlier been shown to be decreased in cortex of morphine-tolerant-dependent rats, and the binding of a more selective delta-opiate ligand [3H]DPDPE was unaffected, it is concluded that central delta-opiate receptors do not play a role in the development of morphine-induced tolerance-dependence or abstinence processes in the rat.     

Down-regulation of brain and spinal cord K-opiate receptors in spontaneously hypertensive, Wistar-Kyoto normotensive, and Sprague-Dawley rats by chronic treatment with U-50, 488H.

The effects of chronic administration of U-50,488H, a K-opiate receptor agonist, on the binding of [3H]ethylketocyclazocine ([3H]EKC) to K-opiate receptors on the cerebral cortical and spinal cord membranes of spontaneously hypertensive (SHR), Wistar-Kyoto normotensive (WKY), and Sprague-Dawley (SD) rats were determined. Age-matched (10 weeks old) male rats of each strain were injected twice daily for 7 days with either U-50,488H (25 mg/kg, i.p.) or its vehicle. On day 8, the rats were killed. The cerebral cortex and the spinal cord were isolated for binding studies. The systolic blood pressure and heart rate of SD and WKY rats did not differ but the blood pressure of SHR rats were higher than that of SD and WKY rats. The receptor density (Bmax) and apparent dissociation constant (Kd) values of [3H]EKC binding to the spinal cord of WKY and SHR rats did not differ. However, the spinal cord of SD rats had higher Bmax and Kd values than WKY or SHR rats. The cortex of the SD rats had a lower Bmax value than the other two strains. Treatment with U-50,488H decreased the Bmax value of [3H]EKC in spinal cord of SD rats, increased the Kd value in SHR rats, and had no effect in WKY rats. Decreases in the Bmax value were produced in the cortex of all strains of rats, but a greater effect was observed in WKY and SHR rats than in SD rats.     

Nitric oxide modulates the amphetamine effect on [3H]glucose uptake in the brain of rats prenatally exposed to lead

Glucose is the main source of energy for the central nervous system (CNS). In this study, we examined the effects of the psychostimulant amphetamine (AMPH) and the neuronal mediator nitric oxide (NO) on [3H]glucose uptake in the brain of adult rats that had been prenatally exposed to lead. Lead [Pb(CH3COO)2 . 3H2O; 250 ppm] was added to the drinking water of pregnant Wistar rats for the duration of pregnancy. On the day of parturition, lead was discontinued as an additive in the drinking water. Offspring remained ith dams for 21 days. The control group consisted of rats that consumed water without lead. In adulthood, male offspring from both groups (lead-exposed and control) were pretreated with 7-nitroindazole (nNOS blocking agent) (10.0 mg/kg ip) or saline (1.0 ml/kg ip), 30 min before AMPH (1.0 mg/kg ip). After another 30 min, and 15 min before termination, all rats were injected with 6-[3H]-D-glucose (500 muCi/kg ip). Brain specimens were taken (striatum, frontal cortex, hippocampus, and thalamus with hypothalamus, and pons with medulla oblongata) for determination of radioactivity in a liquid scintillation counter.We found that lead did not alter [3H]glucose uptake in brain regions studied (with exception of frontal cortex) but that AMPH increased [3H]glucose uptake in the striatum, frontal cortex and hippocampus, and that the AMPH effect was lessened in the hippocampus of lead-exposed rats. Moreover, the AMPH effect on [3H]glucose uptake in the frontal cortex, hippocampus, thalamus with hypothalamus and pons of control rats was potentiated by 7-NI pretreatment. Similar effect was observed in lead-intoxicated rats (striatum, frontal cortex and hippocampus). These results indicate that NO modulates AMPH-induced [3H]glucose uptake in the brain of rats prenatally exposed to lead.