RESUMEN
Pluronic® F-127 (poloxamer 407) is a versatile pharmaceutical excipient, offering many opportunities for designing novel therapeutic systems. One of its applications is the formation of a thermosensitive solution as a base for concentrated suspensions or emulsions. When such uses are considered, the need for viscosity enhancement emerges, especially when a long-term stability of dispersion is expected. This study covers the evaluation of chosen natural gums (Acacia, Xanthan Gum, Tragacanth and Guar Gum) as viscosity and gelation enhancers for thermosensitive Pluronic F-127 solution. The major poloxamer concentration was 17 % (w/w), and the gum additions were in the range of 0.125 - 0.5 %. Solutions were evaluated by rotational rheometry at fixed temperatures (20, 25 and 37 °C), as well as with continuous temperature increase and decrease. These studies were also supplied by visual inspection during the Tube Inversion Method experiments. Xanthan Gum turned out to be the most effective viscosity enhancer, giving transparent and stable formulations, while Tragacanth gave lesser viscosity enhancement and left the formulations slightly turbid. Acacia significantly inhibited the gelation, and Guar Gum revealed a major incompatibility (precipitation) with poloxamer. Irreversible gelation was not observed in any case.
Asunto(s)
Galactanos/química , Geles/química , Goma Arábiga/química , Mananos/química , Gomas de Plantas/química , Poloxámero/química , Polisacáridos Bacterianos/química , Viscosidad , TemperaturaRESUMEN
Simvastatin (SIM) solid dispersions with Pluronic F127 (PLU) obtained by kneading and fusion methods were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR). DSC studies demonstrate that the SIM/PLU solid dispersions formed a simple eutectic phase diagram. FTIR spectroscopy and XRPD studies of obtained mixtures showed no interaction between the components in the solid state and confirmed the absence of terminal solid solutions. Intrinsic dissolution studies of solid dispersions in 0.5% sodium lauryl sulfate solution (SLS) indicated that the dissolution rate markedly increased in these solid dispersions systems compared with pure SIM. The increase in dissolution rate strongly depended on ratios of drug to carriers and selection of the method of preparations of mixtures. The solid dispersions prepared in the weight ratios of 60.0/40.0% and 69.9/30.1% w/w of SIM/PLU by the kneading method showed the highest improvement in wettability and dissolution rate of SIM. Approximately 100% of the drug was dissolved from these mixtures in comparison to 3.84% of pure simvastatin within 120 min.
Asunto(s)
Excipientes/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Poloxámero/química , Simvastatina/química , Rastreo Diferencial de Calorimetría , Portadores de Fármacos , Solubilidad , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Crohn's Disease (CD), one of the types of inflammatory bowel disease, poses a significant challenge to modern healthcare. This condition severely impacts patients' quality of life, and its incidence is continuously rising. Despite constant research, current treatment options are limited and largely unsuccessful and result in serious side effects, therefore new therapy alternatives are needed. Liposomal formulation provides a new hope for disease management. In our study, we characterized the anti-inflammatory activity of mesalazine (5-ASA) and chlorogenic acid (CGA) encapsulated in liposomal formulation in the animal model of CD. Liposomes were obtained by thin film hydration method and characterized in terms of suspension stability and particle size and distribution. Colitis was induced in mice by intracolonic (i.c.) administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The effect of treatment with liposomal suspensions of 5-ASA and CGA was evaluated macroscopically and by measuring myeloperoxidase (MPO) activity. We observed that liposome-encapsulated 5-ASA (5 mg/kg), but not CGA (20 mg/kg) attenuated colitis as evidenced by a decreased macroscopic and microscopic scores. It may be hypothesized that the composition of liposomal lipid bilayer as well as the switch in macrophage populations leading to unfavorable accumulation of anti-inflammatory agents in the cells may underly the efficiency of obtained liposomes and need to be taken into consideration in further studies on drug delivery.
Asunto(s)
Ácido Clorogénico/química , Ácido Clorogénico/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Liposomas/química , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Masculino , Mesalamina/química , Mesalamina/farmacología , Ratones , Ratones Endogámicos BALB C , Peroxidasa/metabolismo , Calidad de Vida , Ácido TrinitrobencenosulfónicoRESUMEN
Development of the mammalian CNS requires formation and stabilization of neuronal circuits and synaptic connections. Sensory stimulation provided by the environment orchestrates neuronal circuit formation in the waking state. Endogenous sources of activation are also implicated in these processes. Accordingly we hypothesized that sleep, especially rapid eye movement sleep (REMS), the stage characterized by high neuronal activity that is more prominent in development than adulthood, provides endogenous stimulation, which, like sensory input, helps to stabilize and refine neuronal circuits during CNS development. Young (Y: postnatal day (PN) 16) and adolescent (A: PN44) rats were rapid eye movement sleep-deprived (REMSD) by gentle cage-shaking for only 4 h on 3 consecutive days (total 12 h). The effect of REMS deprivation in Y and A rats was tested 3-7 days after the last deprivation session (Y, PN21-25; A, PN49-53) and was compared with younger (immature, I, PN9-12) untreated, age-matched, treated and normal control groups. REMS deprivation negatively affected the stability of long-term potentiation (LTP) in Y but not A animals. LTP instability in Y-REMSD animals was similar to the instability in even the more immature, untreated animals. Utilizing immunoblots, we identified changes in molecular components of glutamatergic synapses known to participate in mechanisms of synaptic refinement and plasticity. Overall, N-methyl-d-aspartate receptor subunit 2B (NR2B), N-methyl-d-aspartate receptor subunit 2A, AMPA receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD-95), and calcium/calmodulin kinase II tended to be lower in Y REMSD animals (NR2B, GluR1 and PSD-95 were significantly lower) compared with controls, an effect not present in the A animals. Taken together, these data indicate that early-life REMS deprivation reduces stability of hippocampal neuronal circuits, possibly by hindering expression of mature glutamatergic synaptic components. The findings support a role for REMS in the maturation of hippocampal neuronal circuits.
Asunto(s)
Ácido Glutámico/metabolismo , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Potenciación a Largo Plazo , Transducción de Señal , Privación de Sueño/metabolismo , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Homólogo 4 de la Proteína Discs Large , Regulación hacia Abajo/fisiología , Hipocampo/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Potenciación a Largo Plazo/fisiología , Masculino , Proteínas de la Membrana/metabolismo , Subunidades de Proteína/metabolismo , Ratas , Ratas Long-Evans , Receptores de Glutamato/metabolismo , Transducción de Señal/fisiología , Privación de Sueño/fisiopatología , Sueño REM/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
The forced swim test and tail suspension test are often used in laboratory practice to identify compounds that possess antidepressant-like activity. This experiment was conducted to determine whether housing conditions per se influence the response of mice in these antidepressant screening procedures. Male NIH Swiss mice were housed individually or in groups (five per cage) for 8 weeks prior to testing. After 8 weeks, the animals were exposed to the forced swim and tail-suspension tests. Group housed mice displayed high levels of immobility in the forced swim and tail suspension tests. Desipramine injection 60 min prior testing, in doses 7.5 and 15 mg/kg, produced significant reductions in the immobility time in forced swimming and tail suspension tests. Individually housed mice, when exposed to these tests, displayed lower levels of immobility with a magnitude comparable to the effect of desipramine in group housed mice. Desipramine given to individually housed mice did not reduce the duration of immobility either in the forced swim test or in the tail suspension test. These results indicate that both tests are sensitive to housing conditions. This observation suggests that long lasting group housing may be critical to the behavioral response in these preclinical screening procedures in mice.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Conducta Animal/efectos de los fármacos , Desipramina/farmacología , Vivienda para Animales , Inmovilización , Estrés Fisiológico , Animales , Antidepresivos Tricíclicos/uso terapéutico , Desipramina/uso terapéutico , Masculino , Ratones , Estrés Fisiológico/tratamiento farmacológicoRESUMEN
We investigated the behavioral and biochemical events appearing in rats after withdrawal for 24 h or 8-12 days from two classical neuroleptics, haloperidol and pimozide. The neuroleptics were given for 14 days alone or shortly after injection of the Ca2+ channel blocker nifedipine. We have found that withdrawal effects after haloperidol and pimozide were different. After haloperidol treatment we observed an increase in cortical Ca2+ channel and limbic dopamine D1 receptor density and an increase in spontaneous motor activity and apomorphine-induced hyperactivity and stereotypy. In contrast no biochemical changes were observed during pimozide withdrawal, and locomotor activity and responses to apomorphine were depressed. Co-administration of nifedipine with haloperidol prevented the observed biochemical and behavioral symptoms of withdrawal. Nifedipine administration did not change the depressant effects of pimozide. Our results suggest that the voltage-dependent Ca2+ channel is involved in the observed withdrawal syndrome of neuroleptics, and that the absence of this syndrome after pimozide may be related to its considerable Ca2+ channel-blocking properties.
Asunto(s)
Antipsicóticos/efectos adversos , Canales de Calcio/fisiología , Haloperidol/efectos adversos , Pimozida/efectos adversos , Síndrome de Abstinencia a Sustancias/etiología , Animales , Apomorfina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Nifedipino/farmacología , Nitrendipino/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/prevención & controlRESUMEN
We investigated the differences between the action of haloperidol and pimozide on dopamine metabolism and on catalepsy in periods up to 6 weeks after cessation of chronic administration of the neuroleptics to male Wistar rats. Dopamine and its metabolites (dihydroxyphenylacetic and homovanillic acids) were measured, using high-performance liquid chromatography (HPLC), in the frontal cortex, nucleus accumbens, and striatum. Both neuroleptics produced similar effects after a single dose: catalepsy and an increase of dopamine metabolism in the brain structures. However, haloperidol and pimozide differed after chronic treatment. In haloperidol-treated rats hypersensitivity of the dopaminergic system developed at the end of 2 weeks' administration, as evidenced by depression of dopamine metabolism. The biochemical changes were accompanied by behavioral hyperactivity that lasted up to 3 weeks. Dopamine metabolism in rats treated with pimozide was normal from 24 h after the end of the treatment, while catalepsy was maintained at the high level for up to 8 days and was observable up to 3 weeks after the last dose. Our results suggest that in contrast to haloperidol, pimozide is not able to produce adaptive changes leading to supersensitivity of the dopaminergic system. This may be the consequence of its potent Ca2+ channel blocking action.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Haloperidol/farmacología , Pimozida/farmacología , Animales , Catalepsia/inducido químicamente , Esquema de Medicación , Tractos Extrapiramidales/efectos de los fármacos , Tractos Extrapiramidales/metabolismo , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Masculino , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/metabolismoRESUMEN
Following the finding that nifedipine enhances morphine analgesia and prevents the development of dependence, we have now compared the effect of nifedipine with these of other L-type Ca2+ channel antagonists, nimodipine (a dihydropyridine) and verapamil (a phenylethylalkylamine). Male Wistar rats received the antagonist 20 min before each injection of morphine. Analgesia was measured in a hot-plate test, and the development of dependence was assessed in the naloxone precipitation test after 13 days of morphine (20-30 mg/kg i.p.) administration. L-type Ca2+ channels were assayed in the cerebral cortex as [3H]nitrendipine binding sites. Blood pressure was monitored from the tail by a non-invasive method. We found that all three Ca2+ antagonists enhanced the analgesia, and prevented development of the naloxone-precipitated withdrawal syndrome, although they differed in their efficacy. Nifedipine and verapamil effectively blocked the development of tolerance. While chronic morphine up-regulated L-type Ca2+ channels, co-administration of the antagonists completely prevented this effect. The effects of Ca2+ channel antagonists cannot be ascribed to their potential circulatory effects as, at the dose used, none affected significantly the arterial blood pressure.
Asunto(s)
Analgésicos Opioides/farmacología , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Morfina/farmacología , Nifedipino/farmacología , Animales , Sitios de Unión , Corteza Cerebral/metabolismo , Interacciones Farmacológicas , Tolerancia a Medicamentos , Masculino , Nimodipina/farmacología , Nitrendipino/metabolismo , Ratas , Ratas Wistar , Trastornos Relacionados con Sustancias , Tritio , Verapamilo/farmacologíaRESUMEN
Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test.
Asunto(s)
Antidepresivos/farmacología , Corteza Cerebral/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Receptores Adrenérgicos beta/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Corteza Cerebral/enzimología , Dihidroalprenolol/farmacología , Regulación hacia Abajo , Imipramina/farmacología , Masculino , Ratones , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I , Receptores Adrenérgicos beta/efectos de los fármacosRESUMEN
The following presentation is a review of literature related to application of nonionic polymer, polyvinyl alcohol, in the technology of modern drug form. The review contains the description of physical-chemical properties of this polymer, such as hydrolysis degree, solubility, swelling capacity. Each characteristic is followed by the description of its application as a therapeutical substance carrier in the pharmacy.
Asunto(s)
Preparaciones de Acción Retardada , Portadores de Fármacos , Alcohol Polivinílico , Administración Cutánea , Administración Oral , Disponibilidad Biológica , Gentamicinas/administración & dosificación , Hidrogeles , Liposomas , Soluciones Oftálmicas/administración & dosificación , Polímeros , Verapamilo/administración & dosificación , Verapamilo/farmacocinética , Zidovudina/administración & dosificaciónRESUMEN
Dressings made from polyvinyl alcohol (PAV) and Hydroxypropylmethylcellulose (HPMC) with the addition of glycerol (GLY) differ in adhesiveness and the time of wash out in water, both characteristics depended on polymer and GLY concentration. The research on the release speed which is applied in topical therapy of chlorhexidine digluconate antiseptic in biopharmaceutical model proved the existence of close to rectilinear relation between the amount of released substance and release time for selected formulations.
Asunto(s)
Antiinfecciosos Locales/administración & dosificación , Clorhexidina/análogos & derivados , Clorhexidina/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Ensayo de Materiales , Metilcelulosa/análogos & derivados , Apósitos Periodontales , Adhesividad , Glicerol , Derivados de la Hipromelosa , Polímeros , Alcohol Polivinílico , ReologíaRESUMEN
Several lines of evidence suggest a dysfunctional glutamate system in major depressive disorder (MDD). Recently, we reported reduced levels of metabotropic glutamate receptor subtype 5 (mGluR5) in postmortem brains in MDD, however the neurobiological mechanisms that induce these abnormalities are unclear. In the present study, we examined the effect of chronic corticosterone (CORT) administration on the expression of mGluR5 protein and mRNA in the rat frontal cortex and hippocampus. Rats were injected with CORT (40 mg/kg s.c.) or vehicled once daily for 21 days. The expression of mGluR5 protein and mRNA was assessed by Western blotting and quantitative real-time PCR (qPCR). In addition, mGluR1 protein was measured in the same animals. The results revealed that while there was a significant reduction (-27%, P=0.0006) in mGluR5 protein expression in the hippocampus from CORT treated rats, mRNA levels were unchanged. Also unchanged were mGluR5 mRNA and protein levels in the frontal cortex and mGluR1 protein levels in both brain regions. Our findings provide the first evidence that chronic CORT exposure regulates the expression of mGluR5 and are in line with previous postmortem and imaging studies showing reduced mGluR5 in MDD. Our findings suggest that elevated levels of glucocorticoids may contribute to impairments in glutamate neurotransmission in MDD.
Asunto(s)
Corticosterona/farmacología , Trastorno Depresivo Mayor/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Receptores de Glutamato Metabotrópico/biosíntesis , Animales , Antiinflamatorios/farmacología , Enfermedad Crónica , Trastorno Depresivo Mayor/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Esquema de Medicación , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Masculino , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/genéticaRESUMEN
The previous experiments have demonstrated that NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors have antidepressant- and anxiolytic-like activities in rodents. Moreover, chronic treatments with these agents result in down-regulation of beta-adrenoceptors in the brain cortex with a magnitude comparable to clinically effective antidepressants. However, still little is known about the effect of NOS inhibitors on the regulation of neurotransmitter utilization in vivo. The aim of present study was to elucidate the effect of NOS inhibitor at doses active in forced swim test (FST) on dopamine and serotonin turnover in the mouse brain structures. Mice were treated with imipramine (15 mg/kg ip), electroconvulsive shock (ECS) and NOS inhibitor, N(G)-nitro-L-arginine (L-NA) acutely (at doses of 1, 3, 10 mg/kg ip) and chronically (0.3, 1, 3 mg/kg ip). Experiments were carried out 1 h after single and 3 h after chronic (21 days) administration. Metabolism of dopamine and serotonin was investigated using high pressure liquid chromatography (HPLC) with electrochemical detection. The metabolism rate was calculated as a ratio of a metabolite to the parent amine. FST was performed using protocol described previously by Porsolt et al. Now we report that L-NA decreases the level of immobility with potency similar to imipramine. The effect of L-NA was reversed by NOS substrate, L-arginine. L-NA given acutely at doses active in FST did not change the dopamine metabolism rate but it did decrease the serotonin turnover rate in the frontal cortex in a manner similar to imipramine. Thus, it appears that under basal conditions endogenous NO may influence the serotonin turnover, and the acute inhibition of NOS can mimic the effect of imipramine what may result in the antidepressant-like effect in FST. Imipramine given acutely produced massive increase in the level of serotonin in the frontal cortex as well as in the hypothalamus (by 40%, p < 0.01) what was reflected in significant decreases in the metabolism rate. Contrary to acute effect, chronic treatment of L-NA (the most effective dose was 1 mg/kg) produced increase in the dopamine metabolism rate within all investigated structures. In the present study, we demonstrated for the first time that L-NA may alter the neurotransmitter utilization in vivo and the observed effect may be due to adaptational changes in neuronal function.
Asunto(s)
Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Actividad Motora/efectos de los fármacos , Neurotransmisores/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/anatomía & histología , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Electrochoque , Inhibidores Enzimáticos/administración & dosificación , Lóbulo Frontal/metabolismo , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/metabolismo , Imipramina/administración & dosificación , Imipramina/farmacología , Masculino , Ratones , Nitroarginina/administración & dosificación , Serotonina/metabolismo , NataciónRESUMEN
The level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined in the brains of rats kept 24 h after death at two different temperatures, 4 degrees C and 22 degrees C. The estimations were carried out in the striatum and limbic forebrain containing: nucleus accumbens, septum, limbic cortex, amygdala, tuberculum olfactorium. Brain tissue of control rats was dissected immediately after decapitation, frozen over solid CO2 and stored at -70 degrees C until assayed. DA and its metabolites were measured, using high-performance liquid chromatography (HPLC) with electrochemical detection. The levels of DA, DOPAC and HVA in the striatum were significantly decreased (from 50% to 80%) when rats were kept 24 h after death. The changes were more pronounced at 22 degrees C than at 4 degrees C. As the decrease in DA concentration was stronger than that of its final metabolite HVA, the ratio of HVA/DA concentration measured as an index of the rate of DA metabolism was even increased (from 8 to 11). Different changes occurred in the limbic region, where the levels of DA and HVA did not change neither at 4 degrees C nor 22 degrees C. The level of intraneuronally formed DA metabolite-DOPAC was elevated (by about 60%). The level of 3-MT, extraneuronally formed DA metabolite, was significantly increased both in the striatum (200%) and limbic DA structures (500%). These data demonstrate regional postmortal differences in stability of DA and its metabolite levels, which are in the striatum temperature-, time-, and storage-dependent. That implicates a careful assessment of postmortem studies when measuring the neurotransmitter dynamics in human necropsy material.
Asunto(s)
Dopamina/metabolismo , Sistema Límbico/metabolismo , Corteza Visual/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Autopsia , Cromatografía Líquida de Alta Presión , Criopreservación/métodos , Estabilidad de Medicamentos , Ácido Homovanílico/metabolismo , Técnicas In Vitro , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Disruptions of glutamatergic and noradrenergic signaling have been postulated to occur in depressive disorders. Glutamate provides excitatory input to the noradrenergic locus coeruleus (LC). In this study, the location of immunoreactivity against neuronal nitric oxide synthase (nNOS), an intracellular mediator of glutamate receptor activation, was examined in the normal human LC, and potential changes in nNOS immunoreactivity that might occur in major depression were evaluated. Tissue containing LC, and a non-limbic, LC projection area (cerebellum) was obtained from 11 to 12 matched pairs of subjects with major depression and control subjects lacking major psychiatric diagnoses. In the LC region, nNOS immunoreactivity was found in large neuromelanin-containing neurons, small neurons lacking neuromelanin, and glial cells. Levels of nNOS immunoreactivity were significantly lower in the LC (- 44%, p < 0.05), but not in the cerebellum, when comparing depressed with control subjects. nNOS levels were positively correlated with brain pH values in depressed, but not control, subjects in both brain regions. Low levels of nNOS in the LC may reflect altered excitatory input to this nucleus in major depression. However, pH appears to effect preservation of nNOS immunoreactivity in subjects with depression. This factor may contribute, in part, to low levels of nNOS in depression.