Made available in DSpace on 2015-12-06T23:45:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2011 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Centro Brasileiro de Informações sobre Drogas Psicotrópicas (CEBRID) / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Os benzodiazepínicos (BZDs) são fármacos utilizados como ansiolíticos, hipnóticos/sedativos, coadjuvantes na anestesia, anticonvulsivantes e miorrelaxantes. Entre os psicofármacos, os BZDs são os mais prescritos no Brasil, especialmente para mulheres. Apesar da considerável prevalência e do potencial de abuso, ainda são escassos os estudos sobre o uso indevido desses medicamentos entre mulheres adultas. O objetivo deste trabalho foi estudar, por meio de metodologia de base qualitativa, os contextos e os padrões de uso indevido de benzodiazepínicos entre mulheres adultas residentes no município de São Paulo e imediações. Metodologia: Foi composta uma amostra intencional por critérios de 33 mulheres entre 18-60 anos com histórico de uso indevido de BDZ no ano. Foram realizadas entrevistas semi-estruturadas, cujo conteúdo foi transcrito e submetido à análise de conteúdo com auxílio do software NVivo. Resultado: Foi observado que, entre as usuárias de benzodiazepínicos entrevistadas, a forma mais freqüente de uso indevido foi o uso prolongado (mediana=7 anos). Os principais motivos de uso foram relacionados à ansiedade, insônia e “fuga dos problemas”. A maioria referiu acompanhamento médico, mas poucas relataram percepção de riscos. Mesmo entre aquelas que relataram ter alguma percepção da sua dependência, a maioria afirmou preferir continuar com o uso. Foram referidas estratégias de parada e/ou redução do consumo, entre as quais: rezar, práticas de relaxamento e psicoterapias. Conclusões: Os resultados mostram que o uso indevido relacionado ao tempo prolongado vem acompanhado por ausência de informações adequadas sobre os riscos dos BZD, mesmo com acompanhamento médico. Os resultados ressaltam a importância da orientação e acompanhamento adequado, como campanhas informativas que salientam a necessidade de ampliação da percepção de risco pessoal entre mulheres que fazem uso prolongado de benzodiazepínicos. / Benzodiazepines (BZDs) are drugs used as anxiolytic, hypnotic/sedative, coadjutants in anesthesia, anticonvulsant and muscle relaxant medications. Among the psychoactive drugs, BZDs are the most often prescribed in Brazil, especially to women. In spite of the considerable prevalence and abuse potential, studies on its misuse among adult women are still scanty. The objective of this study was to assess, by means of qualitative methodology, the contexts and patterns of misuse of benzodiazepines among adult women living in and around the city of São Paulo. Methodology: 33 women between 18 and 60 years old, with a history of misuse of BDZ in the year, comprised the intentional sample selected by criteria. They had a semi-structured interview whose content was transcribed and submitted to content analysis with the help of the software NVivo. Result: The most frequent benzodiazepine misuse among the interviewees was the prolonged use (median = 7 years). The main reasons stated for use were related to anxiety, insomnia and “escape from problems”. Most of them reported medical follow-up, but few of them perceived the risks. Even among those who reported some awareness of dependence, most of them declared they would rather continue the use. Some strategies to stop/reduce use were employed, such as praying, practicing relaxation and doing psychotherapies. Conclusions: The results show that misuse regarding prolonged time is associated with lack of adequate information on the risks posed by BZD, even when there is medical orientation. Therefore, the results highlight the importance of adequate guidance and follow-up, such as informative campaigns that stress the need to raise the awareness of personal risks among women who make prolonged use of benzodiazepines. / FAPESP: 08/56061-0 / FAPESP: 08/57576-3 / BV UNIFESP: Teses e dissertações

A depressão é um transtorno que possui maior prevalência nas mulheres do que nos homens. A progesterona pode estar envolvida nos mecanismos que geram estas diferenças. Este hormônio é utilizado clinicamente para mulheres em diversos eventos reprodutivos, e seu efeito na depressão não está bem estabelecido. Estudos em modelos animais mostraram que existe uma influência da progesterona no comportamento tipo-depressivo em roedores, mas estes estudos são inconclusivos. Autores têm demonstrado que as mudanças comportamentais em roedores ocasionadas pela progesterona estão associadas à alterações nas subunidades do receptor GABAA. O ácido Y-aminobutírico (GABA) é o principal neurotransmissor inibitório do sistema nervoso central. O receptor GABAérgico é composto de uma combinação de 5 subunidades que formam um poro iônico. A composição de subunidades mais comum é a composta de 2a1, 2b2 e 1g2. A modulação da atividade GABAérgica pela progesterona é específica à estrutura encefálica utilizada. O estriado é a estação de entrada para os núcleos da base, uma estrutura envolvida em respostas comportamentais. O córtex préfrontal é uma estrutura de grande importância no circuito límbico envolvida no controle de situações estressantes. Estudos têm mostrado uma assimetria funcional nesta estrutura relacionada ao gênero em respostas adaptativas ao estresse e no processamento emocional em humanos. Há também evidências relacionadas à depressão, de assimetria no sistema GABAérgico no estriado. Desta forma, no primeiro artigo, foi investigado o efeito antidepressivo de baixas doses de progesterona com dois protocolos de tratamento: agudo e crônico. No segundo e terceiro artigos foram avaliadas a expressão das subunidades a1 e g2 do receptor GABAA nos hemisférios direito e esquerdo do estriado e do córtex préfrontal de ratos Wistar machos e fêmeas que receberam o tratamento crônico com progesterona e de ratos que, adicionalmente, foram submetidos ao teste do nado forçado. No estriado, foi avaliada a expressão do mRNA, por RT-PCR, e no córtex pré-frontal foi avaliado em machos, adicionalmente, a expressão protéica por Western Blot destas subunidades. O tratamento agudo com progesterona não alterou o comportamento tipodepressivo dos ratos, mas o tratamento crônico diminuiu o comportamento tipodepressivo em fêmeas e aumentou em machos. A dose utilizada não alterou o ciclo hormonal das fêmeas. A análise da imobilidade dos animais que receberam veículo demonstrou que as fêmeas em diestro II foram mais depressivas do que os machos, refletida por sua maior imobilidade no teste do nado forçado. Este resultado comportamental das fêmeas pode estar associado aos mais baixos níveis séricos de progesterona característicos desta fase do seu ciclo reprodutivo. A expressão da subunidade g2 no estriado dos ratos controle foi assimétrica, onde machos mostraram maior expressão no hemisfério esquerdo do que no direito, que pode representar uma característica de risco mais baixo para depressão. Não houve assimetria no estriado das fêmeas ou no córtex pré-frontal dos grupos controle. No estriado e no córtex pré-frontal, o estresse altera a simetria da expressão da subunidade a1, induzindo maior expressão no lado direito do que no esquerdo. Esta resposta assimétrica ocorreu em ratos machos e em fêmeas submetidos ao estresse específico das injeções. Ainda, os machos respondem ao estresse pela alteração da expressão da subunidade a1 e têm a capacidade de se recuperar desta alteração após a exposição a outro tipo de estressor nas duas estruturas analisadas neste trabalho. O estresse, independente do tipo, diminui a expressão da subunidade g2, tanto no estriado como no córtex pré-frontal. O efeito antidepressivo da progesterona nas fêmeas está correlacionado com a maior expressão da subunidade a1 no córtex préfrontal. O efeito pró-depressivo nos machos está correlacionado com o aumento da expressão da subunidade g2 no estriado. Progesterona altera o comportamento tipo-depressivo alterando a eficiência do sistema GABAA no hemisfério direito do córtex pré-frontal de fêmeas e no estriado de machos. A análise da expressão do mRNA e da proteina demonstrou que progesterona e o nado forçado aumentaram bilateralmente a expressão do mRNA da subunidade α1, mas aumentaram a expressão protéica desta subunidade apenas no hemisfério direito. Além disso, progesterona não modificou o mRNA da subunidade g2 mas aumentou sua expressão protéica, indicando a existência de possíveis modificações pós-transcricionais. / Major depression is more prevalent among women than men, and progesterone might be involved in the mechanisms that generate these differences. Progesterone is clinically used for women in several reproductive events, but its antidepressant effect is unclear. Animal studies showed the interference of progesterone on depressive behaviors of rodents, but they are inconclusive, and no study compared different treatment durations. The behavioral changes ocasioned by progesterone has been associated with GABAAR activity modulation. Y-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system, and generally consists of a combination of 2a1, 2β2 and 1g2 subunits. The modulation of GABAA receptor by progeterone is specific to brain region studied. Prefrontal cortex is a nodal point of a limbic circuit involved in the control of stress situations. Studies have shown a sex-related functional asymmetry in this region mediating adaptive coping responses to stress and emotional processing in humans.The striatum is the input station for the basal ganglia, which is involved in behavioral responses. In this structure, there is evidence of brain hemispheric asymmetry in the GABAergic system related to depression. This study investigated the antidepressant effect of low doses of progesterone in male and female rats under acute or chronic administration. Male and female Wistar rats in different phases of the estrous cycle were acutely administered different doses of progesterone (0.0, 0.4. 0.8 and 1.2 mg/kg) and tested in the forced swimming test (FST). The lowest dose of progesterone (0.4 mg/kg) was chronically administered during two complete estrous cycles and diestrous II female and male rats were tested in the FST. One group only received chronic progesterone without have been evalued in the FST. The effects on the GABAA a1 and g2 receptor subunit mRNA expressions by RT-PCR in the striatum and prefrontal cortex these animals were examined. In the prefrontal cortex, the protein expression by Western Blot of these subunits was additionally evaluated. Progesterone decreased depressive-like behaviors only in chronically treated diestrous II female rats and increased immobility in male rats. This low dose of progesterone did not interfere in the hormonal cycling in female rats. Results also showed that diestrous II female rats had greater immobility than male rats in the FST. The greater immobility of diestrous II female rats shows that rats in this estrous phase present more depressive-like behaviors that may be associated with their lower serum levels of progesterone. We showed that progesterone chronically administered at low doses reverses these depressive-like behaviors and has an antidepressant effect during the diestrous II phase of the estrous cycle. In the striatum, the expression of the g2 subunit displayed a gender-specific asymmetry. The stress caused by injections decreased the expression of g2 and a1 mRNA in the striatum of both male and female rats, while stress caused by forced swimming decreased only the expression of g2. Also, the expression of the g2 and a1 subunits modified in according to the nature of the stressor. Chronic progesterone treatment increased both, g2 and a1 subunits, depending on the brain hemisphere, the level of stress, and the gender. A positive correlation between depression-like behavior in male rats treated with progesterone and the expression of the g2 subunit in the right striatum was noted. Our findings suggest that the g2 subunit of GABAAR can play an important role in the regulation of depressive behavior under certain stress conditions. In the pre-frontal cortex, the expression of a1 and g2 mRNA subunits are gender-specific in the control and stressed rats. It occurred a hemispheric specificity in the expression of the a1 and g2 subunits in response to injections stress as well as to progesterone treatment differentially regulated by gender. The mRNA and protein expression analysis demonstrated that progesterone plus forced swimming increased billaterally the expression of α1 mRNA, but the protein expression was increased only in the right prefrontal cortex. Moreover, progesterone did not modify the g2 mRNA but it increased its protein expression, indicating the existence of possible post-transcriptional modifications in this structure. Also, there was a negative correlation between the mRNA and protein expression of α1 subunit in the right prefrontal cortex and the immobility behavior in female rats. Thus, progesterone may improve the depressive behavior of females restoring the efficiency of system GABAA of right prefrontal cortex.

Submitted by Ramon Santana (ramon.souza@ufpe.br) on 2015-03-10T19:07:06Z No. of bitstreams: 2 DISSERTAÇÃO Evandro Medeiros Costa.pdf: 971018 bytes, checksum: e4bb7912dc872933b713f9a139303ded (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-03-10T19:07:06Z (GMT). No. of bitstreams: 2 DISSERTAÇÃO Evandro Medeiros Costa.pdf: 971018 bytes, checksum: e4bb7912dc872933b713f9a139303ded (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2014-02-21 / INTRODUÇÃO: O consumo excessivo de medicamentos pela população é considerado um problema de saúde pública. Entre esses medicamentos destacam-se os benzodiazepínicos que são comumente utilizados para o tratamento da insônia. Diante dos inúmeros problemas trazidos pelo uso indiscriminado desses insumos a Secretaria Municipal de Saúde do Recife buscou uma alternativa ao seu uso, introduzindo assim o medicamento fitoterápico à base de Valeriana Officinalis L. Esse estudo tem como OBJETIVO avaliar a implantação e utilização do medicamento fitoterápico em ex-usuários de benzodiazepínicos das unidades de Saúde da Família do Distrito Sanitário II. MATERIAIS E MÉTODOS: Avaliou-se através de questionários a qualidade do sono dos usuários do novo medicamento, seu conhecimento sobre a fitoterapia fazendo um paralelo comparativo ao uso dos benzodiazepínicos e entrevistou-se também os prescritotes, através de questionários padronizados, sobre questões relacionadas à fitoterapia com destaque para Valeriana Officinalis L. RESULTADOS E DISCUSSÃO: Participaram do estudo 101 pessoas (93 usuários se 8 médicos). Os usuários relataram conhecer as atividades de vinte e seis espécies diferentes de plantas, utilizadas isoladamente para diversos fins medicinais, destacando-se o maracujá (Passiflora incanata) com 8/63 citações, a camomila (Chamomilla recutita (L.)) com 8/63 citações e a laranja (Inga sp.) com 5/63 citações. O Grupo Valeriana (GV) teve um escore global de 12 pontos e o Grupo Controle (GC) apresentou escore global de 4 pontos no Questionário de Qualidade de Sono de Pittsburg, sendo assim o GV apresentou qualidade do sono muito ruim o GC qualidade do sono boa. Vários fatores podem estar relacionados a esse resultado entre eles o desconhecimento dos prescritores sobre o tratamento o que ficou evidente através dos resultados das entrevistas com os médicos. Quando a pergunta foi relacionada à retirada de benzodiazepínicos utilizando a valeriana, metade dos entrevistados relatou que não se sentem seguros e revelaram desconhecimento em relação ao “desmame”. Em relação ao nível de conhecimento sobre a valeriana 5/8 dos prescritores julgaram como sendo regular, 2/8 muito ruim e 1/8 bom. CONCLUSÃO: É de interesse para este estudo que novas pesquisas sobre o tema sejam realizadas e que nelas sejam envolvidas atividades de acompanhamento farmacoterapêutico e de educação em saúde para os usuários e profissionais de saúde envolvidos no processo. Portanto cabe aos profissionais de saúde a apropriação sobre temas tão importantes como a fitoterapia e a retirada gradual de benzodiazepínicos, uma vez que isso poderá afetar diretamente não somente a qualidade do sono, mas a qualidade de vida dos usuários.

Angelman syndrome (AS) is a rare genetic and neurological disorder presenting with severe developmental delay, ataxia, epilepsy, and lack of speech. AS is associated with a neuron-specific loss of function of the maternal UBE3A allele, a gene encoding an E3 ubiquitin ligase. Currently, no cure exists for this disorder; however, recent research using an AS mouse model suggests that pharmacological intervention is plausible, and can alleviate some of the detrimental phenotypes reported in AS patients. Although there is no curative treatment for AS, seizure medication and behavioral therapies are most commonly prescribed in order to minimize symptoms. However, these options only moderately improve quality of life and can cause adverse side effects, such as alterations in mood and cognition following seizure treatment. Unfortunately, epilepsy is a common cause of death in AS and affects greater than 80% of AS patients, with 77% of those patients remaining refractory. The severity of seizures and lack of consistently effective anti-epileptic medications for AS patients demonstrates a considerable need for other therapeutic options. The goal of this work was to evaluate the effects of seizure therapies that have proven beneficial for treating refractory epilepsy in seizure-related disorders. These studies focused specifically on advances in both a pharmacological and dietary therapy evaluated in the AS mouse model. Previous work in our lab has demonstrated the importance of interneurons and GABAergic tone in hippocampal network regulation and cognition. GABA is an important modulator of synaptic plasticity, and learning increases both inhibitory synaptogenesis and GABA release from hippocampal inhibitory neurons. A neuronal excitatory/inhibitory imbalance, coupled with decreased GABAergic tone, altered synaptic plasticity, and impaired cognition have been reported in the AS mouse model. Therefore, we proposed to examine two therapeutic strategies used in seizure treatment – a ketone ester (KE) supplement, which is thought to increase the [GABA]/[glutamate] ratio via alterations in brain metabolism, and ganaxolone, a positive allosteric modulator of GABAA receptors. We evaluated the effects of each therapeutic on learning and cognitive enhancement, alterations in synaptic function, and anticonvulsant activity. We hypothesized that both the KE and ganaxolone would demonstrate anticonvulsant efficacy in both behavioral and chemiconvulsant seizure models. Additionally, as chronic epilepsy has been linked to progressive cognitive and memory impairment which may be related to GABA deficiencies, we hypothesized that both therapeutics would improve cognition and modulate synaptic plasticity (i.e., synaptic function). KE administration produced sustained ketosis and improved motor coordination, learning and memory, and synaptic plasticity in AS mice. The KE was also anticonvulsant and altered brain amino acid metabolism in AS treated animals. Ganaxolone was anxiolytic, anticonvulsant, and improved motor deficits in AS mice. Four weeks of treatment also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that the KE and ganaxolone ameliorate many of the behavioral abnormalities in the adult AS mouse, possibly through modulations of GABAergic tone. These results support clinical investigation of both the KE and ganaxolone in AS, which may lead to the development of a novel treatment for AS patients.

The inhibitory circuitry of the prefrontal cortex (PFC) is involved in working memory and modulation of brain oscillations. Alterations in this network and especially GABAergic cells that express cholecystokinin (CCK), parvalbumin (PV), or somatostatin (SST) may underlie some of the cognitive deficits observed in schizophrenia. To assess the involvement of CCK+, PV+, and SST+ interneurons in PFC-dependent behaviours, we selectively inactivated these in prelimbic and infralimbic PFC via virus-mediated expression of tetanus toxin light chain (TeLC). We found that functional removal of CCK+ or PV+, but not SST+ neurons leads to specific impairments in working memory, and these represent the main cognitive domains affected in schizophrenia. PV-TeLC and CCK-TeLC mice displayed significant Y-maze alternation index reduction (p < 0.05). Targeting of PV+ prefrontal cells causes anxiety-like phenotype. Moreover, PV+ and SST+, but not CCK+ interneurons, appear to play a role in latent inhibition. Functional removal of CCK+, PV+ and CCK+ cells from PFC does not affect circadian activity and does not cause anhedonia. The involvement of PV-network in generation of neuronal activity and acetylcholine homeostasis was assessed. For neurophysiological recordings, each arm of the Y-maze divided into two equal-sized zones – proximal (close to the central decision point) and distal (far end). Zone entry was event-mapped onto continues local field potential recordings from medial PFC and CA1 region of the hippocampus. PV-TeLC animals displayed significantly lower prefrontal power in the decision zone. This suggests that the PV-TeLC animals are unable to modulate neuronal activity depending on the cognitive demand. Functional removal of prefrontal PV+ interneurons also leads to disturbed acetylcholine homeostasis. These results show that prefrontal GABAergic cells drive different behaviours and control task-relevant neuronal activity in different brain regions engaged with working memory such as hippocampus. Similar signalling anomalies may thus underlie cognitive deficits found in schizophrenia.

The basal ganglia (BG) are a group of nuclei in the basal forebrain critical in movement, goal directed behaviour and action selection. Cortical projections to the largest BG nucleus, the striatum, are highly important in theories of BG function. Therefore, we have investigated the role of striatal neurons in modulating the activity of corticostriatal synapses. In an in-vitro preparation of rodent brain slices, we conducted whole-cell patch clamp recordings of single and pairs of striatal neurons and recorded responses of medium spiny neurons (MSNs) to stimulation of corticostriatal fibres. In the presence of opioid, GABAA, NK1 and cholinergic receptor antagonists, antidromic stimulation of a population of MSNs (5 stims, 50 Hz) caused suppression of subsequently evoked EPSPs in MSNs. This suppression was dependent upon the interval between antidromic MSN stimulation and the stimulation of evoked EPSPs; suppression was larger at 500 ms intervals than at 1 or 2 s intervals. These effects were completely blocked by the GABAB antagonist CGP 52432. Bursts of evoked action potentials (5 APs, 50 Hz) in a single MSN were insufficient to cause these effects in a nearby MSN. Similar spikes in single fast spiking interneurons and low threshold spiking interneurons (LTSIs) were also insufficient. Conversely, single neurogliaform interneurons (NGFIs) could suppress evoked EPSPs in nearby MSNs in a GABAB-dependent manner. This suppression was more likely in NGFI-MSN pairs that exhibited direct GABAergic interactions. We also tested long depolarisations in LTSIs, a protocol that preferentially releases NO, which was shown to suppress evoked EPSPs through a non-GABAergic mechanism. Finally, we tested the application of exogenous NPY to slices, which also inhibited corticostriatal transmission. These results provide the first demonstration of how GABAB receptors at corticostriatal synapses are activated by endogenous GABA released by striatal neurons. They also reveal novel mechanisms through which striatal factors influence these synapses.

Cys-loop receptors are ligand-gated ion channels that are involved in fast synaptic neurotransmission in the central and peripheral nervous system. The Cys-loop receptor RDL ('resistant to dieldrin') is a GABA-gated chloride channel from Drosophila melanogaster and is a major target site for insecticides. The aim of this dissertation was to characterise RDL receptors with particular focus on the agonist binding site. To assess the potency of a range of GABA analogues on RDL receptors, I expressed receptors in Xenopus oocytes and used voltage-clamp electrophysiology to detect receptor responses. I carried out computational modelling of these analogues to determine the dipole separation distances and atomic charges. Computational calculations and functional experiments revealed that agonists require a charged ammonium and an anionic centre, with the most potent agonists having a dipole separation distance of ~5 Å. I made a homology model of the extracellular domain of RDL and docked the active analogues into the putative binding site. I then conducted mutagenesis studies to test the accuracy of this model. Functional data from mutagenesis studies broadly support the location of GABA within this model. This model may be useful for further structure-activity studies and rational drug design. Natural compounds from the traditional Chinese medicine 'Ginkgo biloba' (ginkgolide A, ginkgolide B and bilobalide) have potent insecticidal properties and are similar in structure to picrotoxin. I tested the effect of these compounds on RDL receptor function using voltage-clamp electrophysiology. All compounds were found to inhibit RDL receptor function. I probed the binding site of these compounds using site-directed mutagenesis and electrophysiology. Mutations to the 2'A and 6'T channel-lining (M2) residues greatly reduced the potency of these compounds. I then made a homology model of the transmembrane domain of RDL and docked these compounds into the channel. Compounds docked into the channel pore close to the 2' and 6' channel-lining residues and H-bonding interactions were detected at these locations. Ginkgolides are therefore antagonists of RDL receptors, binding in the channel close to the 2' and 6' residues and this may be the mechanism underlying their potent insecticidal properties. The 5-HT3 receptor is a member of the Cys-loop receptor family and shows homology to RDL receptors. To explore different techniques for studying Cys-loop receptor function I assessed the functionality of two brain derived transcripts of the 5-HT3B subunit (Br1 and Br2) using single-channel electrophysiology and a fluorometric assay. Receptors containing Br1 were found to have a conductance identical to the 5-HT3B subunit whilst Br2 receptors were found not to be expressed. This finding has implications for 5-HT3 brain signalling, in which Br1 may play an important role. In conclusion, work here has described how agonists bind to and activate RDL GABA receptors and I have identified a candidate mechanism for the potent insecticidal properties of Ginkgo biloba extracts. I have also confirmed that 5-HT3 receptor brain transcript Br1 forms functional channels with similar properties to the 5-HT3B subunit.

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No description available.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu). / A role has been proposed for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in central cardiovascular control. This proposa 1 was based on the cardiovascular effects of agents which block or mimic the action of GABA on the post-synaptic membrane. This dissertation reported the cardiovascular effects of 3-mercaptopropionic acid (3-MP), an agent which inhibits GABA biosynthesis in the pre-synaptic nerve terminal in anesthetized guinea pigs. 3-MP interrupts GABAergic transmission by decreasing the amount of GABA in the brain. The effect of 3-MP on mean arterial pressure, heart rate and barorflex-induced bradycardia was determined as well as the mechanism(s) involved in observed changes. The content of GABA in four regions of the brain (hypothalamus, medulla, cerebellum and occipital cortex) was determined at the end of each experiment. In anesthetized guinea pigs, 3-MP (195 mg/kg, i.p.) elicited a biphasic response (Type I) in the majority of animals. This response consisted of sympathetically-mediated hypertension and tachycardia superseded by vagally-mediated bradycardia. The other response (Type II) consisted of only the sympathetically-mediated effects. The Type II response was associated with animals in which the vagus nerves were functionally impaired. In all brain regions measured, the GABA levels of both Types I and II were significantly lower than those of control animals. The sympathetically-mediated effects of 3-MP were reversed by chlordiazepoxide, a GABA-facilitory agent. Therefore, the 3-MP-induced cardiovascular effects appeared to reflect GABAergic activity in the bra in which resulted from a reduction of GABA content. The two phases of the Type I response may have resulted from a reduction of GABA content in specific brain regions. A reduction in hypothalamic GABA levels appeared to be related to the sympathetic activation and a reduction in medullary GABA levels appeared to be related to the vagal activation. In unparalyzed animals, 3-MP elicited convulsive movements as well as the described effects on the cardiovascular system. The centrally acting anticonvulsant phenytoin stopped 3-MP-induced motor manifestations of seizure activity without altering either blood pressure or heart rate. Therefore, the cardiovascular effects of 3-MP appeared to occur independent of the convulsive effect of this agent. These results support the hypothesis of GABAergic involvement in the central control of autonomic outflow to the cardiovascular system. The inability of phenytoin to reverse the cardiovascular effects of 3-MP suggests that these effects were independent of 3-MP-induced seizures.