RESUMO
The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.
Assuntos
Proteínas de Transporte/genética , Cocaína/administração & dosagem , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Camundongos Knockout/genética , Camundongos Knockout/fisiologia , Proteínas do Tecido Nervoso , Animais , Sítios de Ligação/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/genética , Autoadministração , Serotonina/fisiologiaRESUMO
The present study compared cocaine-induced hyperlocomotion and cocaine i.v. self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after i.p. cocaine injection (0-60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine i.v. self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical i.v. insertion of an in-dwelling catheter, and required to respond for i.v. cocaine (0.25-4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following i.p. injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior.
Assuntos
Encéfalo/metabolismo , Cocaína/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Cocaína/metabolismo , Condicionamento Operante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , AutoadministraçãoRESUMO
The present experiment tested the hypothesis that 5-HT1B receptors are involved in the reinforcing effects of cocaine. Transgenic mice lacking 5-HT1B receptors were used as subjects and compared with wild-type mice for the acquisition and maintenance of intravenous (IV) cocaine self-administration. Male 129/Sv-ter and 5-HT1B-minus 129/Sv-ter inbred mice (Columbia University, New York) were initially trained to press a lever under a fixed-ratio schedule 2, first for sweetened condensed milk as reinforcer and subsequently for cocaine (2.0 mg/kg/infusion). When a stable baseline of responding was obtained, each subject was tested under different doses of cocaine (1.0, 2.0, and 4.0 mg/kg), with the number of reinforcers per hour used as the dependent variable. Both strains successfully acquired food-shaping and cocaine self-administration, but the mutant mice presented a significantly shorter latency to meet IV cocaine self-administration acquisition criteria (p < 0.05). However, both wild-type and mutant mice had similar dose-response to cocaine. These results suggest that the 5-HT1B receptors may be implicated in the propensity to self-administer cocaine, but other mechanisms might be involved in the maintenance of cocaine self-administration.
Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Autoadministração , Animais , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Reforço PsicológicoRESUMO
The purpose of this study was to compare the ability of two methods of adhesive strapping to provide support to the medial longitudinal arch (MLA) before and after a standardized exercise of 10 minutes of jogging. Ten females, 19 to 35 years of age, were subjects. To determine the position of the MLA, the height of the navicular tuberosity from the floor was measured bilaterally while each subject was standing. Measurements were taken for the following three conditions: barefoot (BARE), before exercise with arches taped (PREEX), and after exercise with arches taped (POSTEX). Methods for taping the MLA were: 1) LowDye and 2) double X. Results of a two-way, within-subjects ANOVA were significant for conditions (F = 45.3, p < 0.0001) and tape methods x conditions interaction (F = 3.6, p < 0.05) but not for tape methods. The Tukey test resulted in a significant difference (p < 0.05) between BARE and PREEX and PREEX and POSTEX but not between BARE and POSTEX. Results indicate that support of the MLA by adhesive strapping was significantly diminished after exercise. J Orthop Sports Phys Ther 1991;14(1):18-23.
RESUMO
The Hydrotrack, a treadmill immersed in a water bath, is designed to provide an in-office approach to aquatic therapy. 24 clinical clients in an outpatient sports medicine practice were invited to use the Hydrotrack as part of their rehabilitation treatment. Our purpose was to describe the way(s) in which the Hydrotrack is useful in rehabilitation treatment. Exercise protocols designed by a physical therapist were used for each subject. We monitored an external criterion, heart rate, to measure the subjects' exertion during the exercise process. Self-reported ratings of exercise efficacy and exertion were also used to quantify the subjects' performance on the Hydrotrack. Heart-rate values and self-report ratings supported the usefulness of this device in physical therapy.
Assuntos
Terapia por Exercício/instrumentação , Frequência Cardíaca/fisiologia , Hidroterapia/instrumentação , Doenças Musculoesqueléticas/reabilitação , Modalidades de Fisioterapia/instrumentação , Adulto , Idoso , Metabolismo Energético/fisiologia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/fisiopatologia , AutoeficáciaRESUMO
In 17 anesthetized dogs, left coronary blood flow (LCBF), left ventricular oxygen extraction [(a-v)O2], and myocardial oxygen consumption (MVO2) were monitored. Coronary perfusion pressure (CPP) was varied over a wide range by hemorrhage, and the effects of alpha-adrenergic blockade elicited by intracoronary phenoxybenzamine were assessed. During normotension (CPP greater than 80 mm Hg), blockade increased LCBF by 31 +/- 6 (SEM) %, but (a-v)O2 was substantially decreased so that MVO2 was increased by only 13 +/- 3%. At lower levels of CPP, the absolute increase in LCBF caused by blockade was similar to that during normotension, but because of the reduced preblockade LCBF, the percentage increase was greater. Thus, at a CPP of 50-80 mm Hg, LCBF increased by 41 +/- 15%, and at CPP less than 50 mm Hg, LCBF increased by 47 +/- 11% (P less than 0.05 compared to percentage of change during normotension). Furthermore, during hypotension the increase in LCBF after blockade was not accompanied by a large decrease in (a-v)O2. Consequently, in severe hypotension (CCP less than 50 mm Hg), both the absolute increase and the percentage increase in MVO2 was significantly greater than during normotension. These data suggest that during hypotension, especially severe hypotension, an alpha-adrenergic tone in the coronary circulation limits coronary flow and myocardial oxygenation.
Assuntos
Circulação Coronária , Vasos Coronários/inervação , Hipotensão/fisiopatologia , Choque Hemorrágico/fisiopatologia , Animais , Cães , Feminino , Masculino , Miocárdio/metabolismo , Consumo de Oxigênio , Fenoxibenzamina/farmacologiaRESUMO
In the present study we determined quantitatively the effects of increased right atrial pressure (RAP) on coronary and collateral flows. In an isolated, blood-perfused, maximally vasodilated dog heart preparation in which the left ventricle was vented, we used the retrograde flow method to assess collateral flow. When RAP was elevated from 5 +/- 1 (control) to 13 +/- 1 and 23 +/- 1 mmHg, retrograde flow from the left circumflex coronary artery (which was open to atmospheric pressure) increased 29 +/- 8 and 97 +/- 21% relative to control while left anterior descending flow decreased 5 +/- 1 and 14 +/- 2%, respectively (P < 0.01; n = 7). The increase in retrograde flow could be due to 1) an increase in collateral flow due to increased pressure at the origin of the collaterals or 2) the elevated RAP (venous outflow pressure), which forces the antegrade collateral flow component in the retrograde direction. To distinguish between these possibilities we embolized the circumflex with 30-microns spheres to eliminate the antegrade flow component. After embolization there was no significant change in retrograde flow with elevated RAP, indicating that the second supposition was correct. We conclude that increased RAP 1) results in a reduction of flow to the collateral-dependent myocardium and 2) reduces perfusion of the unoccluded coronary vessel. Furthermore, we found that under conditions of varying venous outflow pressure, retrograde flow may not serve as a reliable index of collateral flow.
Assuntos
Função do Átrio Direito , Circulação Colateral , Circulação Coronária , Animais , Cães , Técnicas In Vitro , Microesferas , Perfusão , PressãoRESUMO
This study was undertaken to determine the relationship between left ventricular (LV) volume and coronary flow in the presence and absence of coronary vasomotor tone in arrested dog hearts. We utilized an isolated, blood-perfused, potassium-arrested dog heart preparation with vascular vasomotor tone present (n = 5) or after maximal vasodilation with adenosine (n = 7). LV volume was controlled with a balloon while left and right coronary flows were recorded. Left and right coronary flows were plotted as a function of LV volume, and the degree of interdependency was quantitatively assessed by the slope of the linear regression and the correlation coefficient (r) between coronary flow and LV volume. With vasomotor tone present, both left (slope = 0.01 +/- 0.06 min-1) and right (slope = -0.01 +/- 0.01 min-1) coronary arterial flows were maintained relatively constant over a wide range of LV volumes. After maximal vasodilation, left coronary flow decreased linearly with LV volume loading (slope = -2.51 +/- 0.47 min-1, r2 = 0.96 +/- 0.02), whereas right coronary flow, similar to the response with tone present, did not change relative to control in most cases. We conclude that changes in coronary vasomotor tone may take place with LV volume loading to compensate for the mechanical vascular resistance changes secondary to myocardial stretch.
Assuntos
Volume Sanguíneo , Circulação Coronária/fisiologia , Sistema Vasomotor/fisiologia , Função Ventricular Esquerda , Animais , Cães , Técnicas In Vitro , VasodilataçãoRESUMO
The present study was designed to determine the effects of right heart pressure on the compliance of the left ventricle (LV). The studies were conducted on isolated, blood-perfused, potassium-arrested dog hearts with vasomotor tone either present (n = 5) or absent (n = 8). A balloon was used to control LV volume, whereas right heart (RHP) or coronary sinus (CSP) pressures were controlled via a column placed in the right heart or coronary sinus, respectively. Control of CSP independently of RHP allowed us to assess the relative contribution of coronary venous pressure to changes in LV compliance under conditions of elevated RHP. LV volume and compliance at a LV pressure of 15 mmHg (V15 and C15, respectively) were calculated to quantify the shift and slope changes of the LV pressure-volume (P-V) relationships. V15 and C15 decreased with vasomotor tone present from 52.8 +/- 1.4 ml and 1.7 +/- 0.1 ml/mmHg at control, to 43.3 +/- 2.1 ml and 1.4 +/- 0.1 ml/mmHg (P < 0.05) with RHP = 0 and 20 mmHg, respectively. Similar effects were obtained with vasodilation, but C15 was significantly lower relative to autoregulation but C15 was significantly lower relative to autoregulation (1.0 +/- 0.1 at control RHP, P < 0.05). Elevation of CSP with vasomotor tone resulted in an upward shift in the LV P-V relationship: V15 decreased from 53.4 +/- 2.1 at CSP = 0 mmHg to 50.9 +/- 1.6 ml at CSP = 20 mmHg (P < 0.05). After vasodilation there was no detectable shift in the LV P-V relationship with elevation of CSP.