RESUMEN
It has been suggested that stress, via corticosterone secretion, can modulate some of the behavioural responses to cocaine. In particular, we have demonstrated that daily exposure to electric footshock stress or daily pretreatment with corticosterone shifts the ascending limb of the dose-response curve for the acquisition of cocaine self-administration upwards and to the left. It has been suggested that this corticosterone-induced increase in sensitivity to low doses of cocaine is associated with an enhancement of dopaminergic neurotransmission. The present study was designed to test this hypothesis. Adult male rats were pretreated with corticosterone (2.0 mg/kg intraperitoneally) 15 min prior to an injection of cocaine (5.0, 10.0 or 20.0 mg/kg intraperitoneally), and motor activity and extracellular dopamine concentrations in the nucleus accumbens were monitored. Cocaine administration resulted in dose-related increases in motor activity that were unaffected by pretreatment with corticosterone. However, rather than augmenting cocaine-induced increases in dopamine in the nucleus accumbens, corticosterone pretreatment actually caused attenuation at the two highest doses of cocaine tested. These data suggest dissociation between locomotor activation and nucleus accumbens dopamine responses to cocaine, and indicate that other brain regions and/or mechanisms may be involved in the changes in sensitivity to cocaine induced by corticosterone.
Asunto(s)
Cocaína/farmacología , Corticosterona/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Electrochoque , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Medial prefrontal cortex (mPFC) dopamine (DA) modulates the motor-stimulant response to cocaine. The present study examined the specific mPFC DA receptor subtypes that mediate this behavioral response. Intra-mPFC injection of the DA D2-like receptor agonist quinpirole blocked cocaine-induced motor activity, an effect that was prevented by coadministration of the D2 receptor antagonist sulpiride. Intra-mPFC injection of the selective D4 receptor agonist PD 168,077 or the selective D1 receptor agonist SKF 81297 did not alter the motor-stimulant response to cocaine. Finally, it was found that an intermediate dose of quinpirole, which only attenuated cocaine-induced motor activity, was not altered by SKF 81297 coadministration, suggesting a lack of synergy between mPFC D1 and D2 receptors. These results suggest that D2 receptor mechanisms in the mPFC are at least partly responsible for mediating the acute motor-stimulant effects of cocaine.
Asunto(s)
Cocaína/farmacología , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Animales , Mapeo Encefálico , Inyecciones , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: Toluene is a solvent found in many commercial products and is frequently abused by inhalation. Whether previous exposure to toluene alters subsequent responses to other drugs of abuse is not known. OBJECTIVES: This study determined the effects of repeated toluene exposure on the acute motor-stimulant response to cocaine and on cocaine-induced dopamine (DA) concentrations in the nucleus accumbens (NAc). METHODS: One week following bilateral cannulae implantation over the NAc, 27 adult, male Wistar rats began a daily 30-min exposure regimen to either toluene (8,000 ppm) or air for ten sessions. Approximately 24 h or 96 h after their last exposure, animals were injected with either saline or cocaine (15 mg/kg, i.p.) and locomotor activity and DA concentrations in the NAc were measured. RESULTS: Exposure to toluene rendered the rats immobile, and the time required for recovery of normal posture decreased across the ten sessions. In all animals tested, systemic cocaine administration enhanced both locomotor activity and DA concentrations in the NAc. These increases, however, were significantly greater in rats previously exposed to toluene. CONCLUSIONS: Overall, these findings show that repeated toluene exposure enhances behavioral and neurochemical responses to subsequent cocaine administration.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Tolueno/farmacología , Administración por Inhalación , Animales , Sinergismo Farmacológico , Drogas Ilícitas/farmacología , Masculino , Actividad Motora/fisiología , Núcleo Accumbens/metabolismo , Ratas , Ratas WistarRESUMEN
RATIONALE: Considerable evidence suggests that the medial prefrontal cortex (mPFC) is an important region in mediating certain behavioral and neurochemical responses to cocaine. However, a role for cortical dopamine (DA) receptor subtypes in modulating these responses has yet to be elucidated. OBJECTIVES: This study investigated the effects of intra-mPFC administration of DA agonists on the acute motor-stimulant response to cocaine. In addition, in vivo microdialysis techniques were employed to determine the effects of intracortical injection on cocaine-induced extracellular DA concentrations in the nucleus accumbens (NAC). METHODS: One week following bilateral cannulae implantation over the mPFC and the NAC (for dialysis experiments), male Sprague-Dawley rats received an intra-mPFC injection of saline, the DA D2-like agonist quinpirole (0.015, 0.05, 0.15, 0.5, 1.5, or 5.0 nmol per side) or the partial DA D1-like agonist SKF 38393 (0.5, 1.5, or 5.0 nmol per side) approximately 5 min before peripheral administration of saline or cocaine (15 mg/kg, i.p.). For dialysis experiments, only the highest dose of quinpirole was examined. RESULTS: Pretreatment with quinpirole produced a dose-dependent decrease in cocaine-induced motor activity, with the highest doses resulting in a complete abolition of the acute motor-stimulant response to cocaine. In contrast, intra-mPFC administration of SKF 38393 was not shown, at the doses tested, to alter cocaine-induced motor activity. In agreement with the behavioral effects, intra-mPFC quinpirole injection (5 nmol per side) significantly blocked cocaine-induced DA overflow in the NAC. CONCLUSIONS: The results of the present study provide additional support that the mPFC is a neural substrate through which cocaine, in part, produces its motor-stimulant effects. In addition, these data suggest that modulation of cortical DA D2 receptors can block acute cocaine-induced behavioral (locomotor activity) and neurochemical (DA concentrations in the NAC) responses in the rat.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Cocaína/antagonistas & inhibidores , Agonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/antagonistas & inhibidores , Actividad Motora/efectos de los fármacos , Corteza Prefrontal/fisiología , Quinpirol/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Cromatografía Líquida de Alta Presión , Cocaína/farmacología , Agonistas de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Masculino , Microinyecciones , Corteza Prefrontal/anatomía & histología , Quinpirol/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
It has been postulated that behavioral sensitization to cocaine is associated with an attenuation of cocaine-induced dopamine (DA) transmission in the medial prefrontal cortex (mPFC). Hence, experiments were designed to examine the effects of chemically-induced cortical DA depletion on the acute behavioral and neurochemical responses to cocaine. One week following two bilateral 6-hydroxydopamine (6-OHDA) injections into the mPFC, animals received injections of cocaine (7.5, 15 or 30 mg/kg, i.p.) or saline (1 ml/kg, i.p.) in a randomized fashion with a minimum 3 day intertrial interval. Cocaine produced a dose-dependent increase in motor activity which was significantly enhanced in animals depleted (mean of 76%) of dopamine in the mPFC. Likewise, 6-OHDA lesions of the mPFC produced a significant enhancement of cocaine-induced DA transmission in the nucleus accumbens (NAC) as estimated by in vivo microdialysis. These data indicate a permissive involvement of cortical DA in mediating behavioral and neurochemical responses to cocaine, as well as confirm the ability of the mPFC to influence subcortical structures in response to an acute injection of cocaine. Collectively, the present findings suggest that alterations in cortical DA transmission may be a neural substrate mediating the development of sensitization to cocaine, and thus, may contribute to the addictive properties of cocaine.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ácido 3,4-Dihidroxifenilacético/análisis , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Dopamina/análisis , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Ácido Homovanílico/análisis , Ácido Hidroxiindolacético/análisis , Masculino , Microdiálisis , Núcleo Accumbens/química , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxidopamina , Corteza Prefrontal/química , Ratas , Ratas Sprague-Dawley , Simpaticolíticos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Previous studies have indicated that dopamine D1 receptors in the ventral tegmental area (VTA) may play an important role in the development of sensitization to amphetamine. The present study was designed to determine if D1 receptors are also important in the development of cocaine-induced behavioral and neurochemical sensitization. Animals received intra-VTA injections of saline or the dopamine D1 receptor antagonist SCH 23390 (15 nmol/side) 5 min before receiving systemic injections of saline or cocaine (15 mg/kg) on 4 consecutive days. One week later animals were challenged with cocaine. Motor activity and extracellular dopamine concentrations in the nucleus accumbens were monitored on the day the animals received the first of their four daily treatments and/or on the day animals received their cocaine challenge injection. Intra-VTA SCH 23390 attenuated the acute response, but did not alter development of the sensitized motor-stimulant response to cocaine. In contrast to the behavioral data, intra-VTA SCH 23390 blocked both the acute cocaine-induced increase in extracellular dopamine in the nucleus accumbens and development of the sensitized response. These data provide partial support for the role of dopamine D1 receptors in the VTA in the development of cocaine-induced sensitization. The data also suggest, however, that additional mechanisms may play a role in the development of sensitization.
Asunto(s)
Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Química Encefálica/efectos de los fármacos , Cocaína/farmacología , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Área Tegmental Ventral/fisiología , Animales , Benzazepinas/administración & dosificación , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Antagonistas de Dopamina/administración & dosificación , Inyecciones , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Área Tegmental Ventral/anatomía & histologíaRESUMEN
A role for the mesolimbic dopamine system in the development of behavioral sensitization to psychostimulants, such as cocaine and amphetamine, is well established. Previous reports have suggested that the ventral tegmental area (VTA) is involved in the initiation of, while the nucleus accumbens is in involved in the expression of behavioral sensitization. This hypothesis is supported in part, by studies which demonstrated that behavioral sensitization could be induced by repeated intra-VTA, but not intra-accumbal, administration of amphetamine. The present studies were designed to determine whether repeated intra-VTA cocaine would similarly induce behavioral sensitization. Rats receiving four daily injections of cocaine (1.5, 5 or 15 nmol/side) into the VTA did not show a sensitized behavioral response when challenged with cocaine (15 mg/kg, ip) 1 week later. In contrast to this, repeated injection of the specific dopamine reuptake inhibitor, GBR 12909 (15 nmol/side) produced behavioral sensitization to a challenge injection of cocaine. Repeated injections of the cocaine analog WIN 35,065-2 did not induce behavioral sensitization to cocaine, suggesting that the local anesthetic properties of cocaine were not responsible for the inability of intra-VTA cocaine to induce sensitization. In summary, the data suggest that sensitization to cocaine may involve mechanisms different from amphetamine.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/análogos & derivados , Inhibidores de Captación de Dopamina/farmacología , Piperazinas/farmacología , Área Tegmental Ventral/fisiología , Animales , Cromatografía Líquida de Alta Presión , Cocaína/administración & dosificación , Cocaína/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Inyecciones , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Piperazinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
Over three centuries ago, the French philosopher René Descartes described the pineal gland as "the seat of the soul." However, it was not until the late 1950s that the chemical identity and biosynthesis of melatonin, the principal hormone secreted by the pineal body, were revealed. Melatonin, named from the Greek melanos, meaning black, and tonos, meaning color, is a biogenic amine with structural similarities to serotonin. The mechanisms mediating the synthesis of melatonin are transcriptionally regulated by the photoperiodic environment. Once synthesized, the neurohormone is a biologic modulator of mood, sleep, sexual behavior, reproductive alterations, immunologic function, and circadian rhythms. Moreover, melatonin exerts its regulatory roles through high-affinity, pertussis toxin-sensitive, G-protein (or guanine nucleotide binding protein) coupled receptors that reside primarily in the eye, kidney, gastrointestinal tract, blood vessels, and brain. Additional evidence also indicates a role for melatonin in aging and age-related diseases, probably related to its efficient free radical scavenger (or antioxidant) activity. The potential clinical benefit of melatonin as an antioxidant is remarkable, suggesting that it may be of use in the treatment of many pathophysiological disease states including various cancers, hypertension, pulmonary diseases, and a variety of neurodegenerative diseases such as Alzheimer's disease. This review summarizes the biosynthesis of melatonin and its many endocrine and physiological functions, including its therapeutic potential in human disease states. Emphasis is placed on the recent speculations indicating that this pineal hormone serves as an endogenous antioxidant agent with proficient free radical scavenging activity.
Asunto(s)
Antioxidantes , Melatonina/fisiología , Humanos , Melatonina/biosíntesis , Melatonina/metabolismo , Receptores de Superficie Celular/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de MelatoninaRESUMEN
The present study was designed to assess the effects of acute and repeated cocaine exposure on protein kinase C (PKC) activity and the levels of calcium-dependent isoforms of PKC in mesocorticolimbic and nigrostriatal dopamine brain regions. Animals received repeated injections of saline or cocaine and were challenged with saline or cocaine 24 h or 7 days after the last of their daily injections. Animals were sacrificed 2, 6 or 24 h after the challenge injection and their brains were dissected and used in PKC studies. The data demonstrated that previously reported cocaine-induced increases in PKC activity in the ventral tegmental area are transient and not associated with changes in the levels of calcium-dependent isoforms of PKC. In addition, there was a decrease in membrane-associated PKC activity, with a concomitant increase in the levels of PKCbetaI in the medial prefrontal cortex 24 h after the last injection of cocaine. These data suggest that changes in PKC activity in the ventral tegmental area may be involved in the initiation of sensitization whereas changes in PKC activity in the medial prefrontal cortex may be related to the expression of the sensitized response to cocaine.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Neostriado/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Proteína Quinasa C/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Isoenzimas , Masculino , Neostriado/metabolismo , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
The present studies examined the effects of intra-ventral tegmental area (VTA) injection of SCH 23390, a dopamine (DA) D1 receptor antagonist or 7-OH-DPAT, a DA D2/3 receptor agonist, on cocaine-stimulated motor activity. Intra-VTA SCH 23390 (1.5-15 nmol/side) dose-dependently blocked cocaine-induced motor activity. Thus, 15 nmol/side SCH 23390 completely blocked, while 5 nmol/side attenuated, the motor-stimulant response to cocaine. These doses of SCH 23390 did not alter basal motor activity, suggesting the effects on the motor-stimulant response to cocaine were not the result of a generalized suppression of activity. In contrast to previous studies, intra-VTA 7-OH-DPAT did not alter basal motor activity at any of the doses tested (0.5-15 nmol/side). In addition, intra-VTA 7-OH-DPAT (1.5-15 nmol/side) pretreatment did not significantly alter the motor-stimulant response to cocaine. These data suggest that DA D1 receptors in the VTA may play a role in psychostimulant-induced motor activity. However, the role DA D2/3 receptors in the VTA may have in cocaine-induced motor activity remains unclear.
Asunto(s)
Benzazepinas/farmacología , Cocaína/antagonistas & inhibidores , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/antagonistas & inhibidores , Actividad Motora/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Área Tegmental Ventral/fisiología , Animales , Benzazepinas/administración & dosificación , Cocaína/farmacología , Agonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Inyecciones , Masculino , Ratas , Ratas Sprague-Dawley , Estimulación Química , Tetrahidronaftalenos/administración & dosificación , Área Tegmental Ventral/anatomía & histologíaRESUMEN
Previous studies have suggested that increased protein kinase C activity in the ventral tegmental area (VTA) may play a role in the acute and development of the sensitized behavioral responses to cocaine. The present study was conducted to further characterize the role of protein kinases in the development of sensitization. Animals received injections of saline or the nonspecific protein kinase inhibitor H7 into the VTA before each of their four daily systemic injections of saline or cocaine. Animals were tested for sensitization with a challenge injection of systemic cocaine after a withdrawal period of 24 h or 1 week. Tests for sensitization included monitoring cocaine-induced motor activity and/or dopamine concentrations in the nucleus accumbens, as measured by in vivo microdialysis. Pretreatment with H7 in the VTA attenuated the acute motor stimulant response to cocaine as well as the cocaine-induced increase in extracellular dopamine in the nucleus accumbens. In addition, the augmented increase in dopamine in the nucleus accumbens of cocaine-sensitized animals was prevented in animals pretreated with H7 before each of their daily cocaine injections, when tested after a 24 h withdrawal. However, when tested after a 1 week withdrawal, animals demonstrated sensitization to both the cocaine-induced increase in motor activity and the cocaine-induced increase in dopamine in the nucleus accumbens regardless of whether they received intra-VTA saline or H7 before each of their daily cocaine injections. These data suggest that injection of a protein kinase inhibitor into the VTA delays, but does not prevent the development of cocaine-induced behavioral sensitization.
Asunto(s)
1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/administración & dosificación , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Inhibidores Enzimáticos/administración & dosificación , Tegmento Mesencefálico/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Dopamina/metabolismo , Inhibidores Enzimáticos/farmacología , Inyecciones , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The role of protein kinase activity in the development of behavioral sensitization was examined by injecting the protein kinase inhibitor H7 into the A10 dopamine region 5 min before each of four daily peripheral injections of cocaine. Animals then received a challenge injection of cocaine 24 h after the daily treatments. Intra-A10 injection of H7 attenuated the acute motor-stimulant response to cocaine. Daily injections of H7 prevented the development of an enhanced motor-stimulant response, which occurred with daily cocaine injections, such that the animals' behavioral response was similar to that of animals receiving their first cocaine injection. These data suggest that increased protein kinase activity in the A10 dopamine region may be important in the development of behavioral sensitization to cocaine.
Asunto(s)
Cocaína/farmacología , Isoquinolinas/farmacología , Sistema Límbico/fisiología , Actividad Motora/efectos de los fármacos , Piperazinas/farmacología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Animales , Inyecciones , Masculino , Proteína Quinasa C/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
Cocaine produces a motor-stimulant response in part by its actions within the mesolimbic dopamine system. Repeated exposure to cocaine induces an augmented motor activity response which is termed behavioral sensitization, or reverse tolerance. Previous studies have suggested that sensitization may result from increased dopamine neuronal activity in the A10 region; the origin of the mesolimbic dopamine system. However, the exact mechanisms involved in the development of behavioral sensitization remain to be elucidated. Studies on other forms of sensitization in the nervous system suggest a critical role for increased protein kinase C (PKC) activity in the development of the sensitized response. As a first step in examining the role of PKC in cocaine-induced behavioral sensitization, the effect of intra-A10 administration of a PKC inhibitor, H7, on the acute motor-stimulant response to cocaine was studied. Intra-A10 injections of H7 dose-dependently (1.0-30.0 nmol/side) inhibited cocaine (15.0 mg/kg)-induced motor activity. Pretreatment with H7 (30.0 nmol/side) also blocked the cocaine-induced rise of extracellular dopamine in a terminal region of the mesolimbic dopamine system, the nucleus accumbens, as measured by in vivo microdialysis. These data suggest that activation of protein kinases may be important in cocaine-induced motor activity.
Asunto(s)
Cocaína/farmacología , Dopamina/metabolismo , Isoquinolinas/farmacología , Actividad Motora/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/fisiología , Piperazinas/farmacología , Proteína Quinasa C/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina , Análisis de Varianza , Animales , Cocaína/antagonistas & inhibidores , Isoquinolinas/administración & dosificación , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiología , Masculino , Microdiálisis/métodos , Microinyecciones , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Piperazinas/administración & dosificación , Proteína Quinasa C/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
Dopamine neurons in the ventral mesencephalon are under the inhibitory influence of dopamine D2 and gamma-aminobutyric acidB receptors. In a previous report, we demonstrated that intra-A10 injections of baclofen, a gamma-aminobutyric acidB agonist, could inhibit the motor-stimulant response to cocaine and amphetamine. In order to further extend these results, we examined the effects of injection of the D2 agonist quinpirole into the A10 region on cocaine- and amphetamine-stimulated motor activity. The results of this study showed that intra-A10 quinpirole dose-dependently decreased locomotor activity. In addition, an intra-A10 injection of 0.3 nmol/microliter quinpirole, a dose chosen for its near threshold effect, could block the motor-stimulant response to a low dose of amphetamine (0.5 mg/kg) and attenuate the response to moderate doses (1.0 and 2.0 mg/kg). Cocaine-stimulated motor activity, at all doses tested (7.5, 15.0 and 30.0 mg/kg), was not altered by intra-A10 quinpirole pretreatment. In vivo microdialysis revealed that quinpirole was unable to block the amphetamine-induced increase in extracellular dopamine concentrations within the nucleus accumbens, despite blocking the motor-stimulant response. It is suggested that the different mechanisms of action of cocaine and amphetamine, uptake blocker vs. releaser or longloop vs. shortloop feedback inhibition of A10 dopamine neurons, respectively, may account for the differential effects that quinpirole had in blocking the motor-stimulant response to these psychostimulants.
Asunto(s)
Anfetamina/antagonistas & inhibidores , Cocaína/farmacología , Dopaminérgicos/farmacología , Dopamina/metabolismo , Ergolinas/farmacología , Actividad Motora/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopaminérgicos/administración & dosificación , Ergolinas/administración & dosificación , Masculino , Microinyecciones , Quinpirol , Ratas , Ratas EndogámicasRESUMEN
1. Male rats received cannula implants above the nucleus accumbens for monitoring extracellular concentrations of dopamine via in vivo microdialysis. 2. Daily injections with cocaine led to an augmentation in both the behavioral response and the neurochemical response (i.e. cocaine-induced increase in extracellular dopamine within the nucleus accumbens) to this drug. 3. Pertussis toxin injections into the A10 region led to sensitized behavioral and neurochemical responses to an acute injection of cocaine. 4. Prior exposure to footshock stress augmented the cocaine-induced increase of motor activity and of extracellular dopamine within the nucleus accumbens. 5. These data suggest that treatments which lead to behavioral sensitization also lead to sensitization within the mesolimbic dopamine system as measured by an augmented dopamine release in the nucleus accumbens.
Asunto(s)
Núcleo Accumbens/fisiología , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Cocaína/farmacología , Diálisis , Dopamina/metabolismo , Electrochoque , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Pentilenotetrazol/farmacología , Toxina del Pertussis , Ratas , Ratas Endogámicas , Factores de Virulencia de Bordetella/farmacologíaRESUMEN
Inhibitory regulation of dopamine neurons is mediated by dopamine autoreceptor and gamma-aminobutyric acidB receptor opening of potassium channels. Increased potassium conductance by either receptor is G protein dependent. To evaluate the role of G proteins in vivo, pertussis toxin (PTX) was microinjected into the A10 dopamine region and changes in dopamine metabolism and synthesis measured. PTX produced an elevation in dopamine metabolism and synthesis in the A10 region and nucleus accumbens for up to 4 days after injection. By day 7 the levels of the dopamine precursor and metabolites had returned to normal. A less consistent increase was also measured in the A9 dopamine region and the prefrontal cortex. Although dopamine synthesis and metabolism had returned to normal by day 7, the in vitro ADP-ribosylation of G proteins in the A10 region by PTX remained depressed by approximately 50% from day 1 to day 14 after administration, returning to normal by day 30. The data suggest that in vivo ribosylation of G proteins may lead to a short-term attenuation of the tonic inhibitory control of dopamine neurons, which can be compensated for by PTX-insensitive mechanisms.
Asunto(s)
Dopamina/biosíntesis , Mesencéfalo/metabolismo , Toxina del Pertussis , Factores de Virulencia de Bordetella/farmacología , Adenosina Difosfato Ribosa/metabolismo , Animales , Catálisis , Dopamina/metabolismo , Inmunohistoquímica , Masculino , Núcleo Accumbens/metabolismo , Núcleos del Rafe/metabolismo , Ratas , Ratas Endogámicas , Núcleo Rojo/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Rats pretreated with repeated footshock demonstrated an augmentation in cocaine-induced locomotor activity and extracellular dopamine concentrations in the nucleus accumbens. Pertussis toxin injections into the A10 region also led to cocaine- induced enhancement in extracellular dopamine levels in the nucleus accumbens and a strong trend towards elevated locomotor activity. Repeated treatment with cocaine led to a blockade of the footshock-induced increase in extracellular dopamine in the medial prefrontal cortex. Prior treatment with pertussis toxin microinjection into the A10 region resulted in enhanced levels of tissue dopamine metabolites in the medial prefrontal cortex following footshock stress. The pertussis toxin- and daily stress-induced behavioral and neurochemical sensitization suggest that behavioral sensitization to these stimuli involves a loss of inhibitory tone on A10 dopamine cells.
Asunto(s)
Cocaína/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Diálisis , Dopamina/metabolismo , Electrochoque , Ácido Homovanílico/metabolismo , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Toxina del Pertussis , Ratas , Ratas Endogámicas , Estrés Psicológico/fisiopatología , Factores de Virulencia de Bordetella/farmacologíaRESUMEN
We have previously demonstrated that depletion of forebrain norepinephrine (NE) led to an attenuation of neophobia in a novel environment, as defined by a greater preference for novel food over familiar food. To study further the role of forebrain NE in neophobia we chronically infused noradrenergic receptor ligands or forskolin into the lateral ventricles of sham and 6-hydroxydopamine dorsal bundle lesioned rats. Chronic NE infusions into lesioned animals reversed the lesion-induced shift in relative food preference. The beta receptor agonist isoproterenol had moderate effects similar to those of NE in lesioned and sham animals. Phenylephrine, an alpha-1 agonist, was without effect. Forskolin, an adenylate cyclase activator, mimicked the effects of NE infusions. These data suggest a role for noradrenergic stimulation of adenylate cyclase in neophobia.