RESUMO
The role of the ventral pallidum and the dorsal striatum in mediating the rewarding effects of the delta receptor specific agonist [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE) were evaluated in the rat using the intracranial self-stimulation paradigm. Reward shifts were indicated by the change in frequency required to maintain half-maximal responding while motor/performance changes were identified by increases or decreases in the maximum responding. Each hour-long test session consisted of three identical, consecutive 20 min rate-frequency curves. In an effort to ascertain possible heterogeneity of function along the rostrocaudal axis, DPDPE (0.0 nmol = saline dose, 0.3 nmol = low dose, 1.0 nmol = medium dose, 3.0 nmol = high dose) was microinjected into either the rostral or caudal region of the two structures. Microinjections into the caudate were positioned directly above the ventral pallidum placements resulting in centromedial or caudomedial caudate placements. DPDPE microinjections into the rostral ventral pallidum resulted in a significant reward increase (28% increase or -0.14 log Hg shift) only at the high dose. In contrast, caudal ventral pallidal DPDPE microinjections showed a dose-response effect with reward increases of 19, 22 and 31% (-0.09, -0.11 and -0.16 log Hz) for the low, medium and high dose, respectively. DPDPE microinjections into the centromedial caudate resulted in a large reward increase (29% or -0.15 log Hz) at the high dose, while caudomedial caudate DPDPE microinjections had no effect on reward. Motor/performance effects tended to follow the pattern of reward effects, with most regions showing motor increases ranging from 25 to 75% over baseline activity. The only exception was found in the caudomedial caudate, where microinjections of the high dose of DPDPE resulted in an approximate 20% suppression of motor/performance activity. These results demonstrate that the ventral pallidum and the mediocentral caudate play a role in modulating opiate rewards, and adds to the growing body of literature regarding the regional heterogeneity within the caudate and ventral pallidum.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Corpo Estriado/fisiologia , Encefalinas/farmacologia , Receptores Opioides delta/fisiologia , Recompensa , Animais , Núcleo Caudado/fisiologia , D-Penicilina (2,5)-Encefalina , Masculino , Microinjeções , Ratos , Receptores Opioides delta/agonistas , AutoestimulaçãoRESUMO
The ventral pallidum receives a major projection from the nucleus accumbens, a heavily studied terminus of the mesolimbic dopamine system that is known to be involved in a variety of reward and behavioral functions. Recently, ventral pallidum microinjections of the mu opiate receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol-enkephalin (DAMGO) have been shown to increase motor activity while ventral pallidum lesions have been shown to reduce opiate and cocaine self-administration behaviors. These results suggest a possible continuation of the mesolimbic reward/motor circuit from the nucleus accumbens into the ventral pallidum. This study investigated the effects of ventral pallidum DAMGO microinjections on reward and motor/performance through the use of the intracranial self-stimulation rate-frequency curve-shift paradigm. Microinjections of DAMGO (vehicle, 0.03 nmol, and 0.33 nmol) were administered bilaterally in a random dose order with a minimum of 3 days between injections. Rats were tested over three consecutive rate-frequency curves immediately following the opiate microinjections to investigate the time course of drug effects. DAMGO microinjections in the rostral ventral pallidum produced decreases in reward and motor/performance when compared to normal baseline activity or vehicle microinjections. In contrast, DAMGO microinjections into the caudal ventral pallidum produced increases in reward and motor/performance. These data confirm a role for the ventral pallidum in limbic function and extend it to intracranial self-stimulation reward. They also suggest reward modulation in the ventral pallidum is a regionally heterogeneous function and that the rostral ventral pallidum may be a transition area between the nucleus accumbens and the ventral pallidum.
Assuntos
Analgésicos/farmacologia , Encefalinas/farmacologia , Globo Pálido/fisiologia , Receptores Opioides mu/fisiologia , Recompensa , Autoestimulação , Análise de Variância , Animais , Encéfalo/fisiologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Encefalinas/administração & dosagem , Globo Pálido/efeitos dos fármacos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Especificidade de Órgãos , Ratos , Receptores Opioides mu/efeitos dos fármacos , Reforço PsicológicoRESUMO
Microiontophoresis was used to investigate the influence of morphine on the GABA- and glutamate-evoked responses of ventral pallidal neurons recorded extracellularly from chloral hydrate-anesthetized rats. Of the GABA-sensitive neurons (50 of 69 tested) in the ventral pallidum, all displayed a decreased firing rate when GABA was applied, whereas all of the glutamate-sensitive neurons (29 of 40 tested) increased neuronal activity in the presence of glutamate. The majority of ventral pallidal cells tested (65 of 83) were sensitive to iontophoretically applied morphine, and both increases and decreases in neuronal activity were observed. The ability of morphine to alter the ratio between amino acid-evoked activity ("signal") and spontaneous firing ("noise") was used as an indicator of morphine modulation. A morphine subthreshold ejection current, i.e. one that did not change spontaneous firing rate, and a morphine ejection current that produced approximately 50% of the maximum opioid-induced neuronal response were chosen for this evaluation. When morphine was co-iontophoresed with GABA or glutamate, attenuation of the amino acid signal-to-noise ratio was generally seen, though some potentiations were observed. These changes were independent of the direction of morphine-induced changes in spontaneous firing rate. Both sub- and suprathreshold ejection currents were capable of affecting GABA- and glutamate-evoked responses. These data suggest that morphine is a robust ventral pallidal neuromodulator. As ventral pallidal amino acid activity is important in the integration of sensorimotor information, opioid modulation of amino acid transmission in the ventral pallidum may have a profound effect on this integration.
Assuntos
Analgésicos Opioides/farmacologia , Globo Pálido/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Morfina/farmacologia , Ácido gama-Aminobutírico/fisiologia , Animais , Eletrofisiologia , Globo Pálido/citologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Published descriptions of the topography of cardiac ganglia in the human heart are limited and present conflicting results. This study was carried out to determine the distribution of cardiac ganglia in adult human hearts and to address these conflicts. Hearts obtained from autopsies and heart transplant procedures were sectioned, stained, and examined. Results indicate that the largest populations of cardiac ganglia are near the sinoatrial and atrioventricular nodes. Smaller collections of ganglia exist on the superior left atrial surface, the interatrial septum, and the atrial appendage-atrial junctions. Ganglia also exist at the base of the great vessels and the base of the ventricles. The right atrial free wall, atrial appendages, trunk of the great vessels, and most of the ventricular myocardium are devoid of cardiac ganglia. These findings suggest modifications to surgical procedures involving incisions through regions concentrated with ganglia to minimize arrhythmias and related complications. Repairs of septal defects, valvular procedures, and congenital reconstructions, such as the Senning and Fontan operations, involve incisions through areas densely populated with cardiac ganglia. The current standard procedure for orthotopic heart transplantation severs cardiac ganglia and their projections to nodal and muscular tissue. One modification of the current heart transplantation procedure, involving bicaval anastomosis, preserves atrial anatomy and the cardiac ganglia. Preservation of cardiac ganglia within the donor heart may provide additional neuronal substrate for intracardiac processing and targets for regenerating nerve fibers to the donor heart.
Assuntos
Gânglios/anatomia & histologia , Coração/inervação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Parassimpático/anatomia & histologiaRESUMO
Differences in pharmacology, anatomical connections, and receptor densities between the "core" and "shell" of the nucleus accumbens suggest that behavioral activity normally modulated by the accumbens, such as reward and motor functions, may be differentially regulated across the mediolateral axis. This study investigated the effects of opiate receptor-specific agonists on reward and motor functions in either the accumbens core or shell, using the intracranial self-stimulation (ICSS) rate-frequency curve-shift method. Microinjections of the mu opiate receptor-specific agonist, DAMGO (vehicle, 0.03 nmol, and 0.3 nmol), or the delta opiate receptor-specific agonist DPDPE (vehicle, 0.3 nmol, 3.0 nmol), were administered bilaterally in a random dose order with a minimum of 3 days between injections. Rats were tested over three consecutive 20-min rate-frequency curves immediately following a microinjection to investigate the time course of drug effects. Both opiate agonists decreased the ICSS frequency necessary to maintain half-maximal response rates when injected into the medial and ventral shell region of the accumbens. However, DAMGO microinjections into the lateral accumbens core or the control site of the caudate increased the frequency necessary to elicit half-maximal response rates, while DPDPE microinjections into these regions had no effect. Evaluation of motor effects show that administration of DAMGO resulted in a suppression of activity in all locations. In contrast, DPDPE microinjections resulted in little or no effect on lever pressing activity at any location.
Assuntos
Analgésicos/farmacologia , Condicionamento Operante/efeitos dos fármacos , Encefalinas/farmacologia , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina , D-Penicilina (2,5)-Encefalina , Masculino , Microinjeções , Ratos , Ratos Endogâmicos , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Fatores de TempoRESUMO
The role of ventral striatum in the maintenance and transmission of a hypothalamic intracranial self-stimulation (ICSS) reward signal was investigated using the rate-frequency multiple-curve shift paradigm. The excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the nucleus accumbens (15 micrograms per side), the ventral pallidum (15 micrograms per side) or the juncture between the two structures (20 micrograms per side) creating three lesion groups. Both the nucleus accumbens (NAC) lesion group and the ventral pallidum (VP) lesion group displayed substantial NMDA-induced damage which was generally restricted to the intended limbic structure. The NMDA lesions in the third group displayed extensive damage to both the NAC and VP, as intended, but also typically diffused into adjacent medial structures. NMDA-induced lesions in all groups caused a suppression in motor/performance activity at all currents tested. Contrary to motor effects, reward efficacy was relatively unaffected for the NAC and VP groups. The lack of reward effects may be due to plasticity of neuronal systems and redundancy of circuit connections. However, this explanation is questionable given the fact that NMDA lesions which encompassed both the NAC and VP had little effect on reward efficacy. The above data suggests that the nucleus accumbens and the ventral pallidum are not critical for ICSS rewards stimulation and that hypothalamic ICSS reward signals are processed downstream from these limbic structures.
Assuntos
Globo Pálido/fisiologia , Região Hipotalâmica Lateral/fisiologia , N-Metilaspartato/farmacologia , Núcleo Accumbens/fisiologia , Recompensa , Autoestimulação , Animais , Mapeamento Encefálico , Globo Pálido/efeitos dos fármacos , Globo Pálido/patologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/patologia , Ratos , Ratos EndogâmicosRESUMO
The role of the nucleus accumbens (NAC) and ventral pallidum (VP) in food reward modulation was investigated using Heyman's [24] curve fitting approach in food deprived rats. All rats were maintained at 80% normal body weight, and trained to lever press for food reinforcement. Each rat was tested daily with a series of four variable-interval (VI) reinforcement schedules (80, 40, 20, and 10 s) designed to approximate an exponential distribution, and randomly administered in ascending or descending order. The maximum response rate (Rmax) and the reinforcement rate required to maintain half-maximal responding (Re50) were recorded for each rat's daily test session. Following the establishment of baseline responding, the excitotoxin N-methyl-D-aspartic acid (NMDA) was bilaterally administered into the NAC (30 micrograms per side) or VP (20 micrograms per side) over a 10 min period. Both groups displayed substantial damage to the intended structure, with the lateral regions typically sustaining more damage than medial regions, and minor damage to surrounding areas. When tested at three weeks post-lesion, a suppression of motor activity was evident in all animals when compared to pre-lesion baseline. Moreover, in almost all rats, Re50 decreased, suggesting that the rewarding efficacy of food had increased. These data are surprising, given the extensive literature on the relationship between damage in the NAC and loss of reward efficacy. However, based on pharmacological and anatomical findings, both brain regions have been divided into several subregions. Behavioral studies suggest that these subregions may differentially regulate reward and motor functions. The results from the present study suggest that (1) both the NAC and VP are involved in the modulation of food reward, (2) that lateral subregions in each structure may function to dampen food reward efficacy, and (3) that medial subregions may enhance food reward.
Assuntos
Ração Animal , Privação de Alimentos/fisiologia , Globo Pálido/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Animais , Comportamento Animal/efeitos dos fármacos , Globo Pálido/efeitos dos fármacos , Masculino , N-Metilaspartato/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Reforço PsicológicoRESUMO
Acute activation of opioid receptors in the ventral pallidum increases motor behaviors in rats. The present study was designed to investigate the possibility that the ventral pallidum influences motor responses induced by chronic opiate treatments and to examine the receptors that may be involved in such an effect. For five consecutive days, ambulations were quantified after rats received once-daily intraperitoneal (i.p.) injections of morphine (10 mg/kg) or saline following bilateral intra-ventral pallidal injections of either saline (0.5 microl/hemisphere), the mu antagonist CTOP (2. 1 microg/0.5microl/hemisphere), or the D1 antagonist SCH23390 (0.25 microg/0.5microl/hemisphere). Behavioral sensitization to an acute morphine challenge (10 mg/kg i.p.) was assessed 72 h after terminating the repeated treatment regimen. Rats who repeatedly received the intra-ventral pallidal saline + i.p. morphine exhibited increases in ambulations during the chronic treatment protocol and this effect was greatly enhanced (i.e., sensitized) following the post withdrawal acute morphine challenge. Rats repeatedly treated with intra-ventral pallidal CTOP + i.p. morphine did not display a motor response either during the chronic treatment regime or to the acute morphine challenge; an effect not seen when CTOP was injected into brain structures located dorsal to the ventral pallidum. The rats repeatedly treated with intra-ventral pallidal injections of SCH23390 + i.p. morphine demonstrated a motor response during the chronic protocol but the magnitude of this response was not significantly enhanced by the acute morphine challenge. These results demonstrate that: 1) mu opioid and D1-like dopamine receptors in the ventral pallidum influence the increase in locomotion that occurs during repeated morphine treatments; and 2) mu opioid (but not D1) receptors in the ventral pallidum are important in the postwithdrawal sensitized response to morphine. Such observations indicate that the ventral pallidum plays a critical role in morphine-induced behavioral sensitization.
Assuntos
Comportamento Animal/efeitos dos fármacos , Globo Pálido/efeitos dos fármacos , Morfina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Receptores Opioides mu/efeitos dos fármacos , Animais , Comportamento Animal/fisiologia , Dopamina/metabolismo , Esquema de Medicação , Globo Pálido/citologia , Globo Pálido/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
The present study characterized the responses of ventral pallidal (VP) neurons to intravenously (iv) administered cocaine (0.003, 0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg) in chloral hydrate-anesthetized rats. Eighty-four percent (16/19) of the tested neurons displayed rate changes following cocaine administration. Fifty-three percent responded by increasing firing rate, with an EMAX of 217 +/- 26% of basal activity and an ED50 of 0.07 +/- 0.03 mg/kg. Neurons that responded with a rate decrease (26%) had an EMAX of 14.3 +/- 9.0% of basal control and an ED50 of 0.04 +/- 0.02 mg/kg. One neuron (5%) displayed a biphasic response pattern. Haloperidol (0.2 mg/kg) attenuated cocaine-induced effects in 90% of the tested neurons. Given the responsiveness of VP neurons to cocaine, the extensive innervation of the VP by the nucleus accumbens (NAC), and the importance of the NAC in regulating cocaine-induced effects, it is likely that NAC activity may affect VP responses to cocaine. To test this possibility, the influence of NAC on cocaine-induced VP activity was evaluated. Unilateral inactivation of the NAC with microinjections of procaine (40 mu g/2 mu l/2 min) did not alter the proportion of VP neurons responsive to subsequent systemic administration of cocaine (0.1, 1.0 mg/kg iv) or the EMAX for those neurons showing a rate decrease. However, for the population of neurons showing a cocaine-induced rate increase, intra-NAC procaine significantly enhanced EMAX to 392 +/- 74% of control. These data suggest that the ability of VP neurons to respond to iv cocaine is independent of the NAC. However, the magnitude of the cocaine-induced effect appears to be dependent on NAC influences.
Assuntos
Cocaína/farmacologia , Globo Pálido/citologia , Globo Pálido/efeitos dos fármacos , Entorpecentes/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Potenciais de Ação/efeitos dos fármacos , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Animais , Cocaína/administração & dosagem , Cocaína/antagonistas & inibidores , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Injeções Intravenosas , Masculino , Microinjeções , Entorpecentes/administração & dosagem , Procaína/administração & dosagem , Procaína/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Microiontophoresis was used to investigate the influence of dopamine on GABA- and glutamate-induced responses from ventral pallidal neurons recorded extracellularly in chloral hydrate-anaesthetized rats. Modulation was determined by comparing dopamine-induced alterations in amino acid-induced activity ('signal') with dopamine-induced effects on spontaneous firing ('noise'). A dopamine ejection current-response curve was generated to determine the current levels that did not alter spontaneous firing ('subthreshold') and those that produced approximately 50% of the maximal dopamine-induced response (ECur50). Co-iontophoresis of dopamine with GABA generally diminished the inhibitory influence of GABA on pallidal neuron firing; 70% of neurons tested with ECur50 dopamine demonstrated a decrease in the signal-to-noise ratio whereas 10% displayed an increase. At subthreshold dopamine ejection currents, 59% of neurons responded with a decrease and 18% responded with an increase in the GABA signal-to-noise ratio. When ECur50 dopamine was co-iontophoresed with glutamate, 84% of the neurons displayed a decrease in the signal-to-noise ratio for glutamate-evoked excitations whereas 11% demonstrated an increase. Subthreshold dopamine ejection currents decreased the signal-to-noise ratio in 62% of the ventral pallidal neurons excited by glutamate and increased the ratio in 23%. These data illustrate that dopamine substantially alters GABA- and glutamate-evoked responses even at ejection currents that are below those necessary to change spontaneous firing. Thus, it appears that neuromodulation is an important means by which dopamine influences ventral pallidal neuronal activity.
Assuntos
Dopamina/farmacologia , Globo Pálido/efeitos dos fármacos , Globo Pálido/fisiologia , Ácido Glutâmico/farmacologia , Ácido gama-Aminobutírico/farmacologia , Animais , Eletrofisiologia , Iontoforese , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Phosphatidylethanolamine N-methyltransferase (PEMT) activity was measured by a radioenzymatic assay in homogenates of brain and liver obtained from Sprague Dawley rats fed a choline-free or control (0.3 g/kg of choline chloride) diet for seven days. Choline deficiency increased PEMT activity in the liver of male rats by 34% but had no effect on hepatic PEMT in females. In contrast, brain PEMT activity was increased in brain of choline deficient females (by 49%) but was unaltered in males. Activation of the PE methylation pathway in female brain may constitute a compensatory mechanism to sustain PC synthesis during choline deficiency.
Assuntos
Encéfalo/enzimologia , Deficiência de Colina/enzimologia , Fígado/enzimologia , Metiltransferases/metabolismo , Análise de Variância , Animais , Colina/administração & dosagem , Colina/farmacologia , Ativação Enzimática , Feminino , Masculino , Fosfatidiletanolamina N-Metiltransferase , Ratos , Ratos Sprague-Dawley , Caracteres SexuaisRESUMO
BACKGROUND: Cardiac ganglia were originally thought to contain only cholinergic neurons relaying parasympathetic information from preganglionic brain stem neurons to the heart. Accumulating evidence, however, suggests that cardiac ganglia contain a heterogeneous population of neurons that synthesize or respond to several different neurotransmitters and neuropeptides. Reports regarding monoamine and histamine synthesis and neurotransmission within cardiac ganglia, however, present conflicting information or are limited in number. Furthermore, very few studies have examined the neurochemistry of adult human cardiac ganglia. The purpose of this study was, therefore, to determine whether monoamine- and histamine-synthesizing enzymes and neurotransmitters exist within neurons of adult human cardiac ganglia. METHODS AND RESULTS: Human heart tissue containing cardiac ganglia was obtained during autopsies of patients without cardiovascular pathology. Avidin-biotin complex immunohistochemistry was used to demonstrate tyrosine hydroxylase, L-dopa decarboxylase, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, tryptophan hydroxylase, and histidine decarboxylase immunoreactivity within neurons of cardiac ganglia. Dopamine, norepinephrine, serotonin, and histamine immunoreactivity was also found in ganglionic neurons. Omission or preadsorption of primary antibodies from the antisera and subsequent incubation with cardiac ganglia abolished specific staining in all cases examined. CONCLUSIONS: Our results suggest that neurons within cardiac ganglia contain enzymes involved in the synthesis of monoamines and histamine and that they contain dopamine, norepinephrine, serotonin, and histamine immunoreactivity. Our findings suggest a putative role for monoamine and histamine neurotransmission within adult human cardiac ganglia. Additional, functional evidence will be necessary to evaluate what the physiological role of monoamines and histamine may be in neural control of the adult human heart.