RESUMEN
RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Bupropión/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Fumar/psicología , Adulto , Afecto/efectos de los fármacos , Euforia/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Desempeño Psicomotor/efectos de los fármacos , Caracteres Sexuales , Cese del Hábito de Fumar/psicología , Síndrome de Abstinencia a SustanciasRESUMEN
Baclofen has been reported in uncontrolled clinical studies to reduce craving for abused drugs and reduce their rewarding effects. The objective of the present study was to measure the acute effects of a single dose of baclofen on cigarette smoking, craving for nicotine, cigarette taste, and smoking satisfaction. Tobacco smokers (n = 16) who were not trying to quit received baclofen (20 mg) or placebo after overnight abstinence during two laboratory sessions in a within-subjects design. We measured the subjective effects of baclofen on mood and self-reported ratings of craving for nicotine, and on the number of cigarettes smoked of the subjects' preferred brand during a 3-h ad libitum smoking period. Baclofen did not change the number of cigarettes smoked by the subjects nor did it change ratings of nicotine craving. However, baclofen altered the sensory properties of smoked cigarettes (e.g., increasing ratings of 'harsh' and decreasing ratings of 'like cigarette's effects'). It also produced mild sedative-like subjective effects, such as increases in feeling 'relaxed'. Thus, although baclofen did not reduce cigarette craving or smoking in the present study, it did produce some mood-altering effects and changes in sensory aspects of smoking that may facilitate smoking cessation.
Asunto(s)
Baclofeno/uso terapéutico , Agonistas del GABA/uso terapéutico , Autorrevelación , Prevención del Hábito de Fumar , Tabaquismo/rehabilitación , Enfermedad Aguda , Adulto , Afecto/efectos de los fármacos , Baclofeno/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Agonistas del GABA/administración & dosificación , Humanos , Masculino , Nicotina/efectos adversos , Índice de Severidad de la Enfermedad , Cese del Hábito de Fumar , Síndrome de Abstinencia a Sustancias/etiología , Encuestas y CuestionariosRESUMEN
RATIONALE: Recent preclinical and clinical data suggest that co-administration of a serotonin-1A (5-HT-1A) receptor antagonist with an antidepressant drug has greater therapeutic efficacy than when the antidepressant drug is administered alone. OBJECTIVE: The purpose of the present experiment was to determine whether pretreatment with the selective 5-HT-1A receptor antagonist N-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY-100635; 0.003, 0.03, 0.3 mg/kg, s.c.) would alter the effects of the antidepressant fluoxetine (2.5-10 mg/kg, i.p.) on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule. The DRL 72-s schedule is a behavioral screen selective and sensitive to antidepressant drugs. RESULTS: WAY-100635 had no behavioral effects on its own. The lower doses of fluoxetine (2.5 mg/kg and 5 mg/kg) had no effects, but 10 mg/kg increased reinforcement rate without affecting response rate. The increase in reinforcement rate was blocked by pretreatment with 0.03 mg/kg and 0.3 mg/kg WAY-100635, although the combination of fluoxetine and WAY-100635 also significantly reduced response rate. Interestingly, 0.003 mg/kg or 0.03 mg/kg WAY-100635 administered with 5.0 mg/kg fluoxetine increased reinforcement rate, even though this dose of fluoxetine had no effect on performance. CONCLUSION: These data demonstrate that the behavioral effects of fluoxetine are modified by 5-HT-1A receptor blockade.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Fluoxetina/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT1 , Esquema de RefuerzoRESUMEN
High (+/-)-8-hydroxy-dipropylaminotetralin HBr (8-OH-DPAT)-sensitive (HDS) rats and low 8-OH-DPAT-sensitive (LDS) rats were selectively bred for differences in sensitivity to the hypothermic effect of the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-OH-DPAT in 30 to 35-day-old rat pups. These rats were trained on the differential reinforcement of low rate 72-s operant schedule. On this schedule, LDS rats had a higher response rate and a lower reinforcement rate than HDS rats. Drugs with primary action on the 5-HT system, 8-OH-DPAT, ketanserin, and fluoxetine, decreased response rate of HDS and LDS rats but increased the reinforcement rate of only the LDS rats. However, a drug with primary action on the norepinephrine system, desipramine, decreased response rate and increased reinforcement rate of HDS and LDS rats, suggesting that norepinephrine function was similar in the two lines of rats. The finding with desipramine indicates that increases in reinforcers on the differential reinforcement of low rate 72-s task are not simply dependent on baseline response or reinforcement rate. We also observed that 8-OH-DPAT engenders a greater hypothermic response in adult (90-day-old) HDS rats than in adult LDS rats. The 5-HT(1A) receptor antagonist WAY-100635 antagonized the hypothermic response. Tissue levels of 8-OH-DPAT from several brain regions in LDS and HDS rats did not differ from each other at either 15- or 30-min postinjection. Because the LDS and HDS rats have different responses to 5-HT-acting drugs, these rats may be useful for studying the role of the serotonergic system in depression.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Conducta Animal/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/análisis , Inhibidores de Captación Adrenérgica/farmacología , Factores de Edad , Animales , Monoaminas Biogénicas/análisis , Química Encefálica/efectos de los fármacos , Condicionamiento Operante , Desipramina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fluoxetina/farmacología , Hipotermia/inducido químicamente , Ketanserina/farmacología , Masculino , Ratas , Receptores de Serotonina/clasificación , Esquema de Refuerzo , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Factores de TiempoRESUMEN
Three experiments were conducted to investigate the behavioral functions of dopamine in the nucleus accumbens and ventrolateral striatum. In the first experiment, dialysis probes were implanted in the nucleus accumbens or ventrolateral striatum of rats previously trained to respond on fixed interval lever pressing schedules for food reinforcement. During the dialysis test session, both schedule- and site-dependent effects on dopamine release were observed. Overall, lever pressing on a fixed interval 30-s schedule produced a greater increase in extracellular dopamine than did responding on a fixed interval 120-s schedule. The fixed interval 30-s schedule was also accompanied by a higher rate of lever pressing. Rats with nucleus accumbens probe placements showed significantly higher increases in dopamine release than rats with ventrolateral striatal placements. An additional dialysis experiment showed that baseline levels of dopamine were suppressed by 1.0 microM tetrodotoxin to a similar extent in the nucleus accumbens and ventrolateral striatum. In the third experiment, 6-hydroxydopamine was injected locally into either the nucleus accumbens or the ventrolateral striatum in order to deplete dopamine. Nucleus accumbens dopamine depletions produced only a minor decrease in operant responding, whereas rats with ventrolateral striatal dopamine depletions showed low levels of responding that differed from both the control group and from the group that had accumbens dopamine depletions. Thus, these results are somewhat paradoxical, in that the structure that showed the greatest increase in dopamine release (i.e. the nucleus accumbens) was also the terminal region at which dopamine depletions had very little effect on operant responding. Ventrolateral striatal dopamine appears to be largely permissive over lever pressing, in that normal levels of dopamine in the ventrolateral striatum are critical for responding, although dopamine levels do not fluctuate much during behavioral sessions.
Asunto(s)
Conducta Animal/fisiología , Cuerpo Estriado/fisiología , Dopamina/fisiología , Núcleo Accumbens/fisiología , Animales , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Masculino , Microdiálisis , Microinyecciones , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxidopamina/farmacología , Ratas , Ratas Sprague-Dawley , Tetrodotoxina/farmacologíaRESUMEN
The anticholinesterase tacrine induces tremulous jaw movements in rats, and considerable evidence indicates that this response is dependent upon ventrolateral striatal mechanisms. Three experiments were conducted to study the relation between ventrolateral striatal acetylcholine and the production of tremulous jaw movements. In Experiment 1, intracranial microinjection of the acetylcholine synthesis inhibitor hemicholinium-3 into the ventrolateral neostriatum reduced tremulous jaw movements induced by 5.0 mg/kg tacrine. Microinjection of hemicholinium into a cortical site dorsal to striatum (Experiment 2) was without significant effect upon tacrine-induced tremulous jaw movements. In Experiment 3, rats were implanted with dialysis probes in the ventrolateral striatum to measure extracellular levels of acetylcholine during tacrine-induced jaw movements. Tacrine (2.5-5.0 mg/kg) increased both extracellular acetylcholine and tremulous jaw movements. The 5.0 mg/kg dose of tacrine produced a substantial increase in ventrolateral striatal acetylcholine levels (324% of baseline within 30 min). Across all tacrine-treated rats there was a significant linear correlation between tremulous jaw movements and acetylcholine levels (r = +0.56) during the first 30-min postinjection period. This correlation was largely due to the group that received 5.0 mg/kg tacrine; within this group, there was a very high correlation (r = +0.87) between tremulous jaw movements and acetylcholine levels in the first sample after injection. These data are consistent with the notion that tremulous jaw movements induced by tacrine are mediated by ventrolateral striatal acetylcholine. Moreover, these results suggest that dialysis methods could be used to monitor the relation between striatal acetylcholine and tremulous movements induced by a variety of different conditions.
Asunto(s)
Acetilcolina/fisiología , Inhibidores de la Colinesterasa/farmacología , Maxilares/fisiología , Movimiento/efectos de los fármacos , Neostriado/fisiología , Tacrina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Colinérgicos/administración & dosificación , Colinérgicos/farmacología , Inhibidores de la Colinesterasa/administración & dosificación , Espacio Extracelular/metabolismo , Hemicolinio 3/administración & dosificación , Hemicolinio 3/farmacología , Masculino , Microdiálisis , Microinyecciones , Neostriado/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tacrina/administración & dosificaciónRESUMEN
Four muscarinic receptor antagonists with varying selectivities for the four pharmacologically-defined muscarinic receptor subtypes (M1-M4) were administered into the lateral ventricle to determine their relative potency in reducing tremulous jaw movements induced by i.p. injection of the muscarinic receptor agonist pilocarpine (4.0 mg/kg). All four muscarinic receptor antagonists reduced tremulous jaw movements in a dose-dependent manner, with the following rank order of potency: scopolamine > methoctramine > or = telenzepine > pirenzepine. This pattern is inconsistent with the rank order of affinity of these agents at the muscarinic M1 receptor, and is consistent with their rank order of affinity at muscarinic M2 or M4 receptors. Because tremulous jaw movements are related to striatal function, and the muscarinic M4 receptor is more predominant than the muscarinic M2 receptor as a post-synaptic receptor in striatum, the present results suggest that pilocarpine induces jaw movements due to muscarinic M4 receptor stimulation. In view of the hypothesized relation between parkinsonism and cholinomimetic-induced jaw movements, these data suggest that a centrally-acting muscarinic M4 receptor antagonist could be useful as an antiparkinsonian agent.
Asunto(s)
Maxilares/efectos de los fármacos , Agonistas Muscarínicos/toxicidad , Antagonistas Muscarínicos/farmacología , Pilocarpina/toxicidad , Receptores Muscarínicos/efectos de los fármacos , Temblor/fisiopatología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Diaminas/farmacología , Relación Dosis-Respuesta a Droga , Maxilares/fisiopatología , Masculino , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Receptor Muscarínico M4 , Receptores Muscarínicos/fisiología , Escopolamina/farmacología , Temblor/inducido químicamenteRESUMEN
Several compounds were tested on the differential-reinforcement-of-low-rate 72-sec (DRL 72-sec) schedule, a behavioral screen to determine putative antidepressants; these compounds were evaluated in two outbred stocks of rats, Harlan and Holtzman Sprague-Dawley rats. A dose-response determination for the tricyclic antidepressants, imipramine and desipramine, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, the 5-HT2 receptor antagonist, ketanserin, the 5-HT1A receptor agonist, (+/-)8-hydroxy-di-propylamino tetralin (8-OH-DPAT) and the dopamine releasing compound, amphetamine, were assessed in both rat stocks. The two stocks of rats differed in their baseline performance on the DRL 72-sec schedule. The Harlan rats had a higher reinforcement rate and a lower response rate than the Holtzman rats. In Holtzman, but not in Harlan rats, imipramine, ketanserin, fluoxetine and 8-OH-DPAT increased reinforcement rate and decreased response rate on the DRL 72-sec schedule, confirming previous studies. However, desipramine was the only drug to increase reinforcement rate and decrease response rate in both Holtzman and Harlan rats; in Harlan rats, drugs that primarily act upon the 5-HT system, imipramine, ketanserin, fluoxetine and 8-OH-DPAT, disrupted the DRL 72-sec performance and did not increase the number of reinforcements over baseline as was seen in Holtzman rats. Amphetamine disrupted DRL 72-sec performance in both Holtzman and Harlan rats in a similar manner. The hypothermic response to 8-OH-DPAT was also assessed in the two stocks of rats; Holtzman rats had a smaller decrease in core body temperature than Harlan rats. The observed behavioral and pharmacological differences between Holtzman and Harlan rat stocks may be genetically and/or environmentally mediated.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Antidepresivos/farmacología , Condicionamiento Operante/efectos de los fármacos , Hipotermia/inducido químicamente , Agonistas de Receptores de Serotonina/farmacología , Animales , Antidepresivos Tricíclicos/farmacología , Temperatura Corporal/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Hipotermia/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Antagonistas de la Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Especificidad de la EspecieRESUMEN
Rats were implanted with fine-wire electromyograph (EMG) electrodes and were videotaped to identify the local frequency characteristics and muscle activity associated with tacrine-induced tremulous jaw movements. All rats received intraperitoneal injections of 2.5 mg/kg tacrine. The videotape sessions were played back in slow motion (i.e., one-sixth normal speed), and an observer entered each jaw movement into a computer program that recalculated the interresponse time and the local frequency (in hertz) for each movement within a burst. Analyses of the distribution of frequencies showed that the peak frequency of jaw movements was in the 3- to 5-Hz frequency range, with an average frequency of 4.0 Hz. EMG electrodes were implanted into three jaw muscles: temporalis, anterior belly of digastricus, and masseter. Tremulous jaw movements were not accompanied by consistent changes in masseter activity. The anterior belly of digastricus showed bursts of EMG activity during some jaw movements, although the temporal relation between jaw movements and EMG activity was somewhat inconsistent. The muscle that showed activity most closely related to tremulous jaw movements was the temporalis. During bursts of jaw movements, temporalis muscles across several different rats showed bursts of EMG activity. Sections of videotape corresponding to bursts of EMG activity were reanalyzed by freeze-frame examination of the tape; typically, the temporalis showed a burst for each jaw movement, with the burst of activity occurring during the jaw-closing phase and the transition between jaw closing and opening. These results indicate that the local frequency of tremulous jaw movements is within the 3- to 7-Hz frequency that is typically associated with parkinsonian tremor. Moreover, the EMG data suggest that temporalis is a major contributor to the muscle activity that underlies tremulous jaw movements.
Asunto(s)
Conducta Animal/efectos de los fármacos , Inhibidores de la Colinesterasa/efectos adversos , Discinesia Inducida por Medicamentos/fisiopatología , Discinesia Inducida por Medicamentos/psicología , Electromiografía/efectos de los fármacos , Maxilares/fisiología , Tacrina/efectos adversos , Animales , Electrodos Implantados , Masculino , Ratas , Ratas Sprague-Dawley , Grabación de Cinta de VideoRESUMEN
A computerized finger-tapping test was used in which nonclinical subjects were asked to tap a telegraph key with their index finger as rapidly as possible during five 10-s trials. Comparisons were made between young (mean age = 18 years) and aged (mean age = 75 years) subjects. Consistent with previous findings, aged subjects performed significantly fewer taps than younger subjects. Computerized analysis of finger-tapping patterns in the present study allowed for the determination of novel temporal parameters of tapping responses. Response initiation time was defined as the time from the offset of one finger tap until the onset of the next finger tap. Aged subjects had significant and substantially longer response initiation times than younger subjects. Response duration times also were measured: this parameter was defined as the time from the onset of one finger tap until the offset of the same finger tap. Although the magnitude of the effect was small, aged subjects had significantly longer response duration times than younger subjects. Thus, although the deficit in response rate of a voluntary repetitive response in aged subjects was largely due to impairments in response initiation times, the response duration also contributes to the overall deficit in responding. Using these methods it is possible that greater insight into aging or extrapyramidal motor disorders, such as parkinsonism, may be obtained; it is also possible that these data may be useful as a research tool to aid in drug development and evaluation.
Asunto(s)
Envejecimiento/psicología , Dedos/fisiología , Desempeño Psicomotor/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Caracteres Sexuales , Factores de TiempoRESUMEN
Several pharmacological and neurochemical conditions in rats induce 'vacuous' or 'tremulous' jaw movements. Although the clinical significance of these movements has been a subject of some debate, considerable evidence indicates that the non-directed, chewing-like movements induced by cholinomimetics, dopamine antagonists and dopamine depletions have many of the characteristics of parkinsonian tremor. These movements occur within the 3-7 Hz peak frequency range that is characteristic of parkinsonian tremor. Tremulous jaw movements are induced by many of the conditions that are associated with parkinsonism, and suppressed by several different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, amantadine and clozapine. Striatal cholinergic and dopaminergic mechanisms are involved in the generation of tremulous jaw movements, and substantia nigra pars reticulata appears to be a major basal ganglia output region through which the jaw movements are regulated. Future research on the neurochemical and anatomical characteristics of tremulous jaw movements could yield important insights into the brain mechanisms that generate tremulous movements.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Enfermedades Maxilomandibulares/fisiopatología , Enfermedad de Parkinson/fisiopatología , Temblor/fisiopatología , Animales , Antipsicóticos/uso terapéutico , Ganglios Basales/anatomía & histología , Ganglios Basales/fisiología , Antagonistas Colinérgicos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Humanos , Enfermedades Maxilomandibulares/inducido químicamente , Enfermedades Maxilomandibulares/tratamiento farmacológico , Vías Nerviosas , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Enfermedad de Parkinson Secundaria/fisiopatología , Ratas , Temblor/inducido químicamente , Temblor/tratamiento farmacológicoRESUMEN
Nucleus accumbens (DA) has been implicated in a number of different behavioral functions, but most commonly it is said to be involved in "reward" or "reinforcement". In the present article, the putative reinforcement functions of accumbens DA are summarized in a manner described as the "General Anhedonia Model". According to this model, the DA innervation of the nucleus accumbens is conceived of as a crucial link in the "reward system", which evolved to mediate the reinforcing effects of natural stimuli such as food. The reward system is said to be activated by natural reinforcing stimuli, and this activation mediates the reinforcing effects of these natural stimuli. According to this view, other stimuli such as brain stimulation and drugs can activate this system, which leads to these stimuli being reinforcing as well. Interference with DA systems is said to blunt the reinforcing effects of these rewarding stimuli, leading to "extinction". This general model of the behavioral functions of accumbens DA is utilized widely as a theoretical framework for integrating research findings. Nevertheless, there are several difficulties with the General Anhedonia Model. Several studies have observed substantial differences between the effects of extinction and the effects of DA antagonism or accumbens DA depletions. Studies involving aversive conditions indicate that DA antagonists and accumbens DA depletions can interfere with avoidance behavior, and also have demonstrated that accumbens DA release is increased by stressful or aversive stimuli. Although accumbens DA is important for drug abuse phenomena, particularly stimulant self-administration, studies that involve other reinforcers are more problematic. A large body of evidence indicates that low doses of dopamine antagonists, or depletions of accumbens DA, do not impair fundamental aspects of food motivation such as chow consumption and simple instrumental responses for food. This is particularly important, in view of the fact that many behavioral researchers consider the regulation of food motivation to be a fundamental aspect of food reinforcement. Finally, studies employing cost/benefit analyses are reviewed, and in these studies considerable evidence indicates that accumbens DA is involved in the allocation of responses in relation to various reinforcers. Nucleus accumbens DA participates in the function of enabling organisms to overcome response costs, or obstacles, in order to obtain access to stimuli such as food. In summary, nucleus accumbens DA is not seen as directly mediating food reinforcement, but instead is seen as a higher order sensorimotor integrator that is involved in modulating response output in relation to motivational factors and response constraints. Interfering with accumbens DA appears to partially dissociate the process of primary reinforcement from processes regulating instrumental response initiation, maintenance and selection.
Asunto(s)
Conducta Animal/fisiología , Dopamina/farmacología , Núcleo Accumbens/fisiología , Animales , Modelos NeurológicosRESUMEN
Several experiments were conducted to study the effects of established or potential antiparkinsonian drugs on the tremulous jaw movements induced by the anticholinesterase tacrine (9-amino-1,2,3,4-tetrahydroaminoacridine hydrochloride). In the first group of four experiments, separate groups of animals that received 2.5 or 5.0 mg/kg tacrine showed a dose-dependent decrease in tremulous jaw movements following co-administration of the non-selective dopamine receptor agonist apomorphine, the full dopamine D2 receptor agonist bromocriptine, and the full dopamine D1 receptor agonist APB (R(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine). Co-administration of the partial dopamine D1 receptor agonist SKF 38393 (R(+)-2,3,4,5-tetrahydro-7,8-dihydroxy-l phenyl-1 H-benzazepine: 7.5-30.0 mg/kg) did not reduce tremulous jaw movements produced by 2.5 or 5.0 mg/kg tacrine. In animals treated with 2.5 mg/kg tacrine, co-administration of SKF 38393 resulted in a dose-related trend towards a potentiation of tremulous jaw movements. In the second group of experiments, all rats received 2.5 mg/kg tacrine. The dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine), the dopamine and norepinephrine releasing agent amantadine, and the muscarinic receptor antagonist benztropine all reduced tremulous jaw movements induced by 2.5 mg/kg tacrine. Across all experiments, it was noted that apomorphine, bromocriptine and benztropine were more potent than amantadine and L-DOPA. These results are broadly consistent with the therapeutic doses of these agents noted in the clinical literature. The results of these experiments indicate that tremulous jaw movements in rats may be a useful model for evaluating potential antiparkinsonian agents.
Asunto(s)
Antiparkinsonianos/farmacología , Inhibidores de la Colinesterasa/efectos adversos , Masticación/efectos de los fármacos , Tacrina/efectos adversos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Antiparkinsonianos/administración & dosificación , Apomorfina/administración & dosificación , Apomorfina/farmacología , Bromocriptina/administración & dosificación , Bromocriptina/farmacología , Inhibidores de la Colinesterasa/administración & dosificación , Colinesterasas/efectos de los fármacos , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Interacciones Farmacológicas , Masculino , Ratas , Ratas Sprague-Dawley , Tacrina/administración & dosificaciónRESUMEN
Previous work has shown that cholinomimetic drugs induce "vacuous" or non-directed jaw movements in rats. In the present study, five experiments were conducted to provide a pharmacological, anatomical and behavioral characterization of tacrine-induced vacuous jaw movements. In the first experiment, tacrine produced vacuous chewing in a dose-related manner in a range of 1.25 mg/kg to 1.0 mg/kg. This effect was reduced, also in a dose-related manner, by the co-administration of the muscarinic antagonist scopolamine in a range of 0.125 to 1.0 mg/kg, but not by N-methylscopolamine. The fourth experiment examined the effect of scopolamine (2.5 to 10.0 micrograms) injected into the ventrolateral striatum on vacuous jaw movements induced by 5.0 mg/kg tacrine. Intrastriatal injections of scopolamine completely blocked tacrine-induced jaw movements. The fifth experiment utilized a slow-motion videotaping system to analyze the temporal characteristics of vacuous chewing induced by 5.0 mg/kg tacrine. The vast majority of the movements occurred in rapid "bursts," and analysis of interresponse times (i.e., the time between each jaw movement) showed that most of the jaw movements occurred within a local frequency range of 3 to 7 Hz. Thus, tacrine-induced jaw movements are reduced by antimuscarinic treatment, and most of these movements occur in the parkinsonian tremor frequency range. Tremulous jaw movements induced by tacrine in rats appear to share some characteristics with Parkinsonian tremor.
Asunto(s)
Maxilares/fisiopatología , Parasimpaticomiméticos/toxicidad , Tacrina/toxicidad , Temblor/fisiopatología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Relación Dosis-Respuesta a Droga , Maxilares/efectos de los fármacos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Parasimpaticomiméticos/antagonistas & inhibidores , Enfermedad de Parkinson/fisiopatología , Ratas , Ratas Sprague-Dawley , Escopolamina/administración & dosificación , Escopolamina/farmacología , Tacrina/antagonistas & inhibidores , Temblor/inducido químicamenteRESUMEN
Rats were tested in an instrumental lever pressing procedure, in which a computer program recorded detailed parameters of responding such as response initiation and duration. Initially, rats with ventrolateral striatal dopamine depletions and control rats were tested on days 3-5 after surgery. Dopamine depletions produced by local injections of 6-hydroxydopamine substantially reduced the number of lever presses emitted. Dopamine depleted animals showed significant increases in average response initiation times, average length of fast initiation times, average length of pauses and total pause time. The distribution of initiation times was altered so that DA depleted rats showed significant reductions in the relative number of very high rate responses and also showed increases in the relative number of pauses. On day 7 after surgery, dopamine-depleted rats received one of three drug treatments: injections of ascorbate vehicle, injections of 20.0 mg/kg L-DOPA, and injections of 40.0 mg/kg L-DOPA. Injections of 40.0 mg/kg L-DOPA led to some improvement in several parameters of instrumental responding. Compared to the previous baseline day, the group that received 40.0 mg/kg L-DOPA showed a significant increase in number of responses on the drug treatment day, and also showed significant decreases in average response initiation time and total pause time. The group that received 40.0 mg/kg L-DOPA also showed significant increases in number of responses (expressed as a percent of the previous day) when compared to the control group that received injections of ascorbate vehicle. These results indicate that L-DOPA can partially reverse the skilled motor deficits produced by ventrolateral striatal dopamine depletions, and suggest that this test may be useful for the assessment of antiparkinsonian drugs.
Asunto(s)
Mapeo Encefálico , Condicionamiento Operante/fisiología , Cuerpo Estriado/fisiología , Dopamina/metabolismo , Levodopa/farmacología , Actividad Motora , Tiempo de Reacción , Análisis de Varianza , Animales , Condicionamiento Operante/efectos de los fármacos , Cuerpo Estriado/patología , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/fisiología , Oxidopamina , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacosRESUMEN
Rats were tested using a lever pressing/feeding procedure in which a preferred food (Bioserve pellets) was available by pressing a lever on a fixed ratio 5 schedule, but a less preferred food (lab chow) was also available concurrently in the operant chamber. The effects of repeated (14 day) injections of haloperidol, clozapine and thioridazine were compared. Haloperidol (0.05-0.15 mg/kg) significantly reduced lever pressing and increased chow intake throughout the drug treatment period. Injections of clozapine (2.0-6.0 mg/kg) suppressed lever pressing but failed to produce substantial increases in chow intake. In the haloperidol experiment there was a significant inverse correlation between lever pressing and chow intake, but in the clozapine experiment there was not. Regression analysis indicated that rats treated with the high dose of clozapine showed some tolerance to the suppression of lever pressing. Tests of sedation also were conducted before and after the instrumental behavior sessions. Haloperidol produced little or no sedative effect in the dose range tested. Clozapine produced substantial sedation during the first 10 days of administration, but this effect, like the suppression of lever pressing, showed signs of tolerance. Thioridazine (3.0-9.0 mg/kg) produced some effects that resembled haloperidol, and other effects, including sedation, that resembled clozapine. These studies indicate that haloperidol suppresses lever pressing for food at low doses that do not produce severe motivational or sedative effects that disrupt food intake. In contrast, it appears as though the suppression of lever pressing produced by clozapine stems from a sedative effect that also serves to set limits on chow intake. These results indicate that haloperidol and clozapine suppress lever pressing through different mechanisms.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Condicionamiento Operante/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Haloperidol/farmacología , Tioridazina/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Previous studies have demonstrated that the ventrolateral region of the rat neostriatum is the site at which dopamine depletions produce profound motor deficits that interfere with food handling and lever pressing. In the present work, two experiments were undertaken to investigate the role of ventrolateral striatal dopamine in lever pressing. The first experiment was a detailed characterization of the motor impairments induced by injections of the neurotoxic agent 6-hydroxydopamine into the ventrolateral striatum. Behavioral output during lever pressing on a fixed ratio 5 schedule was recorded by a computerized system that measured the duration and response initiation time for each lever press. Response initiation time was defined as the time from offset of one lever press to the onset of the next one. Dopamine depletions resulting from 6-hydroxydopamine injections profoundly depressed lever pressing response rate. This deficit was largely due to a dramatic increase in the average response initiation time. Analysis of the distribution of response initiation times indicated that dopamine-depleted rats made relatively few responses with fast initiation times (e.g. 0-125 ms), and also that dopamine depletions led to a dramatic increase in the number of pauses in responding (i.e. response initiation times greater than 2.5 s). This slowing of the initiation of movement was very sensitive to the effects of dopamine depletions, and even animals with mild dopamine depletions (29.1% of control levels) showed increased initiation times. Analysis of response durations indicated that dopamine depletions resulted in a shift in the distribution of durations such that depleted rats had a modal response duration of 375-500 ms, in contrast to the control mode of 125-250 ms. There was an overall increase in average response duration among animals with more severe dopamine depletions, although rats with moderate depletions showed no change in average response duration. In the second experiment, in vivo dialysis methods were used to study the dynamic activity of ventrolateral striatal dopamine during lever pressing. During the performance of a 30-min fixed ratio 5 lever pressing session, there was a small but significant increase (20.9% above baseline) in dopamine release. There was not a linear or curvilinear correlation between lever pressing rate and increases in dopamine release. The relatively modest increase in ventrolateral striatal dopamine release during lever pressing and the lack of relation between dopamine release and behavioral output may indicate that dopamine in the ventrolateral striatum plays mainly a permissive role in lever pressing. These results suggest that ventrolateral striatal dopamine depletions in rats produce deficits in skilled motor control that are similar to the motor deficits observed in patients with Parkinson's disease.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Movimiento/fisiología , Animales , Conducta Animal/fisiología , Masculino , Microdiálisis , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.
Asunto(s)
Dopamina/fisiología , Aprendizaje por Laberinto/fisiología , Núcleo Accumbens/fisiología , Animales , Análisis Costo-Beneficio , Dopamina/metabolismo , Alimentos , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxidopamina/farmacología , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Simpaticolíticos/farmacologíaRESUMEN
Two experiments were conducted to study the role of dopamine in the performance of a novel cost/benefit procedure. Rats were trained on a T-maze task in which one arm contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). Different groups of rats were trained either with unobstructed access to both arms from the start area, or under a condition in which a large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the first experiment, rats trained under each procedure received injections of 0.1 mg/kg haloperidol and tartaric acid vehicle as a control procedure. Analysis of variance indicated that there was a significant effect of the barrier on maze arm choice, a significant effect of haloperidol, and a significant drug x barrier interaction. Haloperidol did not affect arm choice in rats tested without the barrier present, but this drug significantly reduced the number of selections of the arm with high reinforcement density when the barrier was present. In the second experiment, groups of rats were trained as described above, and then received intraaccumbens injections of 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions produced by 6-hydroxydopamine decreased the number of selections of the arm with high reinforcement density when the barrier was present, but had no effect on arm choice when the barrier was not present.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Dopamina/fisiología , Metabolismo Energético/efectos de los fármacos , Haloperidol/farmacología , Aprendizaje por Laberinto/fisiología , Motivación , Núcleo Accumbens/fisiología , Animales , Masculino , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Oxidopamina/farmacología , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or approaching and consuming a less-preferred food (Lab Chow). The lever pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever pressing schedule. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonist cis-flupenthixol (0.3 and 0.45 mg/kg) decreased lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both lever pressing and chow consumption.(ABSTRACT TRUNCATED AT 250 WORDS)