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  • 1
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The mechanism by which two D3 receptor-preferring agonists, 7-hydroxydipropylaminotetralin (7-OH-DPAT) and quinelorane, modulate cocaine reinforcement was examined by monitoring nucleus accumbens dopamine levels with in vivo microdialysis while rats intravenously self-administered the following four different drug solutions consecutively: (1) cocaine; (2) a combination of cocaine plus a low dose of either agonist; (3) either agonist alone; and finally, (4) a physiological saline solution. Both 7-OH-DPAT (4 µg/infusion) and quinelorane (0.25 µg/infusion) decreased cocaine (0.25 mg/infusion) intake in a manner indicating an enhancement of cocaine reinforcement and simultaneously decreased the cocaine-induced elevations in nucleus accumbens dopamine levels by 〉50%. Subsequent self-administration of either 7-OH-DPAT (4 µg/infusion) or quinelorane (0.25 µg/infusion) alone resulted in significant, but stable, increases in drug intake, with a concurrent decrease in nucleus accumbens dopamine levels to ∼50% below nondrug baseline levels. These findings indicate that postsynaptic D3 receptor stimulation in the nucleus accumbens enhances the reinforcing properties of cocaine. In a second experiment, local application of 7-OH-DPAT via reverse dialysis (30 and 100 nM perfusate concentrations) dose-dependently decreased nucleus accumbens dopamine efflux to 76 ± 3.9 and 61 ± 6.3% of baseline, respectively, whereas there was no effect of this agonist on dopamine efflux in the ipsilateral striatum of these same animals. Coperfusion with the D3 receptor-preferring antagonist nafadotride dose-dependently blocked the effect of 7-OH-DPAT on nucleus accumbens dopamine efflux. These results suggest that, at low concentrations, 7-OH-DPAT selectively activates D3 receptors in vivo.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Key words Cocaine ; Self-administration ; Dopamine ; D1 ; D2 ; Rhesus monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D1-like and D2-like receptor mechanisms may be involved, recent studies suggest that D1-like and D2-like agonists have differing profiles of cocaine-related actions. Objective: To develop a procedure for rapid assessment of complete dose–effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D1-like and D2-like agonists on cocaine self-administration using this procedure. Methods: Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D1-like and D2-like agonists (administered i.m., 10 min or 30 min prior to the session) were assessed. Results: Complete inverted U-shaped dose–effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose– effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D1-like agonists SKF 82958 (0.32–1.8 mg/kg) and R-6-Br-APB (0.1–1.0 mg/kg) produced downward shifts in the cocaine dose–effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D2-like agonists quinelorane (0.001–0.01 mg/kg) and 7-OH-DPAT (0.01–0.10 mg/kg) shifted the cocaine dose–effect function to the left. D2-like agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding. Conclusions: The results suggest that D1-like and D2-like agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 105 (1991), S. 347-354 
    ISSN: 1432-2072
    Keywords: Prepulse inhibition ; Sensorimotor gating ; Startle ; Hippocampus ; Dopamine ; Schizophrenia ; Carbachol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Prepulse inhibition (PPI) is the decrease in a startle response that occurs when the startling stimulus is preceded by a weaker stimulus or “prepulse”. Schizophrenic patients exhibit abnormally low levels of PPI when the prepulse precedes the startle stimulus by less than 500 ms. A similar deficit in sensorimotor gating can be demonstrated in rats after stimulation of D2 dopamine (DA) receptors by systemic administration of DA agonists or by infusion of DA directly into the nucleus accumbens. We now demonstrate that carbachol infusion into the dentate gyrus of the hippocampal formation disrupts PPI in the rat. This disruption of sensorimotor gating occurs when the startling stimulus is either acoustic or tactile. Carbachol infusion into the neocortex has no effect on PPI. While pretreatment with the D2 DA receptor antagonist spiperone reverses the disruption of PPI caused by systemic administration of apomorphine, this pretreatment fails to reverse the disruption of PPI induced by carbachol infusion into the hippocampus. These results demonstrate that pharmacologic stimulation of the hippocampus disrupts sensorimotor gating in the rat by a mechanism distinct from that of DA agonists. Prepulse inhibition of the startle reflex is an animal model in which pharmacologic stimulation of the hippocampus mimics the deficits in sensorimotor gating observed in schizophrenic patients.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Key words Maternal separation ; Cocaine ; Intravenous self-administration ; Mesolimbic dopamine ; Reward ; Eticlopride ; SCH 23390
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/ injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-2072
    Keywords: Acoustic startle response ; Amygdala ; Dopamine ; Nucleus accumbens ; Orbital cortex ; Prepulse inhibition ; Sensorimotor gating ; Striatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic administration of dopamine (DA) agonists markedly disrupts sensorimotor gating in rats as measured by prepulse inhibition (PPI) of the acoustic startle response. A qualitatively similar, but quantitatively weaker disruption of PPI follows DA infusion into the nucleus accumbens (NAC). The present study was designed to determine whether forebrain DA terminal fields other than the NAC contribute to the DAergic modulation of PPI. PPI was impaired significantly after infusion of DA (0–40 µg) into the NAC or anteromedial striatum, but not after DA infusion into the orbital cortex or posterolateral striatum. DA infusion into the amygdala also disrupted PPI, but this disruption was accompanied by a dose-dependent decrease in startle amplitude. These results suggest that DA overactivity in the both NAC and anteromedial striatum contribute to the gating-disruptive effects of systemically administered DA agonists, and that DA overactivity in mesocortical, mesoamygdaloid and “non-limbic” mesostriatal DA systems are not major substrates for a DAergic modulation of PPI.
    Type of Medium: Electronic Resource
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