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  • 1
    ISSN: 1432-2072
    Keywords: Key words Prepulse inhibition ; Startle ; Clozapine ; Schizophrenia ; Dopamine D4 receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: Cannabinoids ; Pigeon ; SR141716A ; Drug discrimination ; Startle ; Fixed consecutive number ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract SR141716A (Sanofi Recherche), a pyrazole derivative with high affinity for rat and human CB1 cannabinoid receptors, has recently been reported to reverse biochemical, physiological and behavioral effects induced by cannabinoid agonists. The present experiments characterized the activity of SR141716A (SR) in behavioral procedures designed to assess its antagonistic and intrinsic effects on unconditioned behavior and on complex learned behaviors. Six adult male pigeons were trained to discriminate injections of 0.56 mg/kg Δ9-tetrahydrocannabinol (Δ9-THC) from vehicle under a two-key, fixed-ratio schedule of food reinforcement. SR (IM) produced a nearly complete blockade of THC-appropriate responding occasioned by the training dose without inducing significant changes in session response rates, but also produced partial substitution for Δ9-THC when administered alone. In another group of pigeons trained under a multiple schedule of signaled and unsignaled fixed consecutive number (FCN) responding, SR had little effect on accuracy, but Δ9-THC produced dose-related decreases in accuracy under both schedule components. SR was also evaluated in acoustic startle procedures in rats. SR produced little effect either on startle amplitude or prepulse inhibition of acoustic startle. In contrast, the potent cannabinomimetic CP-55, 940 produced large decreases in startle responses elicited by 120 dB [A] broad-band noise. These decreases were completely reversed by SR (10 mg/kg, IP). In concurrent measures, SR blocked the hypothermic effect CP-55,940. These results suggest that SR is an effective antagonist of the psychoactive effects of cannabinoids.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2072
    Keywords: Key words Serotonin ; Pigeon ; Drug discrimination ; Punished responding ; CP-135 ; 807
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  CP-135,807 [3-(N-methylpyrrolidin-2R-ylmeth- yl)-5-(3-nitropyrid-2-yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Acoustic startle response ; Dopamine ; Nucleus accumbens ; Prepulse inhibition ; Schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.
    Type of Medium: Electronic Resource
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