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  • 1
    Electronic Resource
    Electronic Resource
    The paw test: a behavioural paradigm for differentiating between classical and atypical neuroleptic drugs (1987)
    Springer
    Psychopharmacology 93 (1987), S. 343-348 
    Details
    ISSN: 1432-2072
    Keywords: Animal model ; Catalepsy ; Neuroleptics ; Paw test ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An often used animal model based on the effects of neuroleptics on spontaneous behaviour is the catalepsy test. However, this test seems to be particularly insensitive to the atypical neuroleptics thioridazine and, especially, clozapine. We have therefore developed an alternative test, the paw test, which measures the ability of drugs to prevent the spontaneous withdrawal of fore- and hindlimbs in rats, and have compared this with the classical catalepsy test. The results show that: 1) the classical neuroleptic drugs haloperidol and chlorpromazine, the atypical neuroleptic drugs clozapine and thioridazine, the potential atypical neuroleptic drugs molindone and SCH 23390, and the potential classical neuroleptic drug metoclopramide are potent in increasing the hindlimb retraction time; 2) the paw test discriminates between classical neuroleptics which are equipotent in prolonging both the forelimb (FRT) and hindlimb retraction time (HRT) and atypical neuroleptics which are much more potent in prolonging HRT than in prolonging FRT; 3) the non-neuroleptic drugs desipramine, diazepam and morphine do not influence the variables measured in the paw test, although morphine does produce catalepsy; 4) Molindone as well as SCH 23390 behave like atypical neuroleptic drugs in the paw test. In comparison with the classical wood block catalepsy test, the paw test is shown to be superior for predicting the profile of the neuroleptics tested. Although more neuroleptics and non-neuroleptics have to be tested to determine whether false positives and false negatives do occur, we feel that the paw test might be an interesting animal model, because the increase in hindlimb retraction time was associated with the antipsychotic potential, whereas the increase in forelimb retraction time was associated with the potential to induce so-called extrapyramidal side effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00187254
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  • 2
    Electronic Resource
    Electronic Resource
    The nucleus accumbens and forelimb muscular rigidity in rats (1988)
    Springer
    Experimental brain research 72 (1988), S. 299-304 
    Details
    ISSN: 1432-1106
    Keywords: EMG ; Forelimb muscle ; Hindlimb muscle ; Neostriatum ; Nucleus accumbens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present set of experiments were performed to evaluate the role of the nucleus accumbens in the regulation of forelimb muscle tone. Rats were chronically implanted with cannulae aimed at the nucleus accumbens or the neostriatum and with EMG electrodes in the triceps or the gastrocnemius soleus muscle. The experiments were all performed in non-anaesthetised freely moving animals. The results show that haloperidol induced an increase in triceps muscle tone when injected into the nucleus accumbens but not when injected into the neostriatum. Likewise it was found that haloperidol induced an increase in gastrocnemius soleus muscle tone when injected into the neostriatum but not when injected into the nucleus accumbens. The increase in triceps muscle tone seen after intra-accumbens haloperidol was only briefly attenuated by apomorphine, whereas phenylephrine produced a more long lasting antagonism. The present data show that in addition to the cortex, subcortical structures also appear to possess a certain topography, with forelimb rigidity being mediated, at least in part, by the nucleus accumbens, and hindlimb rigidity, at least in part by the neostriatum. In addition it appears that the effects of haloperidol in the nucleus accumbens on triceps muscle tone are primarily mediated by α1 adrenergic receptors, although a minor role of dopamine D2 receptors cannot be fully excluded.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00250252
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  • 3
    Electronic Resource
    Electronic Resource
    Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats (1999)
    Springer
    Psychopharmacology 142 (1999), S. 9-17 
    Details
    ISSN: 1432-2072
    Keywords: Key words NMDA (N-methyl-D-aspartate) ; Schizophrenia ; Prepulse inhibition (PPI) ; Sensory gating ; P50 ; Auditory evoked potentials (AEP) ; Ketamine ; d-Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, IP) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, IP) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050856
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  • 4
    Electronic Resource
    Electronic Resource
    The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm (1997)
    Springer
    Psychopharmacology 129 (1997), S. 112-120 
    Details
    ISSN: 1432-2072
    Keywords: Key words Amphetamine ; Animal model ; Conditioned taste aversion ; Dopamine ; Latent inhibition ; Neostriatum ; Nucleus accumbens ; Schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Repeatedly presenting a non-reinforced stimulus normally retards conditioning to this stimulus when it is coupled to a reinforcer. This phenomenon is called latent inhibition. Since latent inhibition is disturbed after systemic administration of amphetamine, the present study investigated the role of the mesolimbic and nigrostriatal dopamine terminal fields in latent inhibition using a conditioned taste aversion (CTA) paradigm. In this paradigm, a 5% sucrose solution was used as the test stimulus and lithium chloride (LiCl) as the CTA inducing drug. The degree of CTA was assessed by measuring the sucrose preference in a two-bottle sucrose/water choice paradigm 24 h after the LiCl injection. Since conditioned taste aversion has so far not been used to evaluate the role of dopamine in latent inhibition, we first studied the effects of systemic application of amphetamine. The results show that intraperitoneal injections of 0.25 or 0.5 mg/kg d-amphetamine sulphate (given at preexposure and conditioning) significantly disrupted latent inhibition, by selectively reducing sucrose preference in the preexposed group. This could not be attributed to a reduced sucrose intake during preexposure or to a conditioned taste aversion effect of amphetamine itself. In experiment 2 local bilateral administration of 10 μg/0.5 μl amphetamine into the nucleus accumbens or the dorsal striatum was given in the pre-exposed and the conditioning phase, after which the rats were allowed to drink for a fixed period of time. The results show a significant reduction in latent inhibition after intrastriatal, but not after intra-accumbens injections of amphetamine. Intra-accumbens injections of amphetamine, however, significantly reduced fluid intake during preexposure and conditioning. In experiment 3, we therefore repeated this experiment, but allowed the animals to drink only a restricted amount of liquid during preexposure and conditioning. Again the results show a disruption of latent inhibition after intrastriatal, but not intra-accumbens injections of amphetamine. These experiments emphasize the importance of the nigrostriatal dopamine system in the disruption of latent inhibition, at least when using the conditioned taste aversion paradigm. A possible mechanism by which the dorsal striatum might influence latent inhibition is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050170
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  • 5
    Electronic Resource
    Electronic Resource
    Differences in vulnerability and susceptibility to dexamphetamine in Nijmegen high and low responders to novelty: a dose-effect analysis of spatio-temporal programming of behaviour (1997)
    Springer
    Psychopharmacology 132 (1997), S. 181-187 
    Details
    ISSN: 1432-2072
    Keywords: Key words Amphetamine ; Individual differences ; Novelty ; Locomotor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Susceptibility to behavioural effects of dexamphetamine (0.5–2.0 mg/kg, SC) was analyzed in Nijmegen high responders to novelty (HR) and Nijmegen low responders to novelty (LR), using an automated ethological analysis. The main results were that, first, dexamphetamine was more toxic in HR than LR: 5.0 mg/kg dexamphetamine was lethal in 75% HR, respectively, 25% LR. Second, dexamphetamine had effects in HR at doses far lower than in LR: a dose of 0.5 or 1.0 mg/kg dexamphetamine was already sufficient to produce ceiling effects in HR, whereas a minimum dose of 2.0 mg/kg dexamphetamine was required to reach effects of a similar magnitude in LR. Third, the behavioural responses to 2.0 mg/kg dexamphetamine did not differ between HR and LR. These data show that HR are both more vulnerable and more susceptible to the toxic and behavioural effects of intermediate doses of dexamphetamine than LR. It is concluded that knowledge acquired previously about the neurochemical differences between Nijmegen HR (APO-SUS) and Nijmegen LR (APO-UNSUS) rats can be used to analyze further the mechanisms of action underlying individual-specific differences in drug abuse in animals and man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050334
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  • 6
    Electronic Resource
    Electronic Resource
    The olfactory tubercle as a site of action of neuroleptics with an atypical profile in the paw test: effect of risperidone, prothipendyl, ORG 5222, sertindole and olanzapine (1995)
    Springer
    Psychopharmacology 119 (1995), S. 428-439 
    Details
    ISSN: 1432-2072
    Keywords: Atypical neuroleptics ; N. accumbens ; Olfactory tubercle ; Paw test ; Locomotor activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The paw test was used to detect the preclinical profile (classical versus atypical) of five putative, atypical neuroleptics, namely olanzapine, sertindole, risperidone, prothipendyl and ORG 5222. In the paw test classical neuroleptics increase the hindlimb reaction time (HRT), a parameter with predictive validity for antipsychotic efficacy, at doses comparable to those necessary for increasing forelimb reaction time (FRT), a parameter with predictive validity for extrapyramidal side-effects, whereas atypical neuroleptics increase HRT at doses that are much smaller than those increasing FRT. All tested compounds showed the profile of atypical neuroleptics in the paw test. Using the FRT/HRT ratio of minimum effective doses as overall predictor of a favourable ratio of extrapyramidal and therapeutic effects of these drugs, the following order was found: olanzapine (20) 〉 sertindole = risperidone = prothipendyl (10) 〉 ORG 5222 (3). The ability of compounds to attenuate locomotor activity elicited either from the olfactory tubercle (10 µg dopamine: OT test) or from the nucleus accumbens (1 µg ergometrine: ACC test) was used to establish whether the compounds preferentially act in one of these structures. Previous research has shown that classical neuroleptics are far less potent in the OT test than in the ACC test, whereas atypical neuroleptics are far more potent in the OT test than in the ACC test. All five agents preferentially acted in the olfactory tubercle. The order of potency in the olfactory tubercle was as follows: sertindole 〉 ORG 5222 〉 risperidone 〉 olanzapine 〉 prothipendyl. It is concluded that risperidone, prothipendyl, ORG 5222, sertindole and olanzapine not only show the profile of atypical neuroleptics in the paw test, but also preferentially act in the olfactory tubercle, but not in the nucleus accumbens, viz. two features that they share with the atypical neuroleptics clozapine and thioridazine and with the putative, atypical neuroleptics raclopride and remoxipride.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245859
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