A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders.

Human studies have shown that a reduction of 5-HT transporter (SERT) increases the vulnerability for anxiety and depression. Moreover, women are more vulnerable to develop depression and anxiety disorders than men. For that reason we hypothesized that homozygous 5-HT transporter knockout rat (SERT(-/-)) models, especially female, are valuable and reliable animal models for humans with an increased vulnerability for anxiety- and depression-related disorders. As rats are extensively used in neuroscience research, we used the unique 5-HT transporter knockout rat, that was recently generated using N-ethyl-N-nitrosurea (ENU) -driven mutagenesis, to test this hypothesis. Behavioral testing revealed that male and female SERT(-/-) rats spent less time in the center of the open field and spent less time on the open arm of the elevated plus maze compared with wild-type 5-HT transporter knockout rats (SERT(+/+)). In the novelty suppressed feeding test, only male SERT(-/-) rats showed a higher latency before starting to eat in a bright novel arena compared with SERT(+/+) controls. Both male and female SERT(-/-) rats showed a higher escape latency from their home cage than SERT(+/+) littermates. Moreover, SERT(-/-) rats were less mobile in the forced swim test, and sucrose consumption was reduced in SERT(-/-) rats relative to SERT(+/+) rats. Both effects were sex-independent. Neurochemically, basal extracellular 5-HT levels were elevated to a similar extent in male and female SERT(-/-) rats, which was not influenced by the selective 5-HT reuptake inhibitor citalopram. 5-HT immunostaining revealed no difference between SERT(+/+) and SERT(-/-) rats in the dorsal raphe nuclei, in both males and females. These findings demonstrate that SERT(-/-) rats show anxiety and depression-related behavior, independent of sex. Genetic inactivation of the SERT has apparently such a great impact on behavior, that hardly any differences are found between male and female rats. This knockout rat model may provide a valuable model to study anxiety- and depression-related disorders in male and female rats.

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats.

RATIONALE: Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. OBJECTIVES: As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT(-/-)), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT(+/+)) and heterozygous (SERT(+/-)) rats. MATERIALS AND METHODS: Twelve male SERT(+/+), SERT(+/-), and SERT(-/-) rats were treated with standard dose and low-dose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, L: -tryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations were measured, and concentrations of 5-HT and 5-HIAA were measured in the frontal cortex and hippocampus of these rats. RESULTS: Plasma TRP levels and central 5-HT and 5-HIAA levels were decreased in all genotypes after ATD, but effects were stronger in SERT(-/-) rats. The standard dose of ATD impaired object recognition in all genotypes. SERT(-/-) and SERT(+/-) rats were more vulnerable to low dose of ATD in the object recognition task compared to SERT(+/+) rats. CONCLUSIONS: These results indicate a greater sensitivity to ATD in SERT(-/-) and SERT(+/-) rats, which may be related to stronger central depletion effects in these rats.

Characterization of the serotonin transporter knockout rat: a selective change in the functioning of the serotonergic system.

Serotonergic signaling is involved in many neurobiological processes and disturbed 5-HT homeostasis is implicated in a variety of psychiatric and addictive disorders. Here, we describe the functional characterization of the serotonin transporter (SERT) knockout rat model, that is generated by N-ethyl-N-nitrosurea (ENU)-driven target-selected mutagenesis. Biochemical characterization revealed that SERT mRNA and functional protein are completely absent in homozygous knockout (SERT-/-) rats, and that there is a gene dose-dependent reduction in the expression and function of the SERT in heterozygous knockout rats. As a result, 5-HT homeostasis was found to be severely affected in SERT-/- rats: 5-HT tissue levels and depolarization-induced 5-HT release were significantly reduced, and basal extracellular 5-HT levels in the hippocampus were ninefold increased. Interestingly, we found no compensatory changes in in vitro activity of tryptophan hydroxylase and monoamine oxidase, the primary enzymes involved in 5-HT synthesis and degradation, respectively. Similarly, no major adaptations in non-serotonergic systems were found, as determined by dopamine and noradrenaline transporter binding, monoamine tissue levels, and depolarization-induced release of dopamine, noradrenaline, glutamate and GABA. In conclusion, neurochemical changes in the SERT knockout rat are primarily limited to the serotonergic system, making this novel rat model potentially very useful for studying the behavioral and neurobiological consequences of disturbed 5-HT homeostasis.

Treatment of schizophrenia: a clinical and preclinical evaluation of neuroleptic drugs.

Forty years after the first clinical report on the effectiveness of chlorpromazine in psychiatric patients, neuroleptic drugs are still the most widely used drugs in the treatment of schizophrenia. Indeed, there are no other drugs which have proven to be as effective in the treatment of this severe psychiatric disorder. Yet, there are still many unresolved problems relating to neuroleptic drugs. The present review gives a comprehensive overview of our knowledge (and our lack of knowledge) with respect to the clinical and preclinical effects of neuroleptic drugs and tries to integrate this knowledge in order to identify the neuronal mechanisms underlying the therapeutic and side effects of neuroleptic drugs.

The development of various somatic markers is retarded in an animal model for schizophrenia, namely apomorphine-susceptible rats.

UNLABELLED: Although schizophrenia usually sets on after puberty, deviations of normal development exist in pre-schizophrenic children. To investigate the presence of early developmental abnormalities in a valid animal model for schizophrenia, we delineated line-specific developmental differences between apomorphine-susceptible rats (APO-SUS), which share many features with schizophrenic patients, and their counterpart, apomorphine-unsusceptible rats (APO-UNSUS). A battery of somatic developmental markers was assessed in naive animals on postnatal day (PND) 4 and in animals from PND 0 to PND 60. Three comparisons were made: naive APO-SUS and naive APO-UNSUS rats on PND 4; naive and handled APO-SUS and APO-UNSUS rats on PND 4; handled APO-SUS rats and handled APO-UNSUS rats across the initial 60 PND's. Naive APO-SUS rats developed much slower than naive APO-UNSUS rats as far as it concerns digit-separation, anogenital-distance, rooting-reflex, and body-displacement on PND 4, thereby underlining the validity of the APO-SUS rats as model for aspects of schizophrenia. Handling on PND 0-3 retarded the development of both types of rat, implying that early life events have long-lasting effects on pure-somatic markers. Finally, handling from PND 0 to PND 60 had a more pronounced retardation effect in APO-UNSUS rats than in APO-SUS rats. It is suggested that the APO-SUS rats are not affected as much as the APO-UNSUS rats, because they are already overwhelmed by other subliminal stimuli that have no effect on APO-UNSUS rats. IN CONCLUSION: (1) the APO-SUS rat, which is a valid model for schizophrenia, has a retarded development just as pre-schizophrenic children have; (2) early postnatal manipulations have immediate and long-lasting effects on the rodents' morphology; and (3) subchronic, early postnatal handling has a greater effect in APO-UNSUS rats than in APO-SUS rats. The impact of these data for APO-SUS rats as a model for schizophrenia is discussed.

The effects of stress on alcohol consumption: mild acute and sub-chronic stressors differentially affect apomorphine susceptible and unsusceptible rats.

The aim of this study was to investigate the effects of mild acute and mild sub-chronic challenges on alcohol intake and preference in the genetically selected ratlines of apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) animals. Animals from both lines were subjected to the 24 hr continuous alcohol vs. water paradigm under baseline conditions, after a single stressor and after multiple stressors. The intake of alcohol in ml was measured and converted to two values, namely intake in g/kg/24 hour of, and preference for, alcohol. This study shows that under baseline conditions the APO-UNSUS animals consume/prefer more alcohol than the APO-SUS animals. After an acute challenge the APO-SUS animals show a large increase in consumption, whereas the APO-UNSUS animals display only a small increase. Furthermore, sub-chronic challenges can further increase the consumption of the APO-UNSUS rat, but not that of the APO-SUS rat. The APO-SUS/ APO-UNSUS rats represent a good model to study the interaction between genetic factors and stress on directing alcohol consumption.

The long-term effects of maternal deprivation depend on the genetic background.

The neurodevelopmental hypothesis of schizophrenia has led to a series of new animal models in which the long term consequences of early manipulations are investigated. We have recently shown that a single 24-hr period of maternal deprivation (at postnatal day (pnd) 9) increases apomorphine susceptibility and decreases prepulse inhibition in Wistar rats, viz. phenomena also seen in schizophrenic patients. In the present paper, we investigated whether the effects of maternal deprivation were dependent on a specific genetic background, by using different rat strains (Fischer 344 and Lewis) that differ in the Hypothalamus-Pituitary-Adrenal axis and in dopaminergic sensitivity. The data show that in Wistar rats, basal startle amplitude was not affected by maternal deprivation, but prepulse inhibition was reduced, and apomorphine susceptibility enhanced. In Fischer 344 rats on the other hand, neither basal startle amplitude, nor prepulse inhibition were affected, but apomorphine susceptibility was reduced. In Lewis rats, maternal deprivation significantly reduced basal startle amplitude, but did not affect prepulse inhibition or apomorphine susceptibility. The differential response to maternal deprivation can best be explained by differences in baseline dopamine sensitivity between the rat strains. Since a reduced prepulse inhibition and an enhanced susceptibility to apomorphine is also seen in schizophrenic patients, the data indicate that maternally deprived Wistar rats may represent an interesting developmental model for (aspects of) schizophrenia.

Are antagonists of dopamine D1 receptors drugs that attenuate both positive and negative symptoms of schizophrenia? A pilot study in Java monkeys.

Amphetamine is known to elicit stereotyped behavior in various species. For a long time, this effect was considered to be an animal model for the positive symptoms of schizophrenia. In addition, amphetamine is known to induce a strong social isolation in socially living monkeys. Both on symptomatologic and pharmacologic grounds, this amphetamine-induced social isolation has been suggested to represent an animal model for the negative symptoms of schizophrenia. To date no effective treatment has been found for these negative symptoms. We now report that the selective D1 dopamine antagonist SCH 23390 is very effective in antagonizing both the stereotyped behavior and the social isolation in Java monkeys induced by amphetamine. Moreover, SCH 23390 is able to reinstate normal behavior in these animals. These results may have important consequences for our understanding of the functional significance of the D1 receptor as well as for the clinical treatment of the positive and negative symptoms of schizophrenia.

Activity of "seroquel" (ICI 204,636) in animal models for atypical properties of antipsychotics: a comparison with clozapine.

The pharmacologic treatment of schizophrenia still suffers from two major problems: (1) most antipsychotic drugs still induce severe neurologic (extrapyramidal) side effects; (2) few antipsychotic drugs are effective in treating the negative symptoms of schizophrenia. In the present study, we have evaluated the effects of ICI 204,636 in the rat paw test and the amphetamine-induced social isolation in monkeys and compared them with the effects of clozapine. The paw test has been shown to be a valid model for differentiating classic and atypical neuroleptic drugs. The monkey social isolation model seems to represent one of the few animal models with validity for the negative symptoms of schizophrenia. The results show that both ICI 204,636 and clozapine had the profile of an atypical antipsychotic in the paw test, suggesting a reduced propensity to induce extrapyramidal side effects in humans. Likewise, ICI 204,636 and clozapine were found to prevent the amphetamine-induced social isolation in monkeys, suggesting a good therapeutic effect mitigating the negative symptoms in schizophrenia. Overall, the data suggest that ICI 204,636 may represent a new and interesting antipsychotic drug, closely resembling clozapine.

Early maternal deprivation alters hippocampal levels of neuropeptide Y and calcitonin-gene related peptide in adult rats.

Stressful events early in life are reported to be more prevalent among patients with an adult life psychiatric disorder. Early maternal deprivation is considered an animal model of early life stress. Maternally deprived adult rats display long-term alterations in the neuroendocrine system, brain and behavior that are in many ways analogous to depressive and schizophrenic symptomatology. Neuropeptide Y (NPY) and calcitonin-gene related peptide (CGRP) have been implicated in both disorders and also been suggested to play a role in the neuroadaptational response to stress. Consequently, male Wistar rat-pups were subjected to early maternal deprivation or control handling, on postnatal day (pnd) 9. On pnd 21, pups were weaned and split into two groups that were reared either on a saw-dust floor or on a grid-floor, considered to be a mild stressor. On pnd 67, all animals were subjected to the prepulse inhibition test. One week later, the animals were sacrificed, the brains removed and dissected on ice. Levels of NPY-like immunoreactivity (LI) and CGRP-LI were quantified by radioimmunoassay in brain regional extracts. Maternal deprivation led to a significant reduction in basal startle amplitude and disruption of prepulse inhibition. These findings were paralleled by significantly reduced levels of NPY and CGRP in the hippocampus and occipital cortex. It is hypothesised that these changes may be of relevance to aspects of schizophrenic and affective symptomatology. The present study further shows that brain NPY and, in particular, CGRP are sensitive to long-term mild stress and further implicate the involvement of these peptides in the neuroendocrine stress response.

Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex.

The prefrontal cortex has often been implicated in the pathophysiology of schizophrenia. Schizophrenic patients are known to suffer from certain information processing deficits, which can be detected, among others, in the prepulse inhibition and the latent inhibition paradigm. The present study was designed to investigate the role of dopamine receptors in the medial prefrontal cortex in prepulse inhibition and latent inhibition. The results show that the local application of the selective antagonist of the dopamine D1-like receptor family, SCH 39166, into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Likewise, the selective antagonist of the dopamine D2-like receptor family, sulpiride, injected into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Neither of these antagonists, however, influenced latent inhibition as measured with the conditioned taste aversion paradigm. These data further indicate that the neuronal substrates of latent inhibition and prepulse inhibition are clearly different. Since the prefrontal cortex is intimately related to subcortical dopamine, the possible differential involvement of subcortical dopaminergic terminal fields in prepulse inhibition and latent inhibition is discussed.

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell.

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.

Peripheral and central adrenoceptor modulation of the behavioural effects of clozapine in the paw test.

1. In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side-effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test. 2. The alpha 1-adrenoceptor agonist, ST 587 but not the peripherally working alpha 1-agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The alpha 1-antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time. 3. The alpha 2-adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the alpha 2-antagonist rauwolscine nor by the alpha 1-antagonist phenoxybenzamine. Rauwolscine or the peripherally working alpha 2-antagonist L-659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations. 4. In contrast to the beta 2-adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting beta-agonist, (-)-isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The beta-antagonist, (-)-propranolol as well as the peripherally acting beta-antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting beta 1-antagonist, atenolol, as well as low doses of the beta2-antagonist, ICI-118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (-)-isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.5. It is concluded that blockade of central alpha l-adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral beta 1- and/or beta 2-adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the alpha 1-adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side-effects.

The role of genetic and early environmental factors in determining apomorphine susceptibility.

RATIONALE: There is ample evidence that rats show large individual differences in their response to dopaminergic drugs, such as apomorphine. OBJECTIVE: The aim of the present study was to investigate the role of genetic and (early) environmental factors in determining the adult susceptibility to apomorphine. Four experiments were performed: In experiment 1, the original selective breeding of rats for apomorphine susceptibility (leading to APO-SUS and APO-UNSUS rats) was extended and replicated in an independent group of Wistar rats. In experiment 2, APO-SUS males were cross-bred with APO-UNSUS females and vice versa. In experiment 3 APO-SUS litters were cross-fostered to APO-UNSUS mothers or infostered to unknown APO-SUS mothers and vice versa. In experiment 4 APO-SUS and APO-UNSUS rats were maternally deprived on postnatal day 9, for a single 24-h period. METHODS: Adult rats were subcutaneously injected with 1.5 mg/kg apomorphine and their gnawing response was automatically recorded in a gnawing box for 45 min. RESULTS: In experiment 1, the original breeding was extended up to generation 24, leading to a strong and consistent difference in gnawing scores. The replication experiment also succeeded in differentiating APO-SUS and APO-UNSUS. The cross breeding experiments showed that the APO-SUS/UNSUS offspring showed gnawing scores in between the original selection lines. Cross-fostering APO-SUS with APO-UNSUS significantly reduced the gnawing response in the offspring, whereas it did not affect the gnawing score in the APO-UNSUS animals. Maternal deprivation had the opposite effect: increase in gnawing response in APO-UNSUS, with no effect in APO-SUS. CONCLUSION: The results show a clear-cut contribution of both genetic and early environmental factors to the susceptibility of apomorphine.

The role of mesolimbic and nigrostriatal dopamine in latent inhibition as measured with the conditioned taste aversion paradigm.

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 micrograms/0.5 microliter 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 injection 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.

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.

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 micrograms dopamine: OT test) or from the nucleus accumbens (1 microgram 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.

The paw test: a behavioural paradigm for differentiating between classical and atypical neuroleptic drugs.

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) an 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.

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.

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.

Auditory information processing in rat genotypes with different dopaminergic properties.

RATIONALE: Auditory filtering disturbances, as measured in the sensory gating and prepulse inhibition (PPI) paradigms, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In both paradigms, the response to the second stimulus (S2) is attenuated by an inhibitory effect of the first stimulus (S1). Dopamine (DA) agonists have been found to reduce gating of auditory evoked potentials (AEPs) and PPI in healthy human subjects and in rats. These effects have been linked to DA hyperactivity in the mesolimbic system. A non-invasive approach in studying the role of the DA system in PPI and AEP gating is to compare rat genotypes that are marked by distinct DA systems. OBJECTIVES: Several questions were asked in the present study. Are PPI and AEP gating disturbed in (a) rats that are marked by a relatively high DA reactivity of the mesolimbic system, namely apomorphine-susceptible (APO-SUS) and WAG/Rij rats or in (b) rats that are marked by a relatively high DA activity of the nigrostriatal system, namely apomorphine-unsusceptible (APO-UNSUS) and ACI rats? Moreover, is the particular DA balance (c) between the nigrostriatal and mesolimbic system related to deficits in PPI and AEP gating? METHODS: For this purpose, the above-mentioned four rat genotypes (APO-SUS, APO-UNSUS, ACI and WAG/Rij) that vary in DA balance between both systems, were compared in the AEP gating paradigm. PPI was only measured in the ACI and WAG/Rij rats, since it has already been shown in a previous study that APO-SUS rats show diminished PPI as compared to rats of the APO-UNSUS genotype. RESULTS: AEP gating of the vertex N50 was significantly reduced in WAG/Rij rats as compared to the remaining three rat genotypes (APO-SUS, APO-UNSUS and ACI). No PPI deficits were found in the ACI and WAG/Rij rats, although ACI rats had a significantly higher basal startle amplitude. CONCLUSIONS: The PPI deficit in APO-SUS and not in the other genotypes, suggests that especially a relatively high DA reactivity of the mesolimbic system, together with a relatively low activity of the nigrostriatal system, contributes to this deficit. In contrast, the N50 gating deficit in WAG/Rij rats and not in the other genotypes suggests that a relatively high DA activity of the nigrostriatal system together with a relatively high DA reactivity of the mesolimbic system is necessary for the presence of a N50 gating deficit. On the basis of these results we have concluded that both auditory filtering processes are differently regulated by DA in the nigrostriatal and mesolimbic systems.