Pharmacological models predicting antipsychotic actions — what is their future use?

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X08 Validation of animal models in schizophrenia

with treatment outcome. The most common new-onset adverse clinical events were diarrhea, headache, pruritus, gastroinestinal side effects and impairment of libido. Acamprosate was discontinued in 10 (2.3%) of patients because of adverse events, mainly diarrhea. 1 death occured during the study (status asthmaticus). Findings from a linear regression analysis conIirmed no significant effect of age, sex, level of education, marital status, living alone or not, a family history of alcoholism, the duration of alcoholism, and a baseline GGT value on the main criteria. The severity of alcohol dependence according to DSM-111-t’criteria was found to be associated with duration of abstinence (p = 0.003). Some variables of the NEO-FFI scales were found to be possibly associated with treatment outcome. Conclusions: The efficacy of acamprosate in reducing relapse rates in recently detoxified alcoholics has been demonstrated in a number of placebo-controlled double-blind studies. Alcohol research currently tries to link patient characteristics to treatment outcome. The “matching hypothesis” states that clients who are appropriately matched to treatments will show better outcomes. As in the Project Match study on different kinds of psychotherapy (The Project Match Research Group 1997a, b) no relevant differences concerning abstinence could be demonstrated for the different treatment groups. It seems noteworthy that the least intensive and structured (‘brief’) intervention in combination with pharmacotherapy also resulted in a favorable treatment outcome. This tinding suggests that at least a subgroup of alcohol dependent patients clearly benefits from a combination of phannacotherapy and brief intervention therapy. Alcohol history, severity of dependence and certain personality traits may be predictive of treatment outcome. References [l] al Quatari M, Bouchenafa 0, Littleton J. Mechanisms of action of acamprosate.

[2]

[3] [4]

[5]

Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex. Alcohol Clin Exp Res 1998; 22: 81&814 Project Match Research Group. Matching Alcoholism Treatments to Client Heterogeneity: Project MATCh Posttreatment Drinking Outcomes. J Stud Alcohol 1997a; 58: 7-29 Project Match Research Group. Project MATCH secondary a priori hypotheses. Addition 1997b; 92: 1671-1698 Sass H., Soyka M., Mann K., Zieglgiinsberger W. Relapse prevention by acamprosate: results from a placebo controlled study in alcohol dependence. Arch Gen Psychiatry 1996; 53: 673480 Soyka M. Relapse Prevention in Alcoholism: Recent Advances and Future Possibilities. CNS Drugs 1997; 7: 3 13-327

[s.o7.05]

New findings concerning alcoholism

naltrexone

treatment

of

M. Berghmd. Department of Clinical Alcohol Research, Lund University, Malmoe University Hospital, Malmoe, Sweden

Naltrexone treatment of substance use disorders has been increasingly used during the 90ies both in alcohol use disorders and in opiate disorders. The tirst part of the paper concerns treatment of opiate use disorders. Six randomized controlled studies have reported the effect of naltrexone maintenance therapy in opiate use disorders. The studies have in general reported positive effects. In addition, naltrexone has been used in two randomized controlled studies during rapid detox and two during ultrarapid detox of opiate dependence. The reported change of craving during naltrexone treatment in these studies is summarized. The second part of the paper presents data from previous naltrexone studies in alcohol use disorders. The early studies by Volpicelli et al. 1992 and by O’Malley et al. 1992 both reported impressive effect sizes around 30% fewer abusing alcoholics on active drug. Several new US studies support this tinding, while the results of two European studies have shown less convincing results. In these two studies psychosocial treatment “as usual” was used contrary to the US studies, in which cognitive behavior therapy, CBT, was used as one of the treatment alternatives. Prediction of positive effects has been presented in the early US studies including high level of craving and signs of cognitive dysfunction.

In the Swedish Naltrexone Study (Balldin, Berglund, Borg, Mansson et al., 1998) a design with randomization for naltrexone/placebo as well as for coping skill educational program (manual baaed)/treatment as usual was used. 120 alcoholics, 102 men and 18 women, attended the study. The treatment period was 6 months. The attrition rate was 23%. The percentage of heavy drinking days was lower in the CBT group versus the treatment as usual group (21 f 21% vs. 30 -f 7; p < 0.05). The percentage of days with heavy drinking in the placebo/CBT group was 25 f 22% and in the naltrexone/CBT group 16 f 20% (p < 0.05). In the treatment as usual group there was no difference between naltrexone and placebo. Reported craving was significantly lower in the Naltrexone CBT group compared with the other groups. The result of the Swedish Naltrexone Study was similar to the O’Malley study concerning alcoholics sampling alcohol. In a one-year follow-up the outcome was stable contrary to the O’Malley study supporting the importance of a six months treatment period. New positive findings concerning naltrexone treatment in the Swedish study is presented and compared with previous findings in Naltrexone studies both in opiate dependence and in alcohol dependence.

S.08 Validation of animal models in schizophrenia Js.08.011

Pharmacological models predicting antlpsychotic actions - what is their future use?

SO. Ggren. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden Drug development during the past decade has been directed towards compounds (like clozapine) that are effectivs antipsychotic drugs with a low propensity to cause EPS including tardive dyskinesia and with efficacy in treatment resistant patients, e.g. atypical antipsychotic drugs. A combination of various experimental models has been used to characterize “atypical” antipsychotic properties in the rat (see bgren, 1996). A blockade of locomotor hyperactivity elicited by small doses of “DA agonists” such as d-amphetamine or apomorphine has been employed as an animal model for investigations of limbic DA functions and, thus, as a measure of therapeutic efficacy. This model is based on the hypothesis that stimulation of DA receptors within parts of the mesolimbic DA system, e.g. the nucleus accumbens, is at least partly responsible for the locomotor response. Other measures predictive of “antipsychotic” effects include inhibition of apomorphine-induced climbing, inhibition of the conditioned avoidance response (CAR) or a differential action in the paw test. Measures for the potential of inducing EPS have varied. The ability to induce catalepsy in relationship to potency in the “antipsychotic” test has_become a useful measure for assessment of the potential for EPS (Ogren 1996; Amt et al., 1997). Inhibition of oral stereotypies, e.g. gnawing, elicited by high doses of DA agonists such as apomorphine, although earlier used as a measure for antipsychotic effects, is today seen as an indicator of later motor side effects. The relevance of the use of direct or indirect DA agonists such as d-amphetamine as a behavioural model for the acute phase of schizophrenia, e.g. positive or paranoid forms has been extensively documented with classical and novel antipsychotic drugs. The neuropharmacological profile of novel antipsycotic compounds is summarized in Table I. Thus, both DA D2 antagonists such as remoxipride, sulpiride and amisulpiride as well as compounds with multitransmitter interactions such as quietipine, risperidone, sertindole, ziprasidone as well as clozapine and olanzapine are active in these behavioural model. Unlike haloperidol, the novel antipsychotic” drugs preferentially block behaviours associated with the mesolimbic DA system, e.g. locomotion over those associated with the nigrostriatal DA system, e.g. catalepsy. Thus, there exists a clear difference between the doses required to block DA agonist-induced hyperactivity and the doses causing catalepsy or the doses required to block stereotypies (bgren 1996; Amt et al., 1997). The inhibition of DA agonist-induced locomotion suggest a preferential blockade of limbic

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DA neurotransmission which predicts antipsychotic activity. Besides inhibition of DA agonist-induced hyperactivity, blockade of CAR seems to be a property shared by all effective antipsychotic agents. Another important line of research relates to the role of multiple DA receptor subtypes. Since the DA receptor subtypes (Dl, D2, D3 and D4 receptors) are all targets in varying degrees for most antipsychotic drugs, analysis of the role of the various DA subtypes for antipsychotic action is critical. Interestingly, selective D3 and D4 receptor antagonists appear not to be active in the “classical” test models for antipsychotic activity. Among the non-dopaminergic approaches (e.g. ~-HTzA antagonists, 5-HT3 antagonists, sigma antagonists) most compounds tested seem to be ineffective in “classical” models predictive for antipsychotic effects. Catalepsy is regarded as analogous to EPS in man, particularly parkinsonism, and the degree of catalepsy is often used as an important measure for predicting the incidence of EPS. Most studies have shown that clozapine even at high doses fails to induce dose-dependent catalepsy in the rat. In contrast, the clozapine analogue olanzapine is cataleptogenic at high doses, similar to ziprasidone, seroquel and risperidonc while sertindole appears not to be cataleptogenic even at high doses (Ogren 1996; Amt et al., 1997). Table I. The neuropharmacological profile of novel “atypical antipsychotic” drugs.

I, Preferential blockade of DA agonist-induced hyperactivity compared to oral stereotypies 2. Blockade of phencyclidine-induced hyperactivity 3. Blockade of two-way conditioned avoidance (CAR) 4. Induction of catalepsy at high doses 5. Wide separation between blockade of DA agonist-induced hyperactivity (CAR) and catalepsy 6. Upon repeated treatment they diminish the spontaneous firing rate of Al0 DA-neurons without decreasing the rate of A9 neurons 7. Some of these compounds appear not to induce supersensitivity to DA agonists following related treatment Although the profile in the animal tests predicts that the novel drugs can separate between antipsychotic and EPS functions, it is notable that clozapine remains the only drug, with the possible axception of sertindole, which does not include signs of catalepsy in the rat even at very high doses. This fact suggests that EPS separation shown in animal tests may not be sufficient to avoid motor disorders at clinically relevant doses, particularly in sensitive patients. Taken together, by the above criteria it has been possible to differentiate between atypical and classical antipsychotic agents. However, the mechanisms underlying these differencies, e.g. the wide spectrum of receptor action in atypical drugs, e.g. 5-HT#A D2 receptor-ratios cannot easily be related to their behavioural actions. These findings suggest that compounds with an atypical profile may act via multiple interactive mechanisms and that they do not constitute a functionally homogenous group. The available results demonstrate that behavioural models have a major impact on drug discovery and in the evaluation of novel mechanisms. In the next decade further insights into drug action and possibly psychosis will be obtained by the combination of behavioural pharmacology with molecular biology. Improved animal models will be developed based on studies which combine gene expression and transgenic control in relevant forebrain areas with behavioural expression. Important information will also be found from behavioural studies with transgenic mice which overexpress neurotransmitter receptors, e.g. DA D2 receptors. In addition, the deletion of “key” proteins, e.g. protein kinases will make it possible to establish possible different mediators of the behavioural response in knockout animals after treatment with typical and atypical antipsychotic agents. References [1] iigren, S. O., 1996. The behavioral pharamcology of typical and atypical antipsychotic drugs. In: J. G. Csemansky (Ed.), The Handbook of Experimental Pharmacology. Volume: 120. Antipsychotics, Springer, Berlin, pp. 225-244. [2] Amt, J., Skarsfeldt, T., Hyttel, J., 1997. Differentiation of classical and novel antipsychotics using animal models (Review). Int. Clin. Psychopharmacol. 12 (suppl 1), s9-s17.

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Models mimicking schizophrenia

neurodevelopmental

aspects of

G. Wolterink, E.W.P.M. Daenen, M.A.F.M. Gerrits, C.G. Kruse’, J.A.M. Van Der Heijden’, J.M. Van Ree. Rudolf Magnus Institute for Neurosciences, Department of Medical Pharmacology. Utrecht University, Utrecht; ‘Solvay Pharmaceuticals, Weesp. The Netherlands

Several risk factors for schizophrenia and autism have been identified, such as a genetic predisposition, viral infections during pregnancy and pre- or perinatal trauma. Functional and anatomical studies in man have revealed that the normal pattern of brain development may be disturbed in patients with schizophrenia or autism. In particular the medial temporal lobe structures appear to be affected (Weinberger, 1987). It has been hypothesized that early dystiction in medial temporal lobe structures, including the amygdaloid complex and the hippocampus, affects the neuroanatomical and neurochemical organization as well as the functioning of subcortical and cortical areas, such as the neostriatum, basal forebrain, and prefrontal and parietal cortices, which share strong anatomical connections with medial temporal lobe structures (Bachevaher, 1994). Based on this notion Lipska and co-workers (1993) used early hippocampus lesions as an animal model for schizophrenia. In the present paper we further developed this animal model in which temporal lobe structures were damaged at early stages of life. Thus, we studied the effect of brain damage induced at postnatal days 7 and 21, i.e. early and late within the postnatal development period (Verwer et al., 1996), on rat behaviours. When lesions at an early and late stage of development (i.e. PD7 and PD21) result in similar functional disturbances, the structure itself is assumed to be critically involved. However, if a lesion induced on day 7 but not on day 21 of life results in functional deficits, a dysfunction of a structure outside the lesioned area as a result of a disturbed neurodevelopment is likely to be concerned. The brain damage was induced by infusion of the neurotoxin ibotenic acid bilaterally aimed at the basolateral amygdala or ventral hippocampus of male rat and subsequently social and non-social behavioural responses were assessed, A schematic overview of the behavioural consequences of the lesions in the amygdala or ventral hippocampus, induced at day 7 or day 21 of life is presented in table 1. Social play behaviour of juvenile rats and social behaviour in adulthood was markedly decreased in animals with amygdala lesions, induced at day 7 or day 21, but not in animals with ventral hippocampus lesions. Exploratory activity in a novel large open field was affected by both amygdala and ventral hippocampus lesions induced at day 7. Lesions in the amygdala induced an increase in distance moved in the outer area of the open field which is indicative of an increase locomotor activity. The ventral hippocampus lesioned animals on the other hand, particularly explored the center of the open field, and typically produced less droppings during the open field test. This suggests that these animals have a decreased anxiety response. In a small open field the amygdala lesioned animals again showed increased behavioural activity. The behaviour of the ventral hippocampus lesioned animals was not affected in this test. Lesion at day 21 of life of either the amygdala or ventral hippocampus failed to affect the behaviour of the animals in the open field tests. Tests in which animals were treated with low doses of apomorphine before testing in an familiar small open field revealed that amygdala lesions at day 7 of life lead to a supersensitive dopaminergic system, while similar lesions at day 21 or lesions in the ventral hippocampus had no such effect. Subsequent studies, in which apomorphine was locally administered in the nucleus accumbens, indicate that indeed the mesolimbic dopamine system has become supersensitive following early amygdala lesions. In a pre-pulse inhibition experiment it appeared that animals with early amygdala or ventral hippocampus lesions showed a diminished pre-pulse inhibition while lesions induced at day 21 of had no effect in this paradigm. In all animals the amplitude of the startle response was normal. Further studies of the amygdala lesioned animals showed that animals lesioned at day 7 of life failed to show the reduced exploration and increased freezing behaviour during 5 daily 10 min sessions of repeated footshocks and the reduction in ambulatory activity when tested in a small open field