Differences between antipsychotic drugs in persistence of brain levels and behavioral effects

Cohen, Bruce M.; Tsuneizumi, T.; Baldessarini, Ross J.; Campbell, Andrea Louise; Babb, Suzann M.

doi:10.1007/bf02245121

Cited by 59 publications

(25 citation statements)

References 37 publications

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“…LI was likewise more robust in the SAL/CLZ condition following only a single administration in Experiment 3 than following the three injections of Experiment 2. Interestingly, it has been demonstrated that the half-life time of HAL in brain tissue is longer than that of many other neuroleptics, such that both active avoidance and apomorphine-induced activity can be reduced by haloperidol administered on previous days Cohen et al 1992). Such phenomena could underlie the more pronounced ability of repeated HAL compared with repeated CLZ administration to reduce LI.…”

supporting

confidence: 39%

Clozapine and Haloperidol Reinstate Latent Inhibition Following its Disruption during Amphetamine Withdrawal

Russig

Murphy

Feldon

2002

Neuropsychopharmacology

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Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a non-reinforced stimulus retards subsequent conditioning to that stimulus. Deficits in LI may reflect an inability to ignore irrelevant stimuli and are studied as a model of the cognitive/attentional abnormalities found in schizophrenia. We recently determined that pretreatment with escalating doses of the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5 mg/kg, over 6 days) disrupts LI in ratsAmphetamine (AMPH) administration can induce symptoms of psychosis in humans. This outcome is most frequently observed following a chronic high-dose escalating pattern of stimulant abuse (Davis and Schlemmer 1980;Angrist 1994). Given that stimulant-induced psychosis resembles the psychosis observed in patients with idiopathic schizophrenia (Ellinwood 1967;Snyder 1973;Brady et al. 1991), it has been suggested that similar neural adaptations could be responsible for the development of these two phenomena. In experimental animals, repeated exposure to AMPH induces behavioral sensitization, a phenomenon that is indicated by a progressive augmentation of behaviors (e.g. locomotion, stereotypies) to subsequent drug challenges and can persist even after prolonged periods of abstinence (Robinson and Becker 1986). Consequently, it has been proposed that studies of the neural bases of behavioral sensitization in animals may yield insights into the neuropathology of schizophrenia (Kokkinidis and Anismann 1980;Robinson and Becker 1986;Liebermann et al. 1990). 26 , NO . 6 In contrast to the sensitizing effects of repeated psychostimulant challenges on behavior, several reports indicate that withdrawal from repeated stimulant administration induces a state of dysphoria, characterized by symptoms that include anhedonia, anxiety and lethargy. Although such symptoms typically persist for only the first few days of abstinence, these findings have prompted the study of acute psychostimulant withdrawal as an animal model of depression (Leith and Barrett 1976;Kokkinidis et al. , 1986Geyer and Markou 1995;Barr and Phillips 1999;Lin et al. 1999). Given the proposed links between behavioral sensitization to AMPH in rats and psychosis in humans, and evidence of cross-sensitization between AMPH and stress (Antelman et al. 1980), we recently attempted to further characterize how animals in withdrawal from AMPH might demonstrate altered responses to environmental stimulation. We hypothesized that AMPH-withdrawn animals may also exhibit behaviors consistent with recognized models of schizophrenia.Many investigators studying animal models of cognitive deficits in schizophrenia have evaluated the behavioral phenomenon of latent inhibition (LI). LI refers to the process whereby repeated exposure to a conditioned stimulus (CS) without consequence impedes the formation of subsequent associations between the CS (e. g. a tone) and a relevant unconditioned stimulus (UCS; e. g. a footshock; Lubow 1973). Reductions in LI have been reported in acute schizop...

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supporting

confidence: 39%

Clozapine and Haloperidol Reinstate Latent Inhibition Following its Disruption during Amphetamine Withdrawal

Russig

Murphy

Feldon

2002

Neuropsychopharmacology

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“…The concentrations necessary for the antagonistic potencies against 5-HT-evoked Na þ and Ca 2 þ fluxes are within the range of concentrations of antipsychotics reached in rat brain tissue after acute or chronic application, [45][46][47][48] and thus appear to be of therapeutical relevance. Furthermore, haloperidol concentrations in the range between 8.9 and 226 mM have been shown in human post-mortem brain tissue.…”

Section: Discussionmentioning

confidence: 46%

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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The serotonin type 3 (5-HT 3 ) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT 3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT 2 ) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT 3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na þ -inward currents through 5-HT 3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT 3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca 2 þ influx, measured as a change in intracellular Ca 2 þ concentrations ([Ca 2 þ ] i ). All neuroleptic drugs, but not risperidone, antagonized Na þ -and Ca 2 þ -inward currents evoked by 5-HT (10 lM for 2 s and 1 lM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC 50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT 3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na þ and Ca 2 þ currents. Since 5-HT 3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT 3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

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“…The differences in phar macokinetic prohles of both drugs are unlikely to ac count for these effects. In fact, a considerably longer elimination half-life from both brain and plasma of haloperidol (4 to 14 hours [Ohman et al 1977]) or even several days after chronic treatment [Cohen 1992]) as compared with a very rapid elimination rate of cloza pine (1 to 2 hours [Baldessarini et al 1993]) would indi cate that in the rat, haloperidol could still attain detect able levels in brain 5 days after cessation of treatment.…”

Section: Neonatal Hippocampal Damage and Neuroleptics 203mentioning

confidence: 45%

Subchronic Treatment with Haloperidol and Clozapine in Rats with Neonatal Excitotoxic Hippocampal Damage

Lipska

Weinberger

1994

Neuropsychopharmacol

125

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We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mglkg, IP), or clozapine (CLOZ) (4 mglkg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty-and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-Iesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.

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Differences between antipsychotic drugs in persistence of brain levels and behavioral effects

Cited by 59 publications

References 37 publications

Clozapine and Haloperidol Reinstate Latent Inhibition Following its Disruption during Amphetamine Withdrawal

Clozapine and Haloperidol Reinstate Latent Inhibition Following its Disruption during Amphetamine Withdrawal

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Subchronic Treatment with Haloperidol and Clozapine in Rats with Neonatal Excitotoxic Hippocampal Damage

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