PubMed · 15865730
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Andrew McIntosh, Stephen Lawrie. 2004. Schizophrenia.. https://pubmed.ncbi.nlm.nih.gov/15865730/
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RATIONALE: Rat maternal behavior, which entails complex motivational and social factors, is disrupted by the currently available typical and atypical antipsychotics. It is thought that this disruption reflects a side effect of antipsychotics, modeling the neuroleptic-induced negative or deficit state. Amisulpiride and aripiprazole are new atypical antipsychotics with mechanisms of action distinct from the current typical and atypical antipsychotics. The effects of these drugs on maternal behavior have not been explored. OBJECTIVE: In the present study, we systematically examined the behavioral effects of amisulpiride and aripiprazole on maternal behavior in postpartum female rats. METHODS: Various components of maternal behavior (pup retrieval, pup licking, nest building and pup nursing) were examined repeatedly over a period of 24 h after a single injection of three doses of amisulpiride (10, 30, and 100 mg/kg s.c.) and aripiprazole (3, 10, and 30 mg/kg). RESULTS: Amisulpiride at the lower doses (10 and 30 mg/kg) enhanced pup licking, and only at the highest dose disrupted the active components of maternal behavior such as pup retrieval and nest building. Its effect was delayed in onset and prolonged as compared to other antipsychotics. Aripiprazole, even at the highest dose (30 mg/kg) did not impair pup retrieval or pup licking. However, it did disrupt nest building and led to enhanced pup nursing. CONCLUSIONS: The unique effects of these two drugs may be due to their unique actions at the mesolimbic dopamine synapses. The sparing of the major components of maternal behavior by aripiprazole may be related to its partial agonist effects, whereas the enhancement of pup licking by amisulpiride may be related to its dose-dependent preferential effect on the presynaptic autoreceptors. The potential clinical implications of these findings are discussed.
BACKGROUND: A recent meta-analysis rejected the "delayed onset of antipsychotic action hypothesis" that had been described in textbooks for decades. Since meta-analyses are prone to a number of methodological problems, we attempted a replication by a) using a large database of individual patient data rather than meta-analysis, b) including another antipsychotic and c) extending the analysis from four weeks to one year. METHODS: We pooled the data of seven randomized trials involving amisulpride. The data included 1708 patients with schizophrenia and positive symptoms and we examined the incremental percentage Brief Psychiatric Rating Scale (BPRS) reduction over time. RESULTS: The "early onset of antipsychotic action hypothesis" was confirmed, as the reduction of overall and positive symptoms until week two was larger than the additional reduction until week four (p<.0001). Furthermore, in a subset with long-term data (n=748) approximately 68% of the mean BPRS change at one year was already achieved at four weeks in the observed cases. CONCLUSIONS: A substantial amount of the antipsychotic drug effect seems to occur during the first weeks of treatment. Subsequent analyses are needed to establish how long an antipsychotic should be tried before it is considered ineffective and alternative strategies implemented.
The endogenous opioid system is known to have a great influence on the dopaminergic system. Conversely, blockade of the dopaminergic system in D2 receptor knock-out mice triggers an increase in enkephalin supporting the important physiological relationship between both systems. Therefore, the aim of this study was to investigate whether or not chronic treatment with the specific D2 antagonist amisulpride (20mg/kg, i.p., twice daily for 5 days) could lead to a facilitation of behavioral effects of enkephalins, protected from their enzymatic degradation by the dual inhibitor N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-l-phenylalanine benzyl ester (RB101) (5mg/kg, i.v.) in mice. RB101 induced an increase in locomotor activity, antidepressant-like effects in the forced swim test, and antinociceptive effects in the hot-plate test. Chronic treatment with amisulpride potentiated the action of RB101 and this effect seemed to be restricted to behavioral responses induced by opioids acting on delta-opioid receptors (locomotor activity and forced swim test). This was confirmed by the use of the selective delta-opioid receptor agonist, (+)-4-[alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80; 2.5mg/kg, i.p.), and antagonist, naltrindole (5mg/kg, i.p.). Considering the involvement of delta-opioid receptors in mood regulation, the interaction between amisulpride and RB101 could lead to a new therapeutic approach in the treatment of some mood disorders.