Drugs used to treat psychiatric disorders, although effective, are often restricted by adverse events. The use of partial agonists for treating hypertension was found to limit some of the side-effects in some patients. This led to the investigation of partial agonists as a treatment modality in psychiatric disorders. Partial agonists have a lower intrinsic efficacy than full agonists leading to reduced maximum response. They can act as antagonists by competing for receptor binding with full agonists. The level of activity depends on the level of endogenous receptor activity. Buprenorphine, a partial agonist at the mu-opioid receptor, is used to treat patients with addiction and decreases the symptoms of withdrawal and risks of overdose and intoxication. The anxiolytic buspirone shows partial agonism at 5-HT(1A) receptors, and this seems to provide anxioselective effects, without inducing extrapyramidal side-effects, convulsions, tolerance or withdrawal reactions. In schizophrenia, partial dopamine agonism results in antagonistic effects at sites activated by high concentrations of dopamine and agonistic effects at sites activated by low concentrations of dopamine. This stabilizes the dopamine system to effect antipsychotic action without inducing adverse motor or hormonal events. Aripiprazole is the first 'dopamine system stabilizer', and the data are promising, with efficacy at least equivalent to that with current atypical antipsychotics but fewer of the troublesome side-effects. Partial agonists seem to provide a way to fine-tune the treatment of psychiatric disorders by maximizing the treatment effect while minimizing undesirable adverse events.
"Fluoxetine is a potent and highly selective inhibitor of the transporter for serotonin reuptake at the presynaptic membrane, causing increases in serotonin concentrations at postsynaptic receptor sites (Wong et al., 1995). Buspirone exerts anxiolytic effects by acting as a partial agonist at serotonin 5-HT1A receptors (Ohlsen and Pilowsky, 2005), and it also interacts to a lesser degree with other receptors, such as the dopamine D2 receptor (Dhavalshankh et al., 2007). The antipsychotic drug risperidone belongs to the benzisoxazole chemical class (Kumar et al., 2008; Courchesne et al., 2007) and has been reported to act therapeutically by blocking serotonin and dopamine receptors (Grant, 2007); thus, it is useful for studying increases in serotonin neurotransmission . "
"Partial agonists have been widely used to treat psychiatric disorders such as schizophrenia (Ohlsen and Pilowsky, 2005), which act by counteracting excessive dopaminergic activation whilst ensuring sufficient dopamine transmission to avoid adverse motor and other side effects. Examples include preclamol and terguride (Carlsson, 1988) and, more recently, aripiprazole (Ohlsen and Pilowsky, 2005; Tamminga, 2002), which acts as a partial agonist at dopamine D 2 /D 3 receptors and 5-hydroxytryptamine (serotonin) 5-HT 1A receptors, and curiously as a serotonin 5-HT 2A receptor antagonist as well (Burris et al., 2002; Hirose et al., 2004; Shapiro et al., 2003; Stark et al., 2007). Nevertheless, therapeutic doses of this compound fully occupy D 2 receptors with only minor binding at serotonin receptors (Natesan et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favourable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine. The drugs were tested in male Swiss mice for their effects on locomotion, conditioned place preference (CPP) and nociception. Morphine (20mg/kg) increased motor activity, whereas aripiprazole (0.1, 1 and 10mg/kg) did not induce any change. This antipsychotic, however, prevented morphine-induced locomotion. In the conditioning box, aripiprazole did not induce either reward or aversion. Yet, it prevented both the acquisition and the expression of morphine-induced CPP. Finally, none of the doses of this antipsychotic interfere with morphine (5mg/kg)-induced antinociception in the tail-flick test. In conclusion, aripiprazole inhibited the abuse-related effects of morphine at doses that do not interfere with basal locomotion, reward or aversion. Also, it did not alter morphine-induced antinociceptive effects. This antipsychotic should be further investigated as a possible substitutive strategy for treating certain aspects of opioid addiction.
European Journal of Pharmacology 09/2014; 742. DOI:10.1016/j.ejphar.2014.09.004 · 2.53 Impact Factor
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