A genetic determinant of the striatal dopamine response to alcohol in men.

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Some behavioural effects of antidepressant drugs are time-dependent.

1. The effects of repeated administration of antidepressant drugs (imipramine, IMI and citalopram, CIT) on the beta- and alpha2-adrenergic as well as dopaminergic D3 receptors were compared with time-dependent changes in the receptor responsiveness after acute treatment. 2. Repeated treatment with IMI or CIT (administered at a dose of 10 mg/kg p.o. twice a day for 14 days) induced down-regulation of beta-adrenergic receptors, demonstrated by behavioural experiment using salbutamol-induced hypoactivity and by binding studies using [3H]CGP12177. The changes in alpha2-adrenergic receptors were studied using clonidine-induced hypoactivity, which was attenuated by repeated treatment with IMI or CIT. Behavioural responsiveness of dopamine D3 receptors was investigated using two doses of 7-OH-DPAT. This drug at a dose of 0.05 mg/kg s.c. induced locomotor hypoactivity (interpreted as a result of stimulation of presynaptic dopamine D3 receptors), which was reversed by repeated administration of IMI or CIT, while 7-OH-DPAT at a dose of 3 mg/kg s.c. (which stimulated postsynaptic dopamine D3 receptors) induced significant hyperactivity, which was markedly enhanced by repeated administration of antidepressant drugs. 3. The effect of acute administration of IMI or CIT measured 14 days after drug treatment were similar to the described above alterations at the level of alpha2 adrenoreceptors and presynaptic dopamine D3 receptors, i.e. the drugs attenuated clonidine-induced hypoactivity and reversed locomotor hypoactivity evoked by low dose of 7-OH-DPAT. To induce the down-regulation of beta-adrenergic receptors or up-regulation of the behavioural responsiveness of dopaminergic D3 postsynaptic receptors, the repeated administration of IMI or CIT was necessary. 4. Therefore it has been concluded that presynaptic dopaminergic D3 and alpha2-adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 and beta-adrenergic receptors.

The role of dopamine D2 receptor in the behavioral effects of imipramine--study with the use of antisense oligonucleotides.

Antisense strategies have a potential to specifically block the production of a given protein, e.g. receptor subtype, thus may help to uncover its behavioral and/or biochemical function. In the present study we demonstrated the utility of this approach for studying the role of dopamine D2 receptors in the anti-immobility effect of imipramine in the forced swimming test. Following intracerebroventricular (i.c.v.) administration of phosphorothioate oligonucleotide complementary to mRNA encoding for dopamine D2 receptors (D2 antisense ODN; 1 nmol/1 microl H2O, twice a day for 5 days) to the rats, the decrease in the locomotor activity (shortened total distance travelled and decrease in vertical activity, without differences in the stereotypic movements of animals), as well as the decrease of specific binding of [3H]raclopride in the striatum and limbic forebrain were observed. At the same time, i.c.v. administration of D2 antisense ODN reversed the effect of imipramine in the forced swimming test, what may indicate that the dopamine D2 receptors play a significant role in the behavioral anti-immobility effects of imipramine.

Effect of local intracerebral administration of EMD 57445, a selective sigma receptor ligand, on the locomotor activity of the rat.

EMD 57445 is a new compound which has been characterized by high affinity for sigma receptor sites. It has not been shown to bind to any other receptors, including dopamine ones. However, hitherto existing data (behavioral as well as biochemical) have suggested that this drug exhibits functional antidopaminergic activity. Therefore, in the present study, the local cerebral administration of EMD 57445 has been used in order to better elucidate the actual site of action of this compound in the central nervous system. EMD 57445 given unilaterally into the nucleus accumbens, striatum and lateral ventricle decreases the locomotor activity of the rats, the effect being the most pronounced in the case of administration into the nucleus accumbens. Moreover, unilateral intraaccumbal injection of EMD 57445 significantly diminishes apomorphine (given peripherally)-induced hyperactivity. Local administration of EMD 57445 into the prefrontal cortex of the rats also attenuated the locomotor activity but the effect was statistically significant only after bilateral administration of the compound. Additionally, the lack of influence of EMD 57445, administered po, on the dopamine D1 and D2 receptor binding in the striatal membranes was observed in these studies. However, in limbic forebrain the density of D2 receptors decreased after the higher dose of EMD 57445. In conclusion, the results obtained in this paper support the hypothesis that EMD 57445 exerts antidopaminergic activity through indirect inhibition of dopamine system.

Repeated trimipramine induces dopamine D2/D3 and alpha1-adrenergic up-regulation.

Trimipramine (TRI), which shows a clinical antidepressant activity, is chemically related to imipramine but does not inhibit the reuptake of noradrenaline and 5-hydroxytryptamine, nor does it induce beta-adrenergic down-regulation. The mechanism of its antidepressant activity is still unknown. The aim of the present study was to find out whether TRI given repeatedly was able to induce adaptive changes in the dopaminergic and alpha1-adrenergic systems, demonstrated by us previously for various antidepressants. TRI was given to male Wistar rats and male Albino Swiss mice perorally twice daily for 14 days. In the acute experiment TRI (given i.p.) does not antagonize the reserpine hypothermia in mice and does not potentiate the 5-hydroxytryptophan head twitches in rats. TRI given repeatedly to rats increases the locomotor hyperactivity induced by d-amphetamine, quinpirole and (+)-7-hydroxy-dipropyloaminotetralin (dopamine D2 and D3 effects). The stereotypies induced by d-amphetamine or apomorphine are not potentiated by TRI. It increases the behaviour stimulation evoked by phenylephrine (given intraventricularly) in rats, evaluated in the open field test as well as the aggressiveness evoked by clonidine in mice, both these effects being mediated by an alpha1-adrenergic receptor. It may be concluded that, like other tricyclic antidepressants studied previously, TRI given repeatedly increases the responsiveness of brain dopamine D2 and D3 (locomotor activity but not stereotypy) as well as alpha1-adrenergic receptors to their agonists. A question arises whether the reuptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity.

Effect of repeated treatment with milnacipran on the central dopaminergic system.

Milnacipran (MIL) is a representative of a new class of antidepressants (SNRIs) which inhibit the reuptake of serotonin and noradrenaline, but, in contrast to tricyclics, show no affinity for neurotransmitters receptors. The present study was aimed at determining whether repeated MIL administration (given at doses of 10 or 30 mg/kg, twice daily for 14 days) induced the adaptive changes in the dopaminergic system similar to those reported by us earlier for tricyclic antidepressants. The obtained results showed that MIL administered repeatedly did not change the responsiveness of dopamine D1 receptors since it did not change the SKF 38393-induced grooming. Repeated MIL treatment increased the hyperlocomotion induced by D-amphetamine and 7-OH-DPAT, but did not affect the D-amphetamine and apomorphine stereotypies. The binding parameters (Bmax and Kd) to dopamine D1 and D2 receptors in the limbic forebrain were not affected by repeated MIL treatment when [3H]SCH 23390 and [3H]spiperone, respectively, were used as ligands. On the other hand, the increased density of dopamine D2 receptors (Bmax) was observed in the striatum after repeated treatment with MIL. MIL administered acutely or repeatedly did not change the binding of [3H]7-OH-DPAT to dopamine D3 receptors in the islands of Calleja and the shell region of the nucleus accumbens septi. The above results indicate that repeated MIL administration induces the adaptive changes in the dopaminergic system, especially it enhances the functional responsiveness of dopamine D2 and D3 receptors. However, the question whether this increased functional responsiveness is important for the clinical antidepressant efficacy, remains open.

The effect of repeated treatment with pramipexole on the central dopamine D3 system.

The study examined the effect of pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzthiazole dihydrochloride; PRA), a new potent dopamine receptor agonist with the high preference for D3 receptors, as compared to D2 or D4, on the central dopamine D3 system. Experiments were conducted on male Wistar rats. PRA was injected subcutaneously. PRA given repeatedly (14 days, twice a day, in doses of 0.3 and 1 mg/kg), but not acutely, potentiated the locomotor hyperactivity induced by (+/-)-7-OH-DPAT (3mg/kg s.c.), when given 24h after the single or the last dose of PRA. Administration of PRA, 1 mg/kg, for 3 or 7 days produced an effect similar to that described above, whereas a dose of 0.3 mg/kg produced such an effect only after 7, but not 3, days. Repeated treatment with PRA (0.3 and 1 mg/kg, 14 days, twice daily) also enhanced the D3 receptor binding in the islands of Calleja and nucleus accumbens (shell)--the brain region known to be rich in D3 receptors--when [3H]7-OH-DPAT was used as a ligand. Repeated PRA administration did not change the concentration of mRNA coding for D3 receptors in the islands of Calleja. The obtained results indicate that-- like the previously studied typical antidepressants given repeatedly--PRA increases the functional responsiveness and the binding to the brain dopamine D3 receptors. Hence PRA may be considered as a potential antidepressant drug.