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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 [11C]-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. [ABSTRACT FROM AUTHOR]

Summary. 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 (3 mg/kg s.c.), when given 24 h 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. [ABSTRACT FROM AUTHOR]

Venlafaxine (VEN), a representative of a new class of antidepressants (serotonin and noradrenaline reuptake inhibitors, SNRI), administered repeatedly affects—as was demonstrated by us previously—the behavioural responsiveness of α[sub 1] -adrenergic, dopaminergic (D[sub 2] and D[sub 3] ) and serotonergic systems to their agonists. In the present study we aimed to find out whether parallel changes in the binding to the respective receptors also occurred. The experiment was carried out on male Wistar rats. VEN was administered in a dose of 10 mg/kg once or repeatedly (14 days, twice daily). The obtained results showed that VEN did not change the binding (B [sub max] and K [sub D] ) of α[sub 1] -adrenergic receptors to [[sup 3] H]-prazosin in the cerebral cortex, having increased only its displacement by phenylephrine. The binding (B [sub max] and K [sub D] ) to D[sub 1] and D[sub 2] receptors in the limbic forebrain and the striatum was not affected by repeated venlafaxine when [[sup 3] H];-SCH 23390 and [[sup 3] H]-spiperone, respectively, were used as ligands. When [[sup 3] H]-quinpirole was used as a ligand, the binding was enhanced in the striatum, the nucleus accumbens (shell and core) and islands of Calleja. VEN also increased the binding of [[sup 3] H]-7-OH-DPAT to D[sub 3] receptors in islands of Calleja and the nucleus accumbens (shell). In the serotonergic system, a decrease in the density of 5-HT[sub 1A] receptors was observed in the hippocampus, whereas no changes occurred in the binding of 5-HT[sub 2] receptors in the cortex. Thus VEN given repeatedly enhanced the binding (of the ligands that are agonists) to dopamine D[sub 2] and D[sub 3] receptors. Weaker effects were observed in the α[sub 1] -adrenergic and the serotonergic systems. Copyright © 1999 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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 β-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 α1-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-dipropylo-aminotetralin (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 α1-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 α1-adrenergic receptors to their agonists. A question arises whether the re-uptake inhibition is of any importance to the adaptive changes induced by repeated antidepressants, suggested to be responsible for the antidepressant activity. [ABSTRACT FROM AUTHOR]