Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain

Abstract

Pramipexole (PPX) is a D 2 /D 3 receptor agonist that has been shown to be effective in the treatment of depression. Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems are known to be involved in the pathophysiology and treatment of depression. Due to reciprocal interactions between these neuronal systems, drugs selectively targeting one system-specific receptor can indirectly modify the firing activity of neurons that contribute to firing patterns in systems that operate via different neurotransmitters. It was thus hypothesized that PPX would alter the firing rate of DA, NE and 5-HT neurons. To test this hypothesis, electrophysiological experiments were carried out in anesthetized rats. Subcutaneously implanted osmotic minipumps delivered PPX at a dose of 1 mg/kg per day for 2 or 14 days. After a 2-day treatment with PPX the spontaneous neuronal firing of DA neurons was decreased by 40%, NE neuronal firing by 33% and the firing rate of 5-HT neurons remained unaltered. After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%. It was also observed that sustained PPX administration produced desensitization of D 2 /D 3 and 5-HT 1A cell body autoreceptors, as well as a decrease in sensitivity of a 2 -adrenergic cell body autoreceptors. These adaptive changes are implicated in long-term firing rate adaptations of DA, NE and 5-HT neurons after prolonged PPX administration. In conclusion, the therapeutic action of PPX in depression might be attributed to increased DA and 5-HT neurotransmission.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

“…The PD with PG group was taking lower chronic DA agonist doses, along with compensatory increases in levodopa doses, in order to retain benefit to PD symptoms. Since both DA agonists and levodopa effect DA receptor expression (Chernoloz et al, 2009;Kaasinen et al, 2000;Pitts et al, 1995;Subramaniam et al, 1992;Thobois et al, 2004) we chose to match groups on total LEDD, but it must be acknowledged that these differences may have influenced our results.…”

“…However, pre-clinical studies have found that chronic administration of DA agonists cause decreased midbrain autoreceptor sensitivity (Chernoloz et al, 2009;Pitts et al, 1995;Subramaniam et al, 1992); potentially a compensatory mechanism for the temporary reductions in striatal DA release after acute doses. Thus, diminished occupation of D2 autoreceptors during gambling could represent DA agonist-induced lowered sensitivity of midbrain auto-receptors to endogenous DA release.…”

“…For example, two patients with PG were no longer using DA agonists, and the remainder had DA agonists reduced, with concomitant increases in levodopa (Table 2). Thus, we considered it more important to match patients for total levodopa equivalent doses rather than either levodopa or DA agonists, since both may have an impact on DA receptor expression (Chernoloz et al, 2009;Kaasinen et al, 2000;Pitts et al, 1995;Subramaniam et al, 1992;Thobois et al, 2004).…”

Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls

“…These findings indicate that acute occupation of relevant DA receptors is sufficient to enhance discounting; however, the adaptations in this system that were imposed with chronic administration may promote the effect. Chronic PPX treatments can lead to desensitization of DA neuronal D2/D3 autoreceptors (Chernoloz et al, 2009) and an increase in expression of D3R in dopaminoceptive regions (Maj et al, 2000). Whatever the mechanism, the neuroadaptations were reversible in the current study, for when (±)PPX treatment was discontinued for 2 weeks, discounting decreased near baseline levels.…”

Anticipatory postural adjustments stabilise the whole upper-limb prior to a gentle index finger tap

“…In addition, in animal studies, systemic administration of D 2 /D 3 receptor agonists, such as pramipexole or apomorphine, showed little or no effect on the firing rate of LC-NA neurons [26]. Finally, a persistent treatment with Data are reported as median and range (brackets).…”