Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage

Abstract

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5–25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.

Allopregnanolone: An overview on its synthesis and effects

“…Indeed, it decreases the levels of dopamine and the dopamine metabolite 3,4‐dihydroxyphenylacetic acid in the striatum, 194 as well as the dopamine output in the nucleus accumbens and prefrontal cortex in freely moving rats 193 . In addition, females showing high progesterone levels (ie, in pro‐oestrus) are less responsive to ALLO treatment than in other oestrous phases 195 …”

“…193 In addition, females showing high progesterone levels (ie, in pro-oestrus) are less responsive to ALLO treatment than in other oestrous phases. 195 Interestingly, it has been proposed that ALLO may also affect the enzymatic activity of the DNA base excision repair (BER) pathway. Indeed, as recently reported in both natural and stressful conditions, the treatment with this neuroactive steroid is able to modulate the synthesis of BER pathway enzymes in sheep hippocampus and amygdala.…”

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

“…Potential limitations can originate when interpreting results coming from different species, genders, age, phases of lesion, and injury protocols (Table 1 ). In fact, the distribution of GABA ARs and their binding properties might vary among different strains [ 174 ], while also circulating sex hormones affect the sensitivity of GABA ARs to the allosteric endogenous modulator allopregnanolone in females [ 175 ]. Moreover, mechanical properties of the spinal cord change with size, making it hard to compare the severity of experimental injuries among studies of animals at different developmental stages [ 176 ].…”

Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

“…These receptors influence GABA release onto dopamine neurones and consequently dopamine release into the nucleus accumbens. Indeed, allopregnanolone influences dopamine release into the accumbens, an effect influenced by the oestrous cycle 107,108 . Altered expression of these neurosteroid‐sensitive δ‐GABA A Rs in this “reward pathway” could conceivably contribute to aspects of the behaviours associated with depression (e.g., anhedonia).…”