The effects of Δ⁹-tetrahydrocannabinol (THC) on the activity of brain dopaminergic neurons might be subject to gonadal influence. In this work, we tested this hypothesis in relation to the effects of THC on tuberoinfundibular dopaminergic (TIDA) activity, the anterior pituitary sensitivity to dopamine (DA) and prolactin (PRL) secretion. To this end, we examined the effects of an acute dose of this cannabinoid administered during different phases of the estrous cycle in the morning or afternoon. The results were as follows. THC, administered during the morning of estrus, stimulated TIDA activity as reflected by increases in DA and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents and tyrosine hydroxylase (TH) activity in the medial basal hypothalamus. This was accompanied by an increase in the responsiveness of the anterior pituitary to DA, as reflected by the increase in the density of D2 receptors and the corresponding decrease in PRL release. By contrast, plasma PRL levels increased when THC was administered on the afternoon of estrus, in parallel with a significant reduction in the number of D2 receptors in the anterior pituitary gland and no effects on TIDA activity. A similar decrease in the anterior pituitary density of D₂ receptors, but with no changes in plasma PRL levels, was observed when THC was administered during the morning of diestrus. This effect was not accompanied by changes in TIDA activity either. The administration of THC during the aftenoon of diestrus stimulated TIDA activity (increases in DA and DOPAC contents and TH activity in the medial basal hypothalamus), as occurred when the cannabinoid was administered during the morning of estrus, but in this case, it decreased the density of D2 receptors in the anterior pituitary and did not modify plasma PRL levels. These results contrast with the absence of significant changes observed when THC was administered during the morning or the afternoon of proestrus, although the highest plasma PRL levels and TIDA activity were observed during the afternoon of this phase. In summary, the effects of THC on TIDA activity, the sensitivity of the anterior pituitary to DA and PRL release seem to be under gonadal influence. This can be concluded from the observations that THC treatment caused different effects when administered to rats at different stages of the ovarian cycle. The classical inhibitory effect of THC on PRL release via an enhancement of TIDA activity observed in males was observed in females only during the morning of estrus. Different effects were seen during the diestrus and the afternoon of estrus, whereas its administration during proestrus was ineffective.

It was recently reported that anterior pituitary tissue transplanted to an ectopic site contains measurable amounts of dopamine and noradrenaline. To examine the possibility of local catecholaminergic control of prolactin secretion from ectopic pituitaries, pituitary grafted and sham-operated female rats were submitted to several pharmacological treatments modifying catecholamine synthesis. Administration of a single dose of alpha-methyl-p-tyrosine (alpha-MPT) significantly reduced dopamine content in the graft, while noradrenaline content was not modified. Similar changes in the contents of dopamine and noradrenaline after alpha-MPT administration were observed in the hypothalamus and in the in-situ pituitary in both grafted and sham-operated rats. Plasma concentrations of prolactin were increased in both grafted and sham-operated rats after administration of alpha-MPT. A single injection of L-3,4-dihydroxyphenylalanine (L-DOPA) increased dopamine content in the ectopic pituitary gland without altering the noradrenaline content, and produced similar effects in the hypothalamus and in-situ pituitary of grafted and control rats. Plasma prolactin concentrations were decreased by L-DOPA in both pituitary grafted and control rats. Administration of DL-treo-dihydroxyphenylserine (DOPS) increased noradrenaline content in the ectopic pituitary and reduced plasma prolactin concentrations in pituitary grafted rats. In contrast, injection of DOPS to control rats increased both hypothalamic noradrenaline content and plasma prolactin concentrations. These results suggest that dopamine and noradrenaline present in the ectopic pituitary tissue have a role in mediating prolactin release from pituitary transplants.

In order to study the possible role on prolactin secretion of the catecholamines present in ectopic pituitaries, female rats bearing an anterior pituitary graft under the kidney capsule since day 30 of life and their sham-operated controls, were sacrificed at 1,2, 4, 7, 15, 30, 45 and 60 days after the operation. Data obtained showed a significant increase in plasma prolactin levels in grafted rats versus controls from the 4th day on after the grafting (p < 0.01) until the 60th day (p < 0.001). Dopamine content in the ectopic pituitary of grafted rats was higher than in their own in situ pituitaries or on those of sham-operated rats until day 45 being similar to them afterwards. Norepinephrine was also present in the pituitary graft but was not detected in the in situ pituitaries. The grafting of an anterior pituitary gland in an ectopic location was able to induce changes in the local catecholaminergic control of the prolactin secretion.

Recent evidence suggests that increased plasma prolactin (PRL) levels could be modifying the synthesis and release of catecholamines (CA) from the adrenal medulla. In order to study this possibility, female rats bearing an anterior pituitary gland, from a litter-mate donor, under the right kidney capsule since day 30 of life and their sham-operated controls were sacrificed by decapitation 45 days after the transplant operation. Plasma PRL and CA levels and CA content in the adrenal medulla were analyzed. A significant increase in plasma PRL levels was shown in grafted (22 ± 2 µg/1) when compared to control rats (6 ± 0.3 µg/1), together with a significant increase in plasma norepinephrine (NE) (4.2 ± 1.1 µg/1 vs. 1.7 ± 0.7 µg/1) and epinephrine (E) (2.9 ± 0.6 µg/1 vs. 1.6 ± 0.2 µg/1). Similar plasma dopamine (DA) levels were found in both groups (0.6 ± 0.2 µg/1 vs. 0.8 ± 0.3 µg/1). An increase in adrenal DA content (29.1 ± 6.8 ng/mg protein), together with a decrease in NE (33.3 ± 6.8 ng/mg protein) and E content (65.9 ± 11.8 ng/mg protein) was detected in grafted as compared to control rats (DA: 12.0±3.6 ng/mg protein; NE: 79.3 ± 22.1 ng/mg protein; E: 184.2± 39.2 ng/mg protein). We can conclude from these data that the elevation of circulating PRL levels induced by a pituitary graft is able to increase the synthesis and release of CA from the adrenal medulla in female rats.