PERINATAL DELTA(9)-TETRAHYDROCANNABINOL EXPOSURE ALTERS THE RESPONSIVENESS OF HYPOTHALAMIC DOPAMINERGIC-NEURONS TO DOPAMINE-ACTING DRUGS INADULT RATS

We have recently reported that perinatal cannabinoid exposure altered the normal development of dopaminergic neurons in the medial basal hyp othalamus at early postnatal and peripubertal ages. Most of these effe cts tended to disappear in adulthood, although we suspect the existenc e of a persistent, but possibly silent, alteration in the adult activi ty of these neurons. To further explore this possibility, we evaluated the responsiveness of these neurons to pharmacological challenges wit h a variety of dopaminergic drugs administered to adult male and femal e rats that had been exposed to Delta(9)-tetrahydrocannabinol (Delta(9 )-THC) or vehicle during the perinatal period. In the first experiment , we evaluated the sensitivity of hypothalamic dopaminergic neurons to amphetamine (AMPH), which causes enhancement of dopaminergic activity by a variety of mechanisms. The most interesting observation was that both adult males and females, when perinatally exposed to Delta(9)-TH C, showed a more marked AMPH-induced decrease in the production of L-3 ,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metaboli te of dopamine (DA), although this did not affect the prolactin (PRL) release. In the second experiment, we evaluated the in vivo synthesis of DA by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L-DO PA) accumulation caused by the blockade of L-DOPA decarboxylase with N SD 1015. As expected, NSD 1015 increased L-DOPA accumulation and decre ased DOPAC production, with a parallel increase in PRL release, all of similar magnitude in both Delta(9)-THC-and oil-exposed adult animals. In the last experiment, we tested the magnitude of the increase in PR L release produced by the administration of either SKF 38393, a specif ic D-1 agonist, or sulpiride, a specific D, antagonist; Both compounds increased plasma PRL levels in adult animals of both sexes, the effec ts in females being significantly more marked. The perinatal exposure to Delta(9)-THC also modified the degree of increase in plasma PRL lev els induced by both compounds, with opposite responses as a function o f sex. Thus, Delta(9)-THC-exposed females responded more intensely to SKF 38393 and, particularly, to sulpiride than oil-exposed females, wh ereas ag-THC-exposed males responded to SKF 38393 lesser than oil-expo sed males, although both responded equally to sulpiride. In summary, o ur results are consistent with the possible existence of subtle change s in the activity of hypothalamic dopaminergic neurons in adulthood ca used by the exposure to Delta(9)-THC during perinatal development. The se silent changes could be revealed after the administration of drugs such as: (i) AMPH, whose effect producing a decreased DOPAC accumulati on was more marked in hg-THC-exposed males and females; and (ii) SKF 3 8393 and sulpiride, whose stimulatory effects on PRL secretion were of different magnitude in Delta(9)-THC-exposed animals, with an evident sexual dimorphism in the response. The neurochemical basis for these d ifferences remains to be determined. (C) 1997 Elsevier Science Inc.