Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats.
We have recently reported that perinatal cannabinoid exposure altered the normal development of dopaminergic neurons in the medial basal hypothalamus at early postnatal and peripubertal ages. Most of these effects tended to disappear in adulthood, although we suspect the existence of a persistent, but possibly silent, alteration in the adult activity of these neurons. To further explore this possibility, we evaluated the responsiveness of these neurons to pharmacological challenges with a variety of dopaminergic drugs administered to adult male and female 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)-THC, showed a more marked AMPH-induced decrease in the production of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite 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-DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015. As expected, NSD 1015 increased L-DOPA accumulation and decreased 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 PRL release produced by the administration of either SKF 38393, a specific D1 agonist, or sulpiride, a specific D2 antagonist. Both compounds increased plasma PRL levels in adult animals of both sexes, the effects in females being significantly more marked. The perinatal exposure to delta(9)-THC also modified the degree of increase in plasma PRL levels induced by both compounds, with opposite responses as a function of sex. Thus, delta(9)-THC-exposed females responded more intensely to SKF 38393 and, particularly, to sulpiride than oil-exposed females, whereas delta(9)-THC-exposed males responded to SKF 38393 lesser than oil-exposed males, although both responded equally to sulpiride. In summary, our results are consistent with the possible existence of subtle changes in the activity of hypothalamic dopaminergic neurons in adulthood caused by the exposure to delta(9)-THC during perinatal development. These silent changes could be revealed after the administration of drugs such as: (i) AMPH, whose effect producing a decreased DOPAC accumulation was more marked in delta(9)-THC-exposed males and females; and (ii) SKF 38393 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 differences remains to be determined.
García-Gil
L
L
Department of Biochemistry, Faculty of Medicine, Complutense University, Madrid, Spain.
De Miguel
R
R
Muñoz
R M
RM
Cebeira
M
M
Villanua
M A
MA
Ramos
J A
JA
Fernández-Ruiz
J J
JJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000633:toxicity*; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011388:Prolactin / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013469:Sulpiride / Q000494:pharmacology
D015259:Dopamine Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D006834:Hydrazines; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D013759:Dronabinol; D013469:Sulpiride; D011388:Prolactin; C004297:3-hydroxybenzylhydrazine; D000661:Amphetamine; D004298:Dopamine