Perinatal delta 9-tetrahydrocannabinol exposure in rats modifies the responsiveness of midbrain dopaminergic neurons in adulthood to a variety of challenges with dopaminergic drugs.
The present study has been designed to explore further the existence of a persistent, but 'silent' alteration in the adult functionality of midbrain dopaminergic neurons following perinatal cannabinoid exposure. To this end, we evaluated the responsiveness of these neurons, measured at the neurochemical or behavioral levels, to pharmacological challenges with a variety of dopaminergic drugs administered to adult male and female rats that had been exposed to delta 9-tetrahydrocannabinol (THC) or vehicle during the perinatal period. Results were as follows: In the first experiment, we tested the magnitude of motor inhibition caused by administration of dopaminergic receptor antagonists. The most interesting observation was that the administration of SCH 23390, a D1 antagonist, produced a more marked motor inhibition, reflected by a greater decrease in the ambulation measured in an open-field test, in adult animals of both sexes when they had been exposed perinatally to THC. This did not occur with the motor inhibition caused by sulpiride, a D2 antagonist. In the second experiment, we evaluated the sensitivity of midbrain dopaminergic neurons to amphetamine (AMPH), which causes, through different mechanisms, a decrease in dopamine (DA) metabolism. The most interesting observation was that adult females, when exposed perinatally to THC, exhibited a trend to lesser response to AMPH, in terms of decreasing DA metabolism, than oil-exposed females. This was observed in dopaminergic terminals reaching the limbic forebrain area, but not in those terminals reaching the striatum, and was a specific effect for THC-exposed adult females because it was not observed in THC-exposed adult males. In the third experiment, we evaluated the in vivo synthesis of DA in midbrain dopaminergic neurons by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015. The most worthy finding was that, as occurred in the above experiment, adult females, when exposed perinatally to THC, tended to exhibit a higher ability to synthesize DA in vivo in the limbic forebrain but not in the striatum, as reflected by the increased L-DOPA accumulation observed after NSD 1015 administration. As in the above experiment, this was not seen in males. In summary, our results are consistent with the possible existence of subtle and sexually dimorphic changes in the sensitivity of midbrain dopaminergic neurons in adulthood caused by the exposure to THC during perinatal development. These silent changes could be revealed after the administration of drugs which specifically act on key processes of dopaminergic neurotransmission, such as the synthesis, reuptake and catabolism of DA and its binding to receptors.
Instituto Complutense de Drogodependencias, Department of Biochemistry, Complutense University, Madrid, Spain.
L
L
García
R
R
de Miguel
J A
JA
Ramos
J J
JJ
Fernàndez-Ruiz
D000818:Animals; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D013759:Dronabinol / Q000633:toxicity*; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects*; D012733:Sex Differentiation / Q000187:drug effects; D012737:Sex Factors; D009435:Synaptic Transmission / Q000187:drug effects
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D004295:Dihydroxyphenylalanine; D013759:Dronabinol; D004298:Dopamine