Perinatal delta9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA(B), but not GABA(A), receptor agonists in adult rats.
We have extensively reported that delta9-tetrahydrocannabinol (delta9-THC) exposure results in changes in the adult functionality of dopaminergic neurons, in particular, mesotelencephalic pathways, although some changes are evident only after pharmacological challenges. In the present study, we have examined whether similar changes might be observed in gamma-aminobutyric acid (GABA) activity, in particular, in those regions where cannabinoid receptors have been reported to be located in GABA-containing neurons. To this end, we first examined GABA content and glutamic acid decarboxylase (GAD) activity in several brain regions of adult male and female rats that had been perinatally exposed to delta9-THC or oil. Delta9-THC exposure did not modify either GAD activity or GABA content in the ventral-tegmental area, nucleus accumbens, substantia nigra, caudate-putamen, and globus pallidus, thus suggesting no changes in the basal presynaptic activity of GABA-containing neurons. Second, we tested the motor response in the open-field test of these animals after a single injection of muscimol, a GABA(A) receptor agonist, baclofen, a GABA(B) receptor agonist, or vehicle. We observed that the motor inhibition caused by baclofen, in terms of decreased ambulation and stereotypy and increased inactivity, was more marked in magnitude in delta9-THC-exposed males and females. This was not observed for the GABA(A) receptor agonist, muscimol, indicating a receptor specificity. To extend this observation, we also examined whether the potential differences in the behavioral response found in the above experiment might be due to changes at the level of the efficiency of the activation of these receptors by measuring basal and baclofen-stimulated [35S]-guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]-GTPgammaS) binding in adult male and female rats that had been perinatally exposed to delta9-THC or oil. However, our results were negative, because perinatal delta9-THC exposure did not increase baclofen-stimulated [35S]-GTPgammaS binding in the areas studied; in particular, in the substantia nigra, an area of interest for the interactions GABA(B) receptor/cannabinoid receptor. Collectively, the present results indicate that although perinatal delta9-THC did not produce any changes in GABA content and GAD activity in limbic and motor areas in adulthood, it did increase the behavioral response to GABA(B) receptor agonists. However, this increase was not due to changes in GABA(B) receptor activation of signal transduction mechanisms, as revealed the analysis of the percentage of stimulation by baclofen of [35S]-GTPgammaS binding in the substantia nigra and other structures of males and females perinatally exposed to delta9-THC.
Garcia-Gil
L
L
Instituto Complutense de Drogodependencias, Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense de Madrid, Spain.
de Miguel
R
R
Romero
J
J
Perez
A
A
Ramos
J A
JA
Fernández-Ruiz
J J
JJ
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D005865:Gestational Age; D005968:Glutamate Decarboxylase / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009118:Muscimol / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009928:Organ Specificity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D009118:Muscimol; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; D013759:Dronabinol; D005968:Glutamate Decarboxylase; D001418:Baclofen