Perinatal Δ9-Tetrahydrocannabinol Exposure Augmented the Magnitude of Motor Inhibition Caused by GABAB, but not GABAA, Receptor Agonists in Adult Rats

Abstract

GARCIA-GIL, L., R. DE MIGUEL, J. ROMERO, A. PEREZ, J. A. RAMOS AND J. J. FERNÁNDEZ-RUIZ. Perinatal Δ9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABAB, but not GABAA, receptor agonists in adult rats. NEUROTOXICOL TERATOL. 21(3) 277–283, 1999.—We have extensively reported that Δ9-tetrahydrocannabinol (Δ9-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 γ-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 Δ9-THC or oil. Δ9-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 GABAA receptor agonist, baclofen, a GABAB 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 Δ9-THC–exposed males and females. This was not observed for the GABAA 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-(γ-thio)-triphosphate ([35S]-GTPγS) binding in adult male and female rats that had been perinatally exposed to Δ9-THC or oil. However, our results were negative, because perinatal Δ9-THC exposure did not increase baclofen-stimulated [35S]-GTPγS binding in the areas studied; in particular, in the substantia nigra, an area of interest for the interactions GABAB receptor/cannabinoid receptor. Collectively, the present results indicate that although perinatal Δ9-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 GABAB receptor agonists. However, this increase was not due to changes in GABAB receptor activation of signal transduction mechanisms, as revealed the analysis of the percentage of stimulation by baclofen of [35S]-GTPγS binding in the substantia nigra and other structures of males and females perinatally exposed to Δ9-THC.