Determinants of the disposition of 14C-delta 9-tetrahydrocannabinol and 3H-delta 9-tetrahydrocannabinol.
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Biomedical subjects
Publications and source records attributed to G T Pryor.
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The acute, reciprocal dose-response interactions between delta9-tetrahydrocannabinol (delta9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. delta9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by delta9-THC. dA and COC, but not NIC, stimulated photocell activity. delta9-THC completely blocked this effect of dA, whereas there was mutual antagonism between delta9-THC and COC on this measure and NIC markedly potentiated the depression caused by delta9-THC. dA and COC tended to offset the impairment of rotarod performance caused by delta9-THC, whereas NIC augmented it. The bradycardia and hypothermia caused by delta9-THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with delta9-THC and/or each of the three stimulants. There was evidence for tolerance to the effects of delta9-THC on all measures and this tolerance generally resulted in less interactive effects between delta9-THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants or their interaction with delta9-THC. The time course of radioactivity derived from 14C-delta9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.
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Tissue levels of 3H were higher 2 hr after oral administration of 3H-delta9-THC (10 mg/kg in sesame oil) to male Fischer rats in the morning compared with treatment in the afternoon. A corresponding reduction in potency was seen for the impairing effect of delta9-THC on performance of a conditioned avoidance response (CAR). The hypothesis that these effects were related to the interval between feeding (which normally occurs during the night in the nocturnal rat) and drug administration was supported when they were mimicked in overnight fasted and ad lib fed rats. Food deprivation decreased the rate of gastrointestinal absorption of 14C-delta9-THC in sesame oil. Peak plasma levels of 14C occurred 2-4 hr after administration in fed rats compared with 8 hr in fasted rats. When tested 2 hr after oral administration, delta9-THC caused significantly greater impairment of CAR performance in fed than fasted rats, whereas the opposite was found after 8 hr. Extraction and subsequent thin layer chromatography of plasma and brain from fed and fasted rats sacrificed 2 or 8 hr after oral administration of 10 mg/kg 14C-delta9-THC showed that brain levels of 11-hydroxy-delta9-THC rather than delta9-THC were correlated with the behavioral effect.
delta9-Tetrahydrocannabinol (THC; 2.5, 5.0, 10.0 mg/kg, PO) impaired avoidance and rotarod performance, and caused bradycardia and hypothermia. Phencyclidine (PCP; 1.25, 2.5, 5.0 mg/kg, IP) impaired avoidance and rotarod performance and caused a marked increase in photocell activity. When combined, the depressant properties of each drug were enhanced and the stimulation of photocell activity cg/kg THC and its interactions with PCP followed subacute treatment for six days, whereas many of the effects of PCP were enhanced after subacute treatment with a dose of 2.5 mg/kg. Open-field behavior was affected by each drug alone and in combination in a similar way as photocell activity, but the depression caused by their interaction was greater; both drugs caused an increase in urination. Response rates on an FR-10 schedule of food reinforcement were decreased by 2.5 mg/kg PCP, but not by 5.0 mg/kg THC; the combination caused greater response suppression than either drug alone. The functional interactions between THC and PCP were not related to changes in the concentrations of 14C or 3H in plasma or brain derived from 14C-delta9-THC and 3H-PCP, respectively.
Male, Fischer strain rats were resistant to the impairing effects of delta9--THC (15-60 mg/kg, IG) on performance of a conditioned pole-climb avoidance response (CAR) after daily subacute pretreatment for 4 or 6 days. A single administration of 20 mg/kg delta9--THC independent of the performance test did not attenuate the subsequent impairment caused by delta9--THC when tested 1-6 days later; however, administration 2 hr before each test attenuated the effect on subsequent tests given at intervals of 1-5 weeks. Similarly, subacute treatment with 20 mg/kg delta9--THC for 4 days independent of the performance test attenuated the impairment caused by delta9--THC during tests given to separate groups of rats 1 or 6, but not 14 days later. However, when the tests for tolerance were conducted repeatedly in the same rats, the attenuation appeared to persist for intervals up to 5 weeks. The results are discussed in terms of metabolic, functional and compensatory (behavioral) tolerance.
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