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Opiate-induced motor sensitization refers to the progressive and enduring motor response that develops after intermittent drug administration, and results from neuroadaptive changes in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons. Repeated activation of mu-opioid receptors localized on gamma-aminobutyric acid (GABA) neurons in the VTA enhances dopaminergic cell activity and stimulates dopamine release in the nucleus accumbens. We hypothesize that GABA(B) receptor agonist treatment in the VTA blocks morphine-induced motor stimulation, motor sensitization, and accumbal Fos immunoreactivity by inhibiting the activation of dopaminergic neurons. First, C57BL/6 mice were coadministered a single subcutaneous injection of morphine with intra-VTA baclofen, a GABA(B) receptor agonist. Baclofen produced a dose-dependent inhibition of opiate-induced motor stimulation that was attenuated by 2-hydroxysaclofen, a GABA(B) receptor antagonist. Next, morphine was administered on days 1, 3, 5, and 9 and mice demonstrated sensitization to its motor stimulant effects and concomitant induction of Fos immunoreactivity in the NAc shell (NAcS) but not NAc core. Intra-VTA baclofen administered during morphine pretreatment blocked the acquisition of morphine-induced motor sensitization and Fos activation in the NAcS. Intra-VTA baclofen administered only on day 9 blocked the expression of morphine-induced motor sensitization and Fos activation in the NAcS. A linear relationship was found between morphine-induced motor activity and accumbal Fos in single- and repeated-dose treatment groups. In conclusion, GABA(B) receptor stimulation in the VTA blocked opiate-induced motor stimulation and motor sensitization by inhibiting the activation of NAcS neurons. GABA(B) receptor agonists may be useful pharmacological treatments in altering the behavioral effects of opiates.

Relationships between caffeine dose, methylxanthine tissue concentrations, adenosine receptor binding and locomotor activity were examined in CD-1 mice. A method of caffeine infusion via s.c. pumps provided constant steady-state methylxanthine concentrations. Mice receiving caffeine doses of 97 mg/kg/day (with mean plasma concentration of 2.7 micrograms/ml) demonstrated motor activity depression for 6 days after pump implantation (vs. vehicle-treated controls). Mice receiving caffeine doses of 194 mg/kg/day (mean plasma concentration of 7.1 micrograms/ml) demonstrated motor stimulation 4 and 24 hr after implantation. Mice receiving this dose for 6 days developed motor depression. A reduction in the stimulant effects of acute caffeine (20 mg/kg i.p.) was found in mice receiving caffeine infusions (194 mg/kg/day for 6 days) as compared to those receiving vehicle infusions, suggestive of drug tolerance. These dose- and time-dependent behavioral effects during caffeine-infusion were associated with decreases between 20 and 69% in specific binding of A1 adenosine radioligand 1,3-[3H]dipropyl-8-cyclopentylxanthine in vivo. Behavioral alterations during caffeine infusion appear to be mediated by A1 adenosine receptor occupancy. Increasing motor depression developed on days 1 and 2 after pump removal with values returning to control levels by days 4 and 6. Behavioral alterations were associated with in vivo binding increases of 98 and 324%, respectively, and a return to control values on days 4 and 6. In vivo binding alterations were not associated with ex vivo A1 receptor binding changes. Caffeine tolerance and withdrawal effects in this animal model appear to be mediated by chronic occupancy of A1 adenosine receptors. The behavioral and in vivo receptor binding alterations observed after caffeine discontinuation follow a time course similar to caffeine withdrawal in humans.

CD-1 mice were treated with caffeine-sodium benzoate solution (caffeine doses: 0, 5, 15 or 30 mg/kg i.p.) to determine plasma and brain concentrations, effects on benzodiazepine receptor binding based on specific uptake of a high affinity ligand, and locomotor activity. There was a linear relationship between caffeine dose and mean brain or plasma concentrations, but concentrations varied considerably at any given dose. There were also linear relationships between plasma and brain concentrations of caffeine and each metabolite, with caffeine itself having the greatest brain:plasma uptake ratio. Benzodiazepine receptor binding was determined based on uptake of the benzodiazepine receptor ligand [3H]Ro15-1788, 3 microCi i.v. given 40 min after caffeine (30 mg/kg). Nonspecific binding was measured in animals pretreated with saturating doses of clonazepam. Specific uptake (measured by subtracting nonspecific from total [3H] Ro15-1788 uptake) increased significantly with caffeine as opposed to vehicle treatment in the cortex, hippocampus and hypothalamus. Brain caffeine concentrations associated with enhanced uptake were between 11 to 17 micrograms/g. Total locomotor activity and activity at 60 min, measured by an infrared sensor system, increased progressively with brain caffeine concentrations when comparing the following groups: 0, 2 to 9 micrograms/g of brain and 9 to 20 micrograms/g. Animals with brain concentrations exceeding 20 micrograms/g showed a decline in both measures but activity was significantly greater than placebo. In conclusion, brain caffeine concentrations between 9 to 20 micrograms/g are associated with increases in specific ligand uptake and motor activity.