Cannabinoid and Heroin Activation of Mesolimbic Dopamine Transmission by a Common µ ₁ Opioid Receptor Mechanism

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In Sprague-Dawley rats no change in dialysate DA in the NAc was observed after a Δ 9 -THC dose of 0.5 mg/kg ip; a 20% increase occurred after a dose of 1.0 mg/kg ip [J. P. Chen et al. Neurosci. Lett. 129 136 (1991)]. No change in dialysate DA in the NAc and in the caudate-putamen of Long-Evans rats was observed after Δ 9 -THC doses of 1.0 and 10.0 mg/kg administered by gavage [E. Castañeda et al. Pharmacol. Biochem. Behav. 40 587 (1991)]. In the Lewis strain of rats however Δ 9 -THC has been reported to increase dialysate DA in the NAc at doses of 0.5 and 1.0 mg/kg ip (20).

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Concentric dialysis probes were prepared with AN 69 fibers (Hospal Dasco Italy) as described (21). All animal experimentation was conducted in accordance with European Economic Community guidelines for care and use of experimental animals. Male Sprague-Dawley rats (280 to 300 g; Charles River Calco Como Italy) were anesthetized with ketamine (100 mg/kg ip) and placed in a stereotaxic apparatus. The skull was exposed and a small hole drilled to expose the dura on each side. Each rat was implanted with one dialysis probe on each side aimed at the NAc shell on one side and at the core on the other side according to the rat brain atlas of G. Paxinos and C. Watson [ The Rat Brain in Stereotaxic Coordinates (Academic Press Sydney 1987)] [uncorrected coordinates: shell A = +2.0 L = 1.4 V = 8.0; core A = +1.4 L = 2.0 V = 7.8 (A anterior; L lateral; and V ventral)]. Under halothane anesthesia a polyethylene catheter was inserted into the right femoral vein and then tunneled subcutaneously to exit at the nape of the neck. A femoral vein was catheterized and experiments were performed 24 hours after implant of probes. Ringer's solution (147 mM NaCl 2.2 mM CaCl 2 and 4 mM KCl) was pumped through the dialysis probes at a constant rate of 1 μl/min. Dialysate samples (10 μl) were taken every 10 min and injected without purification into a reversed-phase high-performance liquid chromatography apparatus (LC-18 DB 15 cm particle size 5 μm; Supelco) and a coulometric detector (ESA; Coulochem II Bedford MA) to quantify dopamine. The oxidation and reduction electrodes of the detector were set at +130 mV and –175 mV respectively. The mobile phase contained 50 mM NaH 2 PO 4 0.1 mM Na 2 EDTA 0.5 mM n -octyl sodium sulfate and 18% (v/v) methanol (pH adjusted to 5.5 with Na 2 HPO 4 ). The mobile phase was pumped with an LKB 2150 pump at 1.0 ml/min. Assay sensitivity for dopamine was 2 fmol per sample.

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Δ 9 -THC and cannabinol (Makor Chemicals Jerusalem Israel) and WIN55212-2 (RBI Chemicals Amersham Milano Italy) were suspended in 0.3% Tween 80 in saline and administered iv (1 ml/kg).

Heroin (Salars Milano Italy) was dissolved in saline with the aid of a drop of glacial acetic acid and administered iv (1 ml/kg).

SR141716A was suspended in 0.3% Tween 80 in saline and administered ip (3 ml/kg). Naloxone (Sigma Milano Italy) was dissolved in saline and administered sc (1 ml/kg).

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The observation that in the Sprague-Dawley rats naloxone reduces the effect of Δ 9 -THC on dialysate DA in the NAc is consistent with observations in Lewis rats (20).

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We thank R. Frau P. Loddo and A. Marchioni for expert assistance and P. Soubriè for providing SR141716A. Supported by funds from CNR “Disease Factors” project from Ministero Ricerca Scientifica and from European Community project BMH 4-CT 96-0203.