Cocaine is a stimulant with powerful reinforcing properties that strengthen drug-seeking behavior and make it difficult for addicts to abandon its use.  Cocaine is thought to achieve its reinforcing actions by inhibiting the presynaptic reuptake of dopamine (DA), resulting in the accumulation of DA in the synaptic cleft.1 The elevated levels of synaptic DA enhance activation of postsynaptic DA receptors, which have been divided into five subtypes, D1 to D5.2,3,4,5 Research has focused on the involvement of D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors in mediating reinforcement, since past studies have demonstrated that self-administration of D1 and D2 agonist combinations mimic cocaine self-administration patterns in rats.6

Previous findings also suggest that while D
2-mediated reinforcement may require some threshold level of endogenous D1 activation, D1-mediated reinforcement does not depend on D2 activity.7,8   To further study the properties of D1-mediated reinforcement, the present study examines the effects of the D1-selective antagonist SCH23390 and the D2-selective antagonist eticlopride on self-administration of the D1-selective agonist SKF82958.  Since D1 and D2 antagonists have been found to cause compensatory increases in cocaine self-administration and to shift the cocaine dose-response curve to the right, we expect SCH23390 to have the same effect on SKF82958 self-administration.9  If past findings by Self et al. are correct, and if D1-mediated reinforcement does not depend on D2 activation, we expect eticlopride to have no specific effect on SKF82958 self-administration.8

In a similar study by Self et al., the antagonists were administered subcutaneously 30 min before each experimental session, while the agonist was self-administered intravenously during the session.8  This methodology is disadvantageous because it results in an inconsistent, time-dependent antagonist dose, where the effective antagonist dose rises and peaks early in the session, then declines as the session progresses.   To avoid this inconsistent dosing, our study co-administers the antagonist with each self-administered agonist injection, such that both drugs are simultaneously and rapidly distributed throughout the circulation.  Our study also differs from previous ones in that we tested more doses of SKF82958 and used the potent and selective D
2 antagonist, eticlopride.  By making these modifications we hope to replicate and augment precision and thoroughness in our continued investigation of D1-mediated reinforcement.

Materials and Methods

Näive, male Sprague-Dawley rats, initially weighing 260 to 300 g, were maintained under a 12 h light/dark cycle (lights on at 7:00 a.m., experiments conducted during light phase).  Animals were individually housed, handled daily, and provided with food and water ad libitum.  After 3 to 4 d of habituation, rats were food-deprived in preparation for individual lever-press training.  Training was conducted in an experimental chamber (27 cm x 25 cm x 30 cm) equipped with a lever mounted on the back wall, a white cue light situated above the lever, and a food bin adjacent to the lever.  During the daily 20 min training sessions, each rat received one 45 mg food pellet in the food bin for each lever-press (10 g minimum force). Training continued until the rat completed three consecutive days of 100 lever-presses per session.

Trained rats were then surgically implanted with an autoclaved chronically indwelling jugular catheter.  Catheters consisted of a 12 cm length of Silastic7 tubing connected to a guide cannula (22-gauge) bent into a 95° angle and encased in a hemispherical cranioplastic cement base.  A 3.5 cm square of Marlex7 mesh was cemented to the bottom of the base, and a 1.0 cm square of Mersilene7 mesh was glued (Medical Adhesive Silicone Type A) onto the tubing 3.25 cm from its end.  Rats were anaesthetized with an intraperitoneal injection of equithesin (0.35 ml/100 g body weight).   The base of the catheter was placed in a 4 cm incision pocket on the back of the rat beneath the dermal layer.  The tubing was passed subcutaneously over the shoulder and inserted into the external jugular vein, to which the 1 cm square mesh was sutured (4-0 silk thread).  The incisions were sutured, and the portion of the guide cannula emerging from the animal's back was capped with a stylet to prevent infection and clogging. Implanted catheters were flushed twice daily with 0.2 to 0.3 ml of a heparin-saline solution (0.6 ml heparin/30 ml bacteriostatic 0.9% NaCl solution).

Animals began self-administration sessions following a 3 d recovery period and were maintained at weights between 350 to 400 g.  The daily 3 h self-administration sessions were conducted in individual test chambers identical to the one used for lever-press training, however now the food bin was concealed.  At the start of each session, the rat's guide cannula was connected to an external syringe pump system by plastic tubing.  A single press of the lever activated the syringe pump to deliver a 0.1 ml injection of drug solution, lasting 6 s and accompanied by an audible 1800 Hz tone.   The injection period was followed by a 10 s "time out" period during which the cue light was turned off, and the

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Mohammad Helmy - Effects of the D1-Antagonist SCH23390... [1] [2] [3] [4] [5] [6]