Differential involvement of dopamine receptors in conditioned suppression induced by cocaine

Abstract

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.

Fig. 1

Acquisition of conditioned suppression in rats pre-treated with saline before each training session. Mean (±SEM) response rates (responses per min) are presented for the following periods of time: 2 min prior to conditioned stimulus presentation (“Pre”), 1 min during conditioned stimulus presentation (“CS”), and 0–2, 2–5, 5–10, 10–15, and 15–20 min after the cocaine injection given at the end of the conditioned stimulus. Each block of training represents two sessions, and “Test” represents the ninth session, in which cocaine was not delivered. Asterisks indicate rates significantly (P<0.05) lower than the preconditioned stimulus rate in the same block of training (or during the test session for the test data, on the right).

Fig. 2

Mean (±SEM) suppression times over the course of acquisition training in groups treated with vehicle, SCH 23390, or eticlopride before each session. Legend indicates the pre-treatment drug and dose (mg/kg). Cocaine was delivered at the end of conditioned stimulus presentation during each session. Suppression times were measured from the beginning of the conditioned stimulus until the response rate returned to at least 50% of the pre-conditioned stimulus rate. SCH 23390 and eticlopride shared a vehicle-treated control group (solid circles); the data for this control group in Fig. 2 are derived from the same data in Fig. 1.

Fig. 3

Mean (±SEM) suppression times during acquisition training, collapsed across blocks. Each curve in Fig. 2 is seen as a point in Fig. 3. Asterisks indicate that suppression times were significantly reduced (P<0.05) in groups pre-treated with 0.01 or 0.03 mg/kg of SCH 23390 or 0.01 mg/kg of eticlopride.

Fig. 4

Mean (±SEM) suppression times during testing (Day 9) for conditioned effects in groups treated with vehicle, SCH 23390, or eticlopride before each session during acquisition training. During testing, no pre-treatment was given, and the conditioned stimulus was presented without cocaine delivery. Asterisks indicate that suppression times were significantly reduced (P<0.05) in groups pre-treated with 0.003 or 0.01 mg/kg of SCH 23390.

Fig. 5

Mean (±SEM) suppression times during testing for alterations in the expression of conditioned suppression when rats were pre-treated with vehicle, SCH 23390, eticlopride, or BP 897 before the test. Rats were given cocaine paired with the conditioned stimulus during each training session, but no cocaine was given during test sessions. Pre-treatments were given only before test sessions. Each rat was tested with only one pre-treatment drug, but doses within each drug were compared within subjects. Baseline training sessions (with cocaine delivered but no pre-treatment) were interspersed between test sessions. Asterisk indicates that suppression time was significantly reduced (P<0.05) when 0.01 mg/kg of eticlopride was administered before the test session.