Intragastric drug self-administration by rats exposed successively to morphine and ethanol.

Male Sprague-Dawley rats were implanted with intragastric cannulas for self-administration of drug solutions by bar-pressing on a continuous reinforcement schedule in 10-hour daily sessions. Similar levels of responding were observed for doses per infusion of 3.0 mg/kg morphine sulfate and 25 mg/kg ethanol in separate groups of rats. When rats that showed self-administration of a morphine solution over a 5-day period were than given access instead to ethanol for 5 days, the number of infusions taken did not deviate significantly between the two periods. However, rats selected from a small minority that failed to take morphine under these conditions also failed to manifest ethanol self-administration behavior. The data can be seen to support a possible concurrence or similarity between innate factors determining acceptance or rejection of morphine and ethanol as objects of self-administration behavior.

Reinforcement with intragastric infusions of ethanol: blocking effect of FLA 57.

Suppression of oral intake of ethanol by FLA 57 has been reported for rats and was attributed to an inhibition of dopamine beta-hydroxylase. We have demonstrated the ability of FLA 57 (50 mg/kg, IP) to suppress bar-pressing for intragastric (IG) delivery of doses of ethanol (25 mg/kg). This indicates that the effect on oral intake of ethanol may not be attributed to a taste factor, e.g., a decreased palatability of the ethanol solution. The same dose of FLA 57 did not suppress responding for IG doses of sweet milk. Thus, there was not an impairment of appetitive behavior in general through some nonspecific depressant or toxic action. Furthermore, the primary reinforcing action of ethanol, when used to establish a buzzer as a conditioned reinforcer through repeated pairings, was blocked if FLA 57 was given before pairings. This was evidenced by a failure of such rats to bar-press above the baseline level in a later test of conditioned reinforcement, which contrasted with the increased responding seen for rats receiving saline instead of FLA 57 before ethanol. These data support the previous findings on oral ethanol and confirm that FLA 57 can impair the mechanism by which ethanol produces positive reinforcement in rats.

Noradrenergic role in the self-administration of ethanol.

Involvement of noradrenergic and/or dopaminergic processes of the brain in self-administration behavior toward ethanol was assessed in rats allowed to lever-press for 25 mg/kg intragastric doses on a CRF schedule. Initial access to infusions of saline for establishing an operant baseline was followed by one 10-hr session on acquisition contingencies for ethanol and then one extinction session on saline. Prior to a reacquisition session, rats were treated with either (a) saline, (b) alpha-methyl-p-tyrosine (AMT; 225 mg/kg), (c) 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624; 600 mg/kg or 300 mg/kg), or (d) haloperidol (3.5 mg/kg). Only the saline-pretreated control group and the haloperidol-treated rats reacquired lever-press behavior. Groups treated in like fashion, but pressing for a sweet milk reinforcer, all showed reacquisition. Thus, the effects of AMT and U-14,624 are attributed to an inteference with the reinforcing effect of ethanol infusions. Brain levels of norepinephrine were depleted by both compounds, dopamine was depleted only by AMT, and serotonin was elevated by 600 mg/kg of U-14,624 but unaffected by 300 mg/kg. These results suggest that a cerebral noradrenergic system plays an important role in the reinforcing effect of ethanol without an involvement of dopaminergic systems.

Alcohol-associated conditioned reinforcement.

Research was conducted to examine the ability of alcohol to impart conditioned reinforcement. Rats were allowed to self-administer solutions of either saline or alcohol (25, 50, and 100 mg/kg/infusion) by the intragastric route. Superimposed on the infusion interval was a buzzer (conditioned reinforcing stimulus). Tests during extinction revealed that conditioned reinforcement had been acquired. Results also indicated that as the paired unit dose was increased, potency of the conditioned reinforcer increased. In a second study, the lever-pressing response, which produced saline infusion and the buzzer, became available only subsequent to 5 sessions of pairing the buzzer with infusions of saline or alcohol. The results indicated that lever pressing increased with increasing unit dosage of alcohol infusions in prior pairings.

Effect of unit dose and route of administration on self-administration of morphine.

Rats were implanted with intravenous or intragastric cannulas and allowed to self-administer morphine sulfate in doses of 0 (saline), 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg/infusion. For the intravenous route the number of infusions decreased with increasing unit dose, while the amount self-administered was directly related to unit dose. However, for the intragastric route the number of infusions first increased and then decreased as unit dose was elevated, while the amount self-administered again increased with unit dose. Comparisons between routes showed that for intragastric subjects the number of infusions and amount self-administered both were lower at the two lowest doses but higher for all other doses. These results support the expectation that intravenous injection should produce more potent reinforcing effects than intragastric administration.

A dose-response comparison between methadone and morphine self-administration.

Rats were allowed to self-administer a solution of 0.9% saline, or 0.01, 0.03, 0.1 or 0.3 mg/kg/infusion of methadone hydrochloride or 0.03, 0.1 or 0.3 mg/kg/infusion of morphine sulfate. The results showed that number of infusions taken was an inverse function of unit dose, while amount of drug self-administered (mg/kg) was a direct function of unit dose. The data also indicated that more morphine than methadone was self-administered.