Christopher L. Hubbell

Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administrations

For 29 days, rats were given a daily opportunity to take a sweetened ethanol solution (ES) or water when deprived of water. Under this regimen, and throughout all procedures, rats gained weight normally. They eventually took considerable amounts of ethanol (E). Across the next days of the regimen, one group was given an injection of morphine (MOR), 2.5 mg/kg, 30 min before each of 6 consecutive daily opportunities to drink. MOR enhanced intake of ES on every day of injections. Naloxone (NX) (2.5 mg/kg, 10 min before opportunity to drink) was given to rats having had many daily opportunities to take ES. NX reduced intakes day after day. Rats given NX from the first opportunity to take ES did not develop an avidity for ES as other rats given placebo-injections. MOR increased intakes among rats not deprived of water, among rats housed in groups as well as individually, among rats taking unsweetened ES, and among rats presented with various flavors of ES as the only solution during an hour-long session. The data confirm and extend the conclusion that small doses of MOR enhance E-intake, indicate that the effects of opioids on E-intake do not tolerate with repeated administrations, and generally support the idea that an endogenous opioid system is involved in the reinforcement derived from E.

Toward understanding ethanol's capacity to be reinforcing: a conditioned place preference following injections of ethanol

Rats that had previously consumed a 6% ethanol (ETOH) solution daily for 26 days and rats without such a history served as subjects in a test for the ability of ETOH to establish a conditioned place preference. The time of putative conditioning was from 4 to 8 min after injections of ETOH, 1 g/kg. The combination of programming the period of putative conditioning to be shortly after injections and using rats habituated to drinking ETOH allowed a conditioned place preference to emerge after only a few conditioning trials. Such a result potentially reveals features of the way ETOH achieves its reinforcing capability and sets the stage for understanding the mechanism of that reinforcement.

Tests of opioid deficiency hypotheses of alcoholism

Eighty-three male rats were maintained on a daily regimen involving 22 h of deprivation of fluids followed by 2 h of access to water and a sweetened alcoholic beverage (12% ethanol, 5% sucrose). After about 3 weeks of such a regimen, rats eventually take considerable amounts of ethanol daily. In the present study, a series of injections of opioids was given subsequent to establishing stable daily intakes of ethanol. Specifically, before a days opportunity to take fluids, some rats were given a small dose of morphine (2.0 mg/kg), while others were given a dose of naloxone (4.0 mg/kg). When morphine was given 0.5 h before the opportunity to drink, intake of ethanol was increased. However, when morphine was given 4.0 h before the opportunity, intake of ethanol was decreased. Nearly opposite effects were observed when naloxone was given. Other experiments tested the effects of giving morphine 4.0 h before the opportunity to drink plus the effects of a small dose of naloxone or plus the effects of a small dose of morphine. Morphine given 4.0 h before potentiated the effects of a small dose of naloxone and attenuated the effects of another dose of morphine. The effects of morphine were also shown to be similar among rats taking a solution of ethanol and water rather than a sweetened solution. These data provide support for the idea that surfeits, not deficits, in opioidergic activity increase propensity to take alcoholic beverages.

Persistence and specificity of small doses of morphine on intake of alcoholic beverages

Subsequent to water deprivation, male rats were given daily, 1.5-hr opportunities to take either water or a sweetened ethanol solution (ES). Each day, 15 min before the session, rats received a subcutaneous injection of either morphine (1.0 mg/kg) or saline. Across daily sessions, rats given saline gradually increased their intake of ES, until they were eventually taking about 2.0 to 3.0 g of ethanol/kg a session. Rats receiving morphine took greater amounts of ES from nearly the first opportunities. Additional tests assessed the effects of small doses of morphine on intakes of some sucrose solutions, and sweetened solutions containing methanol or propanol. The data support the conclusion that small doses of morphine persistently increase intake of ES across many days (up to 100) of testing, but that the effect is not unique to ES. Even though morphines effects are not specific to ethanol, the fact that morphine persistently increases intake of ES is of interest with respect to theories of alcoholism.

MDMA produces a conditioned place preference and elicits ejaculation in male rats: A modulatory role for the endogenous opioids

Methylenedioxymethamphetamine (MDMA) can produce a conditioned place preference (CPP) among rats. The ability of MDMA to produce a CPP was assessed while some rats were under the influence of naltrexone, 56 mg/kg, given 4 h before conditioning. Naltrexone attenuated MDMAs ability to produce a CPP without completely blocking MDMAs effects. Having noticed previously the production of seminal plugs by rats receiving MDMA, the presence of seminal plugs was recorded across the 8 days of conditioning. Roughly half of the rats receiving 6.3 mg/kg of MDMA left plugs during the conditioning period, while over two-thirds of those receiving a combination of MDMA and naltrexone left plugs. A second study, assessing further doses of MDMA, tabulated the drugs effects on the production of seminal plugs across 3 h. Besides eliciting ejaculation, MDMA also led to increased urination and defecation and a loss of body weight. These results support suggestions that the endogenous opioids modulate the reinforcing properties of stimulant drugs and affect male sexuality.

Morphine and diprenorphine together potentiate intake of alcoholic beverages

Water-deprived rats were given a daily opportunity to take water or an ethanol solution. Prior to some opportunities to drink, some were injected with morphine (across procedures either 2.0, 7.5, or 20.0 mg/kg), diprenorphine (from 0.001 to 10.0 mg/kg), or a combination of diprenorphine and morphine. The small dose of morphine increased intake of alcoholic beverage and the large dose decreased intake, confirming previous observations. Diprenorphine, across a wide range of doses, increased intake of ethanol solution. Morphine and diprenorphine together produced more intake than either given alone. Diprenorphine reversed the depressing effects of large doses of morphine on intake of ethanol solution. Since diprenorphine is an antagonist with respect to opioid analgesia and behavioral depression and an agonist with respect to intake of alcoholic beverages, and since it potentiates the small dose morphine effect, it is concluded that only some effects of morphine are related to opioid-potentiation of intake of alcoholic beverages.

Naltrindole, a δ-opioid antagonist, blocks MDMA's ability to enhance pressing for rewarding brain stimulation

Twelve rats were each fixed with a chronically indwelling bipolar electrode for stimulation of the medial forebrain bundle as it courses through the hypothalamus. These rats were trained to press a bar for intracranial stimulation of 0.3-s trains of 60 Hz sine waves for 10 min daily at three intensities. One intensity was just above threshold for maintaining pressing, one intensity was a high intensity that sustained considerable pressing, but not maximum pressing, and the other was intermediate to the others. After stable rates of pressing were obtained, rats received MDMA daily. MDMA significantly increased rates of pressing. Prior to a day when rats received MDMA, they also received an injection of naltrindole, a selective delta-opioid receptor antagonist. Naltrindole blocked MDMAs enhancement of pressing for reinforcing brain stimulation.

Opioids Modulate Rats’ Intakes of Alcoholic Beverages

This chapter summarizes the evidence supporting the conclusion that “opioids modulate rats’ intakes of alcoholic beverages.” The knowledge that a class of drugs affects a complex behavior, such as ingestion, may not be particularly meaningful with respect to determining the chemical coding of the specific behavior in question. A drug could, for example, make subjects ill and, thereby, reduce intakes. Consequently, initial observations of the effects of a class of drugs on a specific behavior need to be elaborated in order to determine the specificity of the effects. With respect to opioidergic effects on intake of ethanol (E), some of that work has been performed, and the outcomes of that work are summarized here.

PCP, THC, ethanol, and morphine and consumption of palatable solutions.

Water-deprived rats were given daily opportunities (2.0-hr sessions) to take water or a sweet solution (20% or 24% sugar-water). After stable intakes of each fluid were achieved, the effects of phencyclidine hydrochloride (PCP), delta-9-tetrahydrocannabinol (THC), ethanol (E), and morphine (M) on intakes were tested. PCP, THC, and M all enhanced intake of the sweet solution, while E produced varying effects across doses tested. With other rats, nearly the same procedure was used except that the test solution presented with water was 0.9% sodium chloride. Doses of PCP enhanced intake of the salty solution. These data, combined with the data from similar studies of the effects of opioids and benzodiazepines, indicate that a wide variety of agents that are self-administered also modify intake of ingesta.

Further studies of opioids and intake of sweetened alcoholic beverage

Rats were placed on a daily regimen of water deprivation followed by a limited opportunity to take either water or a sweetened alcoholic beverage. Across days of opportunity, they took less water and more alcohol until they were taking considerable amounts of alcohol. Naloxone, the classic antagonist at opioid receptors, was given prior to opportunity to drink and it reduced intakes of alcoholic beverage. Small doses of morphine, the classic agonist, increased intakes of alcoholic beverage at doses as low as 0.41 mg/kg. The effects of two other antagonists at opioid receptors (LY117413 and MR2266) were also tested. Both reduced intakes of alcohol. The data showing that more than one or two opioid antagonists reduce intakes of alcoholic beverages, even palatable beverages usually taken in large amounts, and that morphine increases intakes at very low doses, strengthen the idea that endogenous opioid systems are involved in modulating intake of alcohol.