Edward J. Bilsky

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.

MDL72222, a serotonin 5-HT3 receptor antagonist, blocks MDMA's ability to establish a conditioned place preference

Methylenedioxymethamphetamine (MDMA) has previously been shown to produce a positive conditioned place preference (CPP) among rats. Here the effects of doses of a specific 5-HT3 antagonist, MDL72222, on MDMAs ability to produce a CPP were assessed. A dose of MDL72222 (0.03 mg/kg) blocked the establishment of a MDMA CPP. These results support the suggestions that compounds affecting the 5-HT3 receptor may be of particular interest in studying the pharmacology of self-administered drugs.

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.

Using Antagonists to Assess Neurochemical Coding of a Drug's Ability to Establish a Conditioned Place Preference

Rats were given morphine as an agent of putative conditioning to establish a place preference. Doses of 4 and 8 mg/kg of morphine did establish reliable conditioned place preferences (CPPs). Other rats were given one of the doses of morphine and one of a number of antagonists in procedures designed to assess which antagonists would specifically block morphines ability to establish a CPP indicative of positivity. Doses of naloxone and larger doses of naltrexone but not smaller ones did antagonize morphines effects. A dose of the benzodiazepine antagonist Ro 15-1788 did not attenuate morphines effects. It was concluded that morphines positivity is dependent upon actions by way of receptors sensitive to naloxone and naltrexone, but that morphines positivity is less sensitive to naltrexones effects than morphines analgesia.

THC, An Active Ingredient in Marijuana, and Rats’ Intake of a Sweetened Alcoholic Beverage

There is substantial evidence to indicate that some drugs that are often used recreationally modify intakes of palatable ingesta [1]. For example, delta-9-tetrahydrocannabinol (THC) in small doses enhances caloric intake [1,2]. Among people, THC is also used in combination with other drugs such as ethanol (E). It is interesting to see if a drug such as THC also increases intake of a sweetened alcoholic beverage.

Mianserin, a Serotonergic Antagonist, and Intake of an Alcoholic Beverage

There is evidence showing that manipulations of serotonergic systems affect ingestion. In general, agents enhancing serotonergic activity decrease ingestion, while serotonergic antagonists block this effect and, by themselves, appear to potentiate ingestion [1,2,3,4,5,6,7,8,9]. In addition, there are a number of reports that enhanced serotonergic activity reduces intake of ethanol (E) [10,11,12,13,14,15]. If serotonergic systems are saliently related to propensity to take E, and if increases in serotonergic activity decrease intake, then it is reasonable to predict that decreases (or antagonism) in serotonergic activity should enhance intake of alcoholic beverages. In the present study, we assessed the effects of mianserin, a general serotonergic antagonist, across a range of doses, on rats’ intakes of a sweetened alcoholic beverage.

Cocaine and Rats’ Intake of an Alcoholic Beverage

There are a number of reasons to observe cocaine’s effects on intake of ethanol (E). Among those reasons are: (a) There is a continuing assessment of the specificity of morphine’s effects and results from tests using cocaine can be used as part of that assessment [1]. Morphine increases intake of E [2]. Perhaps, any agent that induces positive affect would also increment such intake. Since cocaine is an agent that induces positive affect, it can be used as part of the assessment of morphine’s specificity, (b) Dopamine (DA) is a neurotransmitter that seems to be critical to a number of motivated behaviors [3]. Consequently, it is of interest to see how agents that modulate endogenous DA levels might affect intake of E. Cocaine increases DA levels by blocking its reuptake [4,5]. If increased DA levels is a setting condition potentiating intake of E, then injections of cocaine should also increase intake of E. (c) A recent report indicated that the gene for the DA D2 receptor was a possible marker for alcoholism among people [6]. This possibility also suggests that manipulation of DA levels should produce systematic shifts in propensity to take E. An additional indication that dopaminergic systems might be critically involved in propensity to take E is the finding that alcohol preferring rats have about a 25% lower content of DA and its metabolites in the nucleus accumbens [7]. McBride et al. suggested that this “abnormality in the dopaminergic system projecting from the ventral tegmental area to the nucleus accumbens” ([7], p. 202) promotes high levels of drinking of E.

Peripheral Administration of Tiqs and Intake of an Alcoholic Beverage

In 1970, two findings indicated that a metabolite of ethanol (E) could combine with certain neurotransmitters to produce potential opioidergic products [1,2]. The idea is that acetylaldehyde (the first metabolic product of E) in the presence of either phenylethylamine, dopamine, norepinephrine or epinephrine yields a class of compounds called tetrahydroisoquinolines (TIQs). Subsequently, it was demonstrated that the central administration of a TIQ increased intake of E among rats [3,4,5]. Although a critical site of action of these putative metabolites of E must be in brain, the question remains:What effects do these agents have on intake of E when administered peripherally? Therefore, we tested the effects of 3 TIQs on rats’ intake of a sweetened alcoholic beverage. The 3 TIQs tested were:(a) 1,2,3,4-tetrahydroisoquinoline (1,2,3,4-TIQ); (b) tetrahydropapaveroline (THP); and (c) 1-salsolinol (SAL).