John D. Delconte

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.

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.

Speed and consistency of human decisions to swallow or spit sweet and sour solutions

Measurements of the frequency and speed of spitting or swallowing citric acid, sodium saccharin, or mixture solutions, using the taste of one of them as the definition of what was to be spit, revealed that ‘correct’ spits occurred on ≥70% of trials with equal reliability and latency among the liquids, indicating that recognition-based rejection decisions in adult humans are as rapid and consistent for an arbitrary sweet taste as for a sour or mixed taste.

alpha(2)-Adrenoceptor antagonists and propensity to take alcoholic beverages.

Rats were maintained on a daily regimen involving a 2h opportunity to take both water and a sweetened alcoholic beverage (12% ethanol, 0.25% saccharin). After 3 weeks on this regimen, rats regularly take substantial amounts of alcohol. After stabilization, injections of alpha(2)-adrenergic antagonists were administered, 15min before the opportunity to drink. Yohimbine and methoxyidazoxan dose relatedly decreased intake of alcoholic beverage and increased intake of water. In Experiment 2, a number of rats were taken off the daily regimen for 9 days, then returned to it. Across the first 12 days of the reinstated daily regimen, half the rats received placebo and half methoxyidazoxan. The group receiving placebo rapidly returned to taking large amounts of alcoholic beverage while the group receiving methoxyidazoxan did not. In Experiment 3, it was shown that a dose of methoxyidazoxan that decreased intakes of alcoholic beverage did not decrease intakes of other palatable beverages. In Experiment 4, it was shown that yohimbine persistently reduced intakes of alcoholic beverage with daily administration. These results indicate that alpha(2)-antagonists might be effective pharmaceutical adjuncts to other treatments for alcohol abuse and alcoholism.

Effects of Differential Handling on Rats’ Intake of Alcohol

Considerations of the effects of stress on propensity to take alcoholic beverages have played a predominant role in theories of alcoholism. Generally, the idea is that stress, in one of its many manifestations, increases propensity to take alcohol. Sometimes it is explicitly stated that alcohol is anxiolytic. The mechanism by which alcohol, then, increases propensity to drink is by way of negative reinforcement, i.e., alcohol is said to provide relief from stress.

RATS' INTAKES OF DIFFERENT ALCOHOLIC BEVERAGES

A major issue associated with rats’ intake of alcoholic beverages is the palatability of the presented ethanol solution (ES). It is well-known that rats prefer sweet solutions and aver bitter ones. Furthermore, rats perceive an ES of only ethanol (E) in water as bitter [1,2]. Consequently, rats do not avidly take solutions of only E and water.

Morphine Enhances Intake of an Alcoholic Beverage Regardless of Type of Flavoring

Small doses of morphine (M) enhance intake of sweetened alcoholic beverages. Doses of naloxone (NX) reduce intakes [1]. M and NX are known to affect intake of palatable beverages [2]. This lack of specificity of opioids on intake of alcoholic beverages is obviously of some concern in terms of theorizing about the importance of endogenous opioidergic systems and alcoholism. The lack of specificity may, in fact, tell us something of importance about the nature of alcoholism (e.g., that alcoholism is more than superficially just an ingestive disorder). On the other hand, it may seriously limit the generality of the findings that opioids affect intake of alcoholic beverages in rats. Here, we provide data to indicate that M, in small doses, increments the intake of a variety of kinds of alcoholic beverages.

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.

LY78335, An Inhibitor of Phenylethanolamine N-Methyltransferase, and Rats’ Intake of an Alcoholic Beverage

Norepinephrine is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) [1,2,3]. Recently, it has been demonstrated that LY78335 (2,3-dichloro-alpha-methylbenzylamine), a PNMT inhibitor, antagonizes the intoxicating effects of ethanol (E) among rats [4]. This suggests that adrenergic systems in brain may mediate some of the effects of E.