Constantine X. Poulos

Sensitization to the behavioral effects of cocaine: Modification by Pavlovian conditioning

Sensitization to the behavioral effects of cocaine was more pronounced following drug administration in the presence of cues previously associated with cocaine administration than in their absence. Furthermore, sensitization was attenuated by repeated presentations of the usual predrug cues followed only by saline, i.e. sensitization was extinguishable. These findings indicate that Pavlovian conditioning contributes to sensitization, and have implications for treatment of stimulant abuse.

The role of Pavlovian processes in drug tolerance and dependence: Implications for treatment

Abstract Evidence for the crucial role of Pavlovian conditional compensatory responses in tolerance to opiates and alcohol is presented. Furthermore, an analysis of the motivational role of Pavlovian conditional compensatory responses to craving and relapse is discussed, and supportive experimental and epidemiological evidence are presented. Given the role ascribed to Pavlovian processes in tolerance, craving, and relapse, it is proposed that extinction of cues which elicit conditional compensatory responses is an essential factor for treatment. Additionally, it is suggested that by virtue of prior Pavlovian conditioning, stress and depression may serve as cues to elicit conditional compensatory responses and attendant craving and these cues can also be extinguished by Pavlovian procedures. Finally, it is suggested that explication of this conditioning analysis to the patient may itself be an important cognitive adjunct to treatment.

Alcohol is an effective cue in the conditional control of tolerance to alcohol

To assess the effectiveness of a pharmacological cue as a conditional stimulus in the Pavlovian model of drug tolerance, two groups of Wistar rats received equal numbers of IP injections of a low and a high dose of alcohol. One group (Paired) received a low dose (0.8 g/kg) of alcohol followed 60 min later by the high dose (2.5 g/kg). Another group (Unpaired) received the low and high doses on an unpaired basis. When tested for tolerance to the hypothermic effect of the high dose of alcohol, only the Paired group showed tolerance, and only if the low dose preceded the high. When a saline injection preceded the high dose injection, the Paired group showed a loss of tolerance. The Paired group also showed a compensatory hyperthermia following the low dose injection. Animals from the Paired group that received repeated administrations of the low dose followed by saline, showed a significant extinction effect as compared with animals that received repeated saline injections only. These findings support the Pavlovian model of conditional tolerance, extending the realm of effective conditional stimuli to include a low dose of a drug.

Amphetamine primes motivation to gamble and gambling-related semantic networks in problem gamblers

Previous research suggests that gambling can induce effects that closely resemble a psychostimulant drug effect. Modest doses of addictive drugs can prime motivation for drugs with similar properties. Together, these findings imply that a dose of a psychostimulant drug could prime motivation to gamble in problem gamblers. This study assessed priming effects of oral D-amphetamine (AMPH) (30 mg) in a within-subject, counter-balanced, placebo-controlled design in problem gamblers (n=10), comorbid gamblerdrinkers (n=6), problem drinkers (n=8), and healthy controls (n=12). Modified visual analog scales assessed addictive motivation and subjective effects. A modified rapid reading task assessed pharmacological activation of words from motivationally relevant and irrelevant semantic domains (Gambling, Alcohol, Positive Affect, Negative Affect, Neutral). AMPH increased self-reported motivation for gambling in problem gamblers. Severity of problem gambling predicted positive subjective effects of AMPH and motivation to gamble under the drug. There was little evidence that AMPH directly primed motivation for alcohol in problem drinkers. On the reading task, AMPH produced undifferentiated improvement in reading speed to all word classes in Nongamblers. By contrast, in the two problem gambler groups, AMPH improved reading speed to Gambling words while profoundly slowing reading speed to motivationally irrelevant Neutral words. The latter finding was interpreted as directly congruent with models, which contend that priming of addictive motivation involves a linked suppression of motivationally irrelevant stimuli. This study provides experimental evidence that psychostimulant-like neurochemical activation is an important component of gambling addiction.

The effects of selective blockade of delta and mu opiate receptors on ethanol consumption by C57BL/6 mice in a restricted access paradigm

The effects of naltrexone, naltrindole (a selective delta opiate receptor antagonist) and beta-funaltrexamine (beta-FNA; a selective mu opiate receptor antagonist) on alcohol intake by C57BL/6 mice in a restricted access paradigm were examined. During the pretreatment baseline phase, mice consumed an average of 1.3 g/kg during 1 h access sessions to a 12% alcohol solution. Treatment with naltrexone reduced alcohol consumption to about 50% of that of the saline controls. Treatment with beta-FNA had no effect on alcohol consumption whereas naltrindole reduced consumption to the same extent as that observed with naltrexone. The pattern of findings indicate that naltrexones ability to reduce alcohol consumption can be attributed to blockade of delta opiate receptors. Implications for treatment in human clinical trials are indicated.

Citalopram decreases desirability, liking, and consumption of alcohol in alcohol‐dependent drinkers

In previous studies serotonin uptake inhibitors such as citalopram decreased alcohol consumption in alcoholics. The mechanism of the effect is not fully understood. This study tested the hypothesis that it is mediated by changes in desire to drink and alcohol effects. After a 1‐week baseline period, subjects (13 men and three women; aged 26 to 69 years; healthy, nondepressed, alcohol‐dependent drinkers [mean, 6.6 drinks per day]) were randomized in a double‐blind fashion to receive 40 mg/day citalopram and placebo for 1 week each, separated by a 1‐week washout period. Daily standard alcoholic drinks (13.6 gm ethanol), nonalcoholic drinks, and tobacco use were recorded; evening urine samples were taken; and interest, desire, craving, and liking for alcohol were rated. Medical status, depression, and anxiety were assessed weekly, but no other treatment or advice was given. Daily alcoholic drinks significantly decreased during citalopram treatment (mean ± SEM = 4.6 ± 0.6) compared with placebo (5.7 ± 0.8; p = 0.01), and the average decrease was 17.5%. Percentage of days abstinent increased during citalopram administration (27.7% ± 5.7%) compared with placebo (15.5% ± 3.7%; p < 0.01). Citalopram decreased interest, desire, craving, and liking for alcohol (all p < 0.05). There was clear internal validation of these measures in that variations in each correlated with alcohol consumption (all r > 0.5, p < 0.05). Nonalcoholic drinks, self‐reports of cigarettes smoked (daily smokers), and body weight did not change significantly. In experimental bar sessions, after the citalopram and placebo periods, subjects were required to consume as many of 18 minidrinks as possible (equivalent to six standard drinks) at 5‐minute intervals. Subjects rated their desire for alcohol, intoxication, and mood. Citalopram had no significant effects on the desirability of alcohol or subjective feelings of intoxication. The findings indicate that serotonin uptake inhibitors may act by decreasing the urge to drink and the reinforcing effects of alcohol. Also, a naturalistic outpatient trial is a sensitive, simple, and economic procedure for detecting these drug effects.

A D2 Antagonist Enhances the Rewarding and Priming Effects of a Gambling Episode in Pathological Gamblers

Previous research indicated shared neurochemical substrates for gambling and psychostimulant reward. This suggests that dopamine substrates may directly govern the reinforcement process in pathological gambling. To investigate this issue, the present study assessed the effects of the relatively selective dopamine D2 antagonist, haloperidol (3 mg, oral) on responses to actual gambling (15 min on a slot machine) in 20 non-comorbid pathological gamblers and 18 non-gambler controls in a placebo-controlled, double-blind, counterbalanced design. In gamblers, haloperidol significantly increased self-reported rewarding effects of gambling, post-game priming of desire to gamble, facilitation of reading speed to Gambling words, and gambling-induced elevation in blood pressure. In controls, haloperidol augmented gambling-induced elevation in blood pressure, but had no effect on other indices. The findings provide direct experimental evidence that the D2 substrate modulates gambling reinforcement in pathological gamblers.

Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivity

Abstract Pathological gambling (PG) is a serious psychiatric disorder afflicting 1-3% of the general population. Experimental evidence indicates shared neurochemical substrates for PG and psychostimulant addiction. Impulsivity characterizes one key subtype of PG. Therefore, medications that ameliorate psychostimulant addiction and impulsive syndromes might also benefit impulsive PG subjects. The atypical stimulant, modafinil reduces cocaine abuse and impulsivity in patients with ADHD. The present study sought to determine if modafinil (200 mg) would reduce the reinforcing effects of slot machine gambling in PG subjects, and if this effect was stronger in high (H-I) vs. low (L-I) impulsivity subjects (N = 20). A placebo-controlled, double-blind, counterbalanced, repeated measures design was employed. Apart from bet size, which declined uniformly in both groups under drug, modafinil had bi-directional effects in the two groups. In H-I subjects, the drug decreased desire to gamble, salience of Gambling words, disinhibition and risky decision-making. In L-I subjects, modafinil increased scores on these indices. Modafinil also differentially affected blood pressure response to the game in the two groups. These findings for modafinil appear to fit well with a growing literature demonstrating bi-directional effects of D2 agonists as a function of trait impulsivity. Impulsivity could critically moderate medication response in PG.

Effects of pentobarbital and cocaine in rats expecting pentobarbital

Rats received extensive exposure to pentobarbital in a distinctive environment, and were subsequently tested for tolerance to the sedative effects of pentobarbital either in the distinctive environment or in an environment previously associated only with saline. Rats tested when expecting pentobarbital (i.e., in the usual drug environment) were tolerant, but rats tested when not expecting the drug (i.e., in the saline environment) were not tolerant. These results extend demonstrations of conditional tolerance to the general behavioral arousal effects of a sedative hypnotic. Subsequently, the same rats were administered cocaine either when expecting pentobarbital or when not expecting pentobarbital. Rats administered cocaine when expecting pentobarbital exhibited more intense forms of cocaine-induced behavior than rats administered cocaine but not expecting pentobarbital. These results establish the phenomenon of conditional cross-potentiation between conditional drug states and unconditional drug-effects.

Parallel roles for dopamine in pathological gambling and psychostimulant addiction.

A variety of evidence suggests important commonalities in the neurochemical basis of reinforcement in pathological gambling (PG) and psychostimulant addiction. This article focuses on the parallel and specific roles that dopamine (DA) activation plays in these two disorders, beyond its generic role in reinforcement. A psychostimulant-mimetic model for PG is proposed based on evidence from the following domains: Acute subjective-behavioral effects of gambling and psychostimulants; Effects of anticipated rewards and uncertainty of reward delivery (key elements of gambling) on DA release; Relationship between DA release and positive arousal; Cross-priming of motivation for gambling by amphetamine; Effects of DA D2 antagonists on gambling and amphetamine reward; Effects of mixed D1-D2 antagonists on clinical symptoms of PG; Effects of DA D2 agonists on experimental measures of risk-taking, gambling, and induction of PG in patients with Parkinsons disease; Electrophysiological and cognitive disturbances associated with chronic exposure to gambling and psychostimulants, and the possible role of sensitization in these effects. Limitations of the model regarding the exclusive role of DA are discussed with particular reference to genetic risk, co-morbidity, and sub-types of PG. Suggestions for future research include isolating the roles of DA receptor subtypes in PG, and parallel within-subject assessment of DA manipulations on gambling and psychostimulant reinforcement in PG subjects and controls.