Katja Sturm

Activation of Muscarinic and Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Core Is Necessary for the Acquisition of Drug Reinforcement

Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of ∼10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Our findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

Intravenous Drug Injection Habits: Drug Users’ Self-Reports versus Researchers’ Perception

The present study was designed to obtain human data on the speed of intravenous (i.v.) injection of cocaine, heroin, and morphine as well as on the rate of onset of their subjective effects and their duration in order to improve the accuracy of animal and human experimental models of i.v. drug abuse. To that end, a questionnaire was submitted both to clients of a substitution therapy outpatient clinic and to members of the drug abuse research community. It was found that i.v. drug abusers injected cocaine, heroin, or morphine much faster and also experienced the drug effects much faster than assumed by the drug abuse researchers. The time course of the reemergence of craving was also greatly misjudged by the researchers. On the other hand, the i.v. drug users’ self-reports were internally consistent and corresponded well to data obtained in several different human behavioral laboratories. Interestingly, more than half of the i.v. drug users reported that injection speed was not important when injecting cocaine (57%), heroin (72%) or morphine (73%) under conditions that guarantee a maximum effect, suggesting that the rate of the rise in the brain concentration of a drug of abuse is less important for its reinforcing effect and, thus, for its abuse liability, than previously assumed, at least within the time frame of an i.v. drug injection.

Subjective Effects of Slow-Release Bupropion versus Caffeine as Determined in a Quasi-Naturalistic Setting

Bupropion (BUP), which in its slow-release formulation (Zyban®) is used as a smoking-cessation drug, increases dopamine overflow in the nucleus accumbens and serves as a reinforcer in animal experiments, both suggesting that BUP may possess some abuse liability. The present study examined if BUP produced subjective effects indicative of abuse liability in a quasi-naturalistic setting, with caffeine (CAF) serving as a positive control. In a randomized double-blind crossover design, male smokers (n = 50) ingested two doses (interdosing interval, 6 h) of placebo (PLC), 178 mg CAF, or 150 mg slow-release BUP in their normal mid-week work environment. They completed questionnaires administered by telephone at regular intervals. CAF significantly increased ratings of ‘pleasant effects’ (p = 0.008) and ‘high’ (p = 0.03), whereas BUP produced a ‘high’ of only very moderate size (p = 0.02). In 3 subjects each, BUP or CAF produced ratings of ‘pleasant effects’ that were >9-fold higher than those for PLC. Finally, BUP increased the number of cigarettes smoked by 29% (i.e., from 24 to 31 per day; p = 0.004) only in those subjects who were unable to report any effect of either BUP or CAF. CAF had no effect on cigarette consumption. These findings suggest that BUP, like CAF, might be of some abuse liability in a small subgroup of smokers (i.e., 6% each of the present sample), and it may transiently increase, rather than decrease, smoking during early phases of treatment in continuing smokers.

Methylenedioxymethamphetamine (MDMA, ‘Ecstasy‘) Serves as a Robust Positive Reinforcer in a Rat Runway Procedure

Although ‘ecstasy’ (3,4-methylenedioxymethamphetamine, MDMA) is, after marijuana, the second most prevalent illegal drug of abuse in European adolescents, animal experimental evidence of MDMA’s reinforcing effect has remained scarce, particularly in the rodent model, raising questions about the robustness of MDMA’s reinforcing effect under controlled laboratory conditions. In the present rat runway study, Sprague-Dawley and Long-Evans rats were given the opportunity to run for intravenous injections of saline or MDMA (1 mg/kg). MDMA significantly decreased runtimes in both rat strains. Thus, MDMA’s positive reinforcing effect can be demonstrated not only across rat strains but also across operant conditioning paradigms. These findings should reassure the drug abuse research community that the investigation of MDMA’s reinforcing effect in the inexpensive and widely used rodent model is indeed feasible.

Peri‐Response Pharmacokinetics of Remifentanil during a Self‐Administration Session Indicates That Neither Blood nor Brain Levels Are Titrated

Abstract:  An individuals drug abuse pattern is determined by a multitude of factors. Among these, simple pharmacological determinants of within‐binge drug consumption are sorely underinvestigated. We therefore determined if within‐session operant responsing to the ultra‐short‐acting mu opioid agonist remifentanil (RMF) was determined by blood or brain RMF levels or changes thereof. Our peri‐response analysis did not detect any “threshold” RMF level, either in blood or in the nucleus accumbens (NAc) core as a deep brain region that might determine a rats “decision” to re‐emit a response during a multiple‐injection drug self‐administration session. The peri‐response analysis also failed to find any peak RMF level, either in blood or in the NAc core, which could serve as a “ceiling” level. Thus, our findings strongly suggest that titration of blood or brain RMF levels does not determine a rats intra‐session operant response.

Abhängigkeit im Experiment

In diesem Kapitel wird beschrieben, wie das Abhangigkeitsrisiko („Suchtrisiko”) einer Substanz bestimmt werden kann und wie neue pharmakologische und psychotherapeutische Behandlungsstrategien bei den Krankheitsbildern „Abhangigkeitssyndrom” und „Schadlicher Gebrauch” getestet werden konnen. An einem Beispiel aus dem Humanverhaltenslabor wird klar, dass unser Korper und unser Unbewusstes viel mehr uber die Anziehungskraft eines Suchtmittels wissen als wir in Worte fassen konnen. Die experimentelle Suchtforschung zeigt zunehmend, dass fur die Entscheidung zum Suchtmittelkonsum neben dem unmittelbaren pharmakologischen Effekt der Droge die Erinnerung an fruhere Drogenerfahrungen bedeutsam ist. Damit gewinnt die Veranderung der Erinnerung an Intoxikationserlebnisse — seit jeher eine Domane der Psychotherapie — mehr an Bedeutung, auch fur mogliche pharmakotherapeutische Interventionen.