Alejandro Zaffaroni

Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: Involvement of dopamine and serotonin

The meso-limbic dopamine (DA) system has an important role in regulating alcohol drinking. Previous findings from our laboratory indicated that Wistar rats self-administered ethanol (EtOH) directly into the posterior, but not anterior, ventral tegmental area (VTA), and that coadministration of a DA D2,3 receptor agonist or a serotonin-3 (5-HT3) receptor antagonist blocked EtOH self-administration. In addition, we reported that alcohol-preferring (P) rats self-administered acetaldehyde (ACD), the first metabolite of EtOH, into the posterior VTA. The objectives of this study were to compare the reinforcing effects of EtOH and ACD within the VTA of P rats to examine the possibility that the reinforcing effects of EtOH within the VTA may be mediated by its conversion to ACD. Adult female P rats were stereotaxically implanted with guide cannulae aimed at either the posterior or anterior VTA. At 1 week after surgery, rats were placed in standard two-lever (active and inactive) experimental chambers for a total of seven to eight sessions. The 4-h sessions were conducted every other day. The results indicated that (a) 75–300 mg% (17–66 mM) EtOH and 6–90 μM ACD were self-administered into the posterior, but not anterior, VTA; (b) the self-administration of 150 mg% EtOH was not altered by coinfusion of a catalase inhibitor; (c) coadministration of the D2/3 agonist quinpirole (100 μM) blocked the self-infusions of 150 mg% EtOH and 23 μM ACD into the posterior VTA; and (d) coadministration of 200 μM ICS205,930 (5-HT3 receptor antagonist) prevented the self-infusion of 150 mg% EtOH, whereas concentrations of ICS 205,930 up to 400 μM had no effect on the self-infusion of 23 μM ACD into the posterior VTA. Overall, the results of this study indicate that EtOH and ACD can independently produce reinforcing effects within the posterior VTA, and that activation of DA neurons mediates these effects. Furthermore, activation of 5-HT3 receptors within the posterior VTA is involved in the self-infusion of EtOH, but not ACD.

The role of acetaldehyde in the central effects of ethanol.

This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired by Kathleen A. Grant. The presentations were (1) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats, by Mercè Correa, Maria N. Arizzi and John D. Salamone; (2) Behavioral characterization of acetaldehyde in mice, by Etienne Quertemont and Sophie Tambour; (3) Role of brain catalase and central formed acetaldehyde in ethanols behavioral effects, by Carlos M.G. Aragon; (4) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by William J. McBride, Zachary A. Rodd, Avram Goldstein, Alejandro Zaffaroni and Ting-Kai Li; and (5) Acetaldehyde increases dopaminergic transmission in the limbic system, by Milena Pisano and Marco Diana.

Salsolinol Produces Reinforcing Effects in the Nucleus Accumbens Shell of Alcohol-Preferring (P) Rats

BACKGROUND The formation of salsolinol (SAL) has been hypothesized to be a factor contributing to alcoholism and alcohol abuse. If SAL is formed under chronic alcohol-drinking conditions, then it may contribute to alcohol addiction by being rewarding itself. Because SAL can be formed by the nonenzymatic condensation of acetaldehyde with dopamine, the reinforcing effects of SAL were tested in the nucleus accumbens shell, a dopamine-rich site considered to be involved in regulating alcohol-drinking behavior. METHODS The intracranial self-administration technique was used to test the reinforcing properties of SAL. Adult, female alcohol-preferring (P) rats were stereotaxically implanted with guide cannulae aimed at the nucleus accumbens shell. After 7 to 10 days to allow recovery from surgery, P rats were attached to the electrolytic microinfusion transducer system, placed in two-lever experimental chambers, and allowed to respond for the self-infusion of 100 nl of modified artificial cerebrospinal fluid (aCSF) or 0.03, 0.3, 3.0, or 12.5 microM SAL (3-1250 fmol/100 nl). Sessions were 4 hr in duration and were conducted in the dark cycle every 48 hr. The effects of coinfusing 10 to 400 microM sulpiride (given in sessions 5 and 6 after four acquisition sessions) on the intracranial self-administration of 3.0 microM SAL were tested in a separate experiment. RESULTS P rats given 0.3 to 12.5 microM SAL received significantly more infusions per session than did the group given aCSF alone (e.g., 50 infusions for 3.0 microM SAL versus 10 or fewer infusions for the aCSF group) and responded significantly more on the active than inactive lever. Coinfusion of 100 or 400 microM sulpiride reduced the responding on the active lever (80-100 responses/session without sulpiride) to levels observed for the inactive lever (fewer than 10 responses/session with sulpiride). This effect was reversible because giving SAL alone in session 7 reinstated responding on the active lever. CONCLUSIONS SAL is reinforcing in the nucleus accumbens shell of P rats at concentrations that are pharmacologically possible, and these reinforcing actions are mediated in part by D2/D3-like receptors.

Endometrial morphology in women exposed to uterine systems releasing progesterone

A blind study was done in 402 endometrial biopsies of women who had intrauterine devices releasing different daily amounts of progesterone or a placebo (empty device): 175 were obtained in what presumably was the proliferative phase and 227 in the secretory stage, as all these subjects were normal, healthy women with a history of previous fertility. With all dose levels of the progesterone-releasing devices there was variation of the endometrium general pattern and the over-all picture varied from normal secretory to suppressed endometrium. In addition to these changes of the endometrial pattern, in 231 specimens there was significant inflammatory infiltration and in six cases even plasma cells were seen. Predecidual reaction was frequently seen and in 45 cases it was diffuse and marked. The significance of these data is discussed on the grounds of the frequent similarities of the changes here reported with those in women using combined oral steroids for contraception.

ALZA: An enterprise in biomedical innovation

Abstract Pharmaceutical innovators confront increasingly severe problems: prolonged lead times for product development and approval; soaring costs; and constraining factors implicit in the chemical approach to inventing or improving drugs. To avoid the problems of the chemical approach, which has previously dominated pharmaceutical R&D, the ALZA Corporation has been working intensively to develop radically new dosage forms for administering medication. The purpose of these dosage forms, called therapeutic systems, is to produce an optimal therapeutic effect and minimize side effects by delivering drugs to the body at precisely controlled rates. Products are now approved, or on the market, for delivering drugs through intact skin, for topically medicating the eye, and for providing hormonal contraception localized to the uterus. Other therapeutic systems are in advanced development, including one taken by mouth — the most favored route of administration. The innovative nature of ALZA products has made their approval and marketing difficult and has generated a need for a continuing high level of financial support. Maintaining an entrepreneurial effort of so unusual a kind has demanded total commitment on the part of corporate leadership and effective communication of that commitment to people at all company levels. Recently ALZA has enlisted large pharmaceutical companies as marketing partners, an arrangement that is likely to accelerate acceptance of its products and of the concept of controlled drug delivery.

Applications of Polymers in Rate-Controlled Drug Delivery

In recent years, polymers have found functional uses as components of new dosage forms that precisely control the therapeutic administration of drugs. These developments, which came about because of the drawbacks of conventional dosage forms, promise advances in many areas of medical treatment.

Contraception by intrauterine release of steroids

Due to the incidence of missed doses in a large population a failure rate of 4-7% for oral contraceptives has been reported. As a result a new group of pharmaceutical products has been developed. The most appropriate drug at the lowest effective concentration and with a minimum of patient intervention was sought. The compound developed by the ALZA Corporation was called Progestasert. It is a T-shaped device for uterine placement. Progesterone is contained within a capsule and released continuously at a rate of 65 mcg/day over a 1-year period. The polymer membrance control element achieves the precision and constancy of drug delivery. Clinical studies in 20 countries with 4200 women for 3600 woman-months of use have resulted in a failure rate of 1% and a continuation rate of 85% after 1 year of use. This method eliminates the need for estrogen and avoids systemic side effects. The total dose of progesterone released by the Progestasert during 1 year of use is less than the amount normally produced by the ovaries each day during the high point of the menstrual cycle. It is the 1st once-a-year hormone fertility control agent and the 1st target-specific hormonal system.

Progestasert: A Uterine Therapeutic System for Long-term Contraception: I. Philosophy and Clinical Efficacy**Presented at the 29th Annual Meeting of The American Fertility Society, San Francisco, April 5 to 7, 1973.

An intrauterine steroid delivery system the Progestasert system, is described and studies of its clinical efficacy are reported. The Progestasert system combines the advantageous features of IUDs and oral minidose progestogen preparations. An internal device continuously delivers progesterone for 1 year to the uterine lumen and endometrium. A T-shaped Progestasert which releases 65 mcg/day has been selected for wide scale clinical use. A total of 3121 parous women used Progestasert systems for 25,389 woman-months. The pregnancy rate was 1%, the expulsion rate 2.8%, and the total removal rate was 13%. The total continuation rate of the Progestasert system of 83.2% compares favorable with that of the Tatum-T-shaped IUD of 68.7%. These initial results aft er 1 year of use are most encouraging and suggest that the goals originally set for a contraceptive approach using intrauterine progester one are well within reach.