Enhanced stimulus-reward learning by intra-amygdala administration of a D3 dopamine receptor agonist

The amygdala is considered to be a critical neural substrate underlying the formation of stimulus-reward associations, and is known to receive substantial innervation from dopaminergic neurons located within the ventral mesencephalon. However, relat- ively little is known about the function of the mesoamygdaloid dopamine projection in stimulus-reward learning. Recently, we have found post-session intra-amygdala microinjections of d-amphetamine to enhance appetitive Pavlovian conditioning as assessed in a discriminative approach task. In the present study, we have examined the effects of dopamine receptor agonists possessing relative selectivity for the D₁, D₂ and D₃ receptor subtypes in order to examine more fully the role of the mesoamygdaloid dopamine projection in stimulus-reward learning. Thus, subjects were trained to associate an initially neutral stimulus (CS⁺) with 10% sucrose reward (US). A second, control stimulus (CS⁻) was also presented but never paired with sucrose reward. In order to measure specifically the conditioned response to CS⁺/CS⁻ presentation, responding during CS and US presentations was measured separately. Immediately following each training session, subjects received bilateral intra-amygdala infusion of 0.1, 1 or 10 nmol/side of SKF-38393, quinpirole or 7-OH-DPAT. Infusions of SKF-38393 or quinpirole were without effect on CS⁺ approach. However, post-session intra-amygdala infusions of 7-OH-DPAT enhanced selectively CS⁺ approach in a dose-dependent fashion. No dose of any drug affected CS⁻approach, US behaviours, or measures of extraneous behaviour. Subsequent acquisition of a novel conditioned instrumental response was also unaffected. Thus, the present data indicate a selective involvement of the D₃ dopamine receptor subtype in the modulation of stimulus-reward learning by the mesoamygdaloid dopamine projection. Received: 12 December 1996 / Final version: 9 April 1997     

Abstracts of the contributed papers

Abstracts of the contributed papers     

Treatment of chronic hepatitis C: Improved combination therapy

There has been considerable progress in the treatment of chronic hepatitis C since the first report that interferon (IFN) monotherapy was effective in 1989. Early results were meager, with sustained loss of hepatitis C virus from blood in fewer than 10% of cases. The combination of IFN with the oral nucleoside analogue ribavirin was a major breakthrough in clinical hepatology; it led to dramatic increases in treatment responses, with 30% to 40% of patients clearing virus. Pegylated IFNs that have prolonged activity and can be dosed once a week have now replaced standard IFNs. The combination of pegylated IFN with ribavirin is the new standard of care; it causes sustained loss of virus in more than half of treated patients. Treatment responses continue to be highly dependent on viral genotype. Patients with genotype 1, the most common type in the United States, have a sustained clearance rate of 42% to 46%, whereas those with genotype 2 or 3 have a response rate approaching 80%.     

Chronic chorioamnionitis: a clinicopathologic study of 17 cases

The clinicopathologic features of 17 cases of an unusual variant of chorioamnionitis distinguished by a pure or predominantly chronic inflammatory infiltrate in the fetal membranes rather than the usual acute inflammatory reaction are reported. In six cases, there was an equal (one case) or minor (five cases) component of acute inflammation in the fetal membranes as well. Concomitant villitis, found in 11 cases, was almost uniformly lymphohistiocytic and destructive, but it varied greatly in severity. Immunoperoxidase stains for cytomegalovirus, herpes simplex I and II, and Toxoplasma gondii; Warthin-Starry, Gomori methenamine silver, Dieterle, Gram and acid fast stains; placental or amniotic fluid culture; and limited maternal serologic studies failed to identify a specific infectious etiology in any case. Seven women had experienced at least one previous spontaneous abortion, fetal death in utero, or preterm birth. No patient reported a history of fever, rash, or flu-like syndrome during pregnancy. Serious antenatal complications were numerous. Preterm birth occurred in 13 cases. Gestational age ranged from 25 to 42 weeks (mean 32 weeks) and birth weight ranged from 740 to 3,230 g (mean 2,100 g). When expressed as a percentile for gestational age, 47% of infants had a birth weight at or below the 25th percentile, and 76% were at or below the 50th percentile. Two infants were born with gross anomalies, and one infant died in the neonatal period.     

Fertility after simulated Fowler-Stephens orchiopexy in rats.

In order to determine the effects of the Fowler-Stephens orchiopexy (FSO) on fertility, young rats underwent simulated FSO, FSO and concurrent contralateral orchiectomy (FSO/OR), unilateral orchiectomy (OR), or sham operation (controls). Twelve weeks after the operation, each male rat was mated to two proven-fertile female rats for 17 days (three ovulatory cycles). Two weeks later, both male and female rats were killed. No pregnancy resulted from the matings of the FSO/OR males. In contrast, pregnancy ensued in 13 of 16 (81%) females in the FSO group, 9 of 14 (64%) in the OR group, and 11 of 12 (92%) in the control group. There were no fertile males in the FSO/OR group. In the FSO group, eight of eight males induced pregnancy in at least one female; in the OR group, six of seven (86%) males were fertile as were all six males in the control group. No differences in litter size or fetal weight were observed between fertile females in various groups.     

Levodopa improves physical fatigue in Parkinson's disease: a double-blind, placebo-controlled, crossover study.

We quantitatively investigated the effect of carbidopa/levodopa (25/100) on physical fatigue during finger tapping and force generation in a double-blind, placebo-controlled crossover study. Parkinson's disease (PD) subjects were randomly assigned to carbidopa/levodopa or placebo for Visit 1 or 2 and participated in the following two studies: (1) Finger tapping. Twenty-five PD patients used their index fingers to strike two keys 20 cm apart on a musical instrument digital interface (MIDI) keyboard. The slopes of the regression line of dwell time and movement time were used to assess the rate of fatigue development. (2) Force generation. Twelve PD patients contracted the wrist extensors maximally to obtain a baseline maximum voluntary contraction (BMVC) force. Then they repetitively contracted the wrist extensors at 50% of the BMVC for 7 seconds and rested for 3 seconds. An interval maximum voluntary contraction (IMVC) was measured every three repetitions. Fatigue was defined as an IMVC of less than 60% of the BMVC. The slope of the regression line of IMVC was used to assess the rate of force decline. These two studies were repeated 1 hour after carbidopa/levodopa (25/100) or placebo. Subjects filled out the Multidimensional Fatigue Inventory (MFI) at the beginning of the first visit. Results showed that the slope of dwell time decreased with levodopa but not with placebo (P = 0.004). The rate of force decline also decreased with levodopa but not with placebo (P = 0.01). The subscores in the dimension of physical fatigue in the MFI did not correlate with the rate changes in dwell time or the rate changes in force decline. We concluded that (1) levodopa improves physical fatigue in finger tapping and force generation, (2) physical fatigue in Parkinson's disease is at least partially related to dopamine deficiency, and (3) the MFI measures different aspects of physical fatigue compared with those measured by finger tapping and force generation.     

The fate of buried vaginal epithelium.

A new technique in the treatment of stress urinary incontinence utilizes a sling fashioned from a rectangular island of buried vaginal epithelium. We developed a model to study the natural history of vaginal wall covered by an epithelial flap in 12 rabbits sacrificed at intervals to 26 weeks. Histopathologic examination demonstrated an immediate acute inflammatory reaction. This early response was followed by formation of an epithelial lining of the potential space overlying the buried vaginal tissue. Acute inflammatory cells continued to enter this lumen until week 20, when granulomas were first detected. Histopathologic examination at twenty-six weeks showed stratified squamous epithelium lining the lumen. No deleterious inflammatory sequelae were detected, and no dysplastic or malignant changes were identified. These results suggest that buried vaginal epithelium is a safe (short term) tissue alternative for sling creation.     

Laparoscopic trans-cystic-duct common-bile-duct exploration

One thousand seventy-one consecutive laparoscopic cholecystectomies were performed. Routine cholangiography was employed with a 99% success rate. One hundred thirty patients were found to have common duct stones (CBDS). In 48 (37%) patients they were unsuspected. One hundred eleven patients underwent attempted trans-cystic-duct extraction techniques (TCD-CBDE). One hundred three (93%) were successful. The following techniques were employed: 101—biliary endoscopy, 23—ampullary balloon dilation, 2—fluoroscopic basket retrieval.The average operative time was 136 min. The average postsurgical stay was 3.7 days. There were 19 (17%) complications—6 (5%) major. There were 4 retained stones (2 intentional) and 1 death. Patients over 65 years of age had more complications and patients with unsuspected CBDS under 65 years of age had the fewest.TCD-CBDE is a safe, effective way to extract common duct calculi. Endoscopy and basket stone retrieval was the primary technique employed.Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), Nashville, Tennessee, USA, 18–19 April 1994