The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat

Rationale: Endogenous opioid systems within the mesencephalic periaqueductal gray matter (PAG) appear to be intricately involved in many affective, defensive, submissive, and reflexive responses, and these systems are activated by aversive stimuli. Objectives: The present experiments evaluated the influence of opioid receptors within the PAG on affective vocal and reflexive responses to aversive stimuli in socially inexperienced, as well as defensive and submissive responses in defeated, adult male Long-Evans rats. Methods: Defeat stress consisted of: (1) an aggressive confrontation with a ”resident” stimulus rat in which the experimental ”intruder” rat exhibited escape, defensive and submissive behaviors [i.e. upright, supine postures and ultrasonic vocalizations (USV)], and subsequently, (2) protection from the resident rat with a wire mesh screen for ca. 25 min. Defeat stress was immediately followed by an experimental session with thermal antinociceptive and tactile startle stimuli (20 psi airpuffs). Results: The μ opioid receptor agonist morphine (0.3, 1, 3 μg IC) attenuated startle-induced USV and the tail-flick reflex in socially inexperienced and defeated rats, with both groups of rats demonstrating equal sensitivity to morphine. Morphine decreased defeat-induced USV and increased the display of the crouch posture in defeated rats; these morphine effects in socially inexperienced and defeated rats were re- versed with the opioid receptor antagonist naltrexone (0.1 mg/kg IP). Conclusions: These results reveal that the ventrolateral PAG is an important site in which μ opioid receptor agonists such as morphine mediate affective vocal and submissive responses, yet this structure is not critical in the display of defeat stress-augmented effects of morphine. Endogenous opioid mechanisms appear to participate in the organization of defensive behavior, namely, to facilitate a shift from active to passive forms of coping. Received: 9 November 1998 / Final version: 29 April 1999     

Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans

The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam. Received: 20 June 1998 / Final version: 4 November 1998     

Dimensions and Disorders of Adolescent Adjustment: A Quantitative Genetic Analysis of Unselected Samples and Selected Extremes

One of the fundamental questions for developmental psychopathology concerns the etiological links between the normal and abnormal. To what extent do disorders differ quantitatively or qualitatively from variation in the normal range? Genetic research on the normal and the abnormal differs in terms of concepts, methods, statistics, and target audiences. An approach, referred to as "DF" analysis, provides a framework for integrating these two worlds of genetic analysis. We applied traditional correlational analyses as well as DF (DeFries & Fulker, 1985) analyses to mother and father ratings of adjustment of adolescent siblings in a 3-year longitudinal twin and step-family study. At wave 1, the sample included 720 sibling pairs (average age of 12.9 years for the younger sibling and 14.5 years for the older siblings) and, in wave 2, 395 pairs still living at home. Both correlational analyses of the entire sample and DF analyses of selected extremes suggested moderate genetic influence and modest shared environmental influence for internalizing and externalizing behavior problems. Similar estimates were found for unselected individual differences and selected extreme groups. A framework is proposed that focuses on quantifying the etiologies of disorders (QED) as measured on continuous dimensions.     

Cannabis interferes with nest-building behavior in mice

Nest-building, a behavioral model shown to be disrupted by hallucinogens, has never been used to answer questions concerning the psychotomimetic effects of ⁹-THC. Several fractions of cannabis and tobacco pyrolysis products were tested consecutively in the same procedure. The following drugs were injected i.p. under a saline-drug-saline schedule: d-amphetamine (6 mg/kg), pentobarbital (25 mg/kg), ⁹-THC (10 mg/kg, 5 mg/kg, 2.5 mg/kg), the cannabis fractions designated I_s (water soluble products), II_s (nonsoluble, nonvolatile products), III_s (it comprises what is inhaled by a common hashish smoker), and analogous fractions of tobacco pyrolysis products designated III_B (what is inhaled by a common tobacco smoker), II_B and I_B.The effects of ⁹-THC (10 mg/kg), II_s, and III_s were quite similar as far as the disruption of the normal behavioral pattern is concerned. d-Amphetamine, ⁹-THC (5 mg/kg), and II_B disrupted the normal behavioral pattern as well. The similarity of the effects of II_s and III_s was unexpected in view of the different contents of cannabinoids in these fractions. Also unexpected was the similarity of the effects of ⁹-THC (10 mg/kg) and III_s (40 mg/kg containing 7% ⁹-THC) as well as the activity of fraction III_B.     

Accelerated development of tolerance during repeated cycles of ethanol exposure

Adult male rats were subjected to 1–4 cycles of daily gastric intubation with ethanol (6 g/kg) for 16 days, separated by 17-day alcohol-free periods. Tolerance produced by this treatment (designated physiological tolerance) was measured by change in effect of a 2.2 g/kg i.p. dose of ethanol on the moving-belt test. It occurred in each cycle, disappeared completely in the drug-free periods, and developed more rapidly in the second and later cycles than in the first. Tolerance produced by the behavioral augmentation technique (daily test practice under the influence of ethanol) also developed more rapidly on a second than on a first cycle. The progression from within-session to between-session tolerance was still evident, but accelerated. With 25-day alcohol cycles, separated by a one-month drug-free period, the carry-over effect (i.e., more rapid acquisition of tolerance in the second cycle) applied equally, regardless of whether or not tolerance was produced by the same technique in both cycles, or by a crossover in either direction between the two techniques.     

Supersensitivity to l-5-hydroxytryptophan after 5,7-dihydroxytryptamine injections in desmethylimipramine- and nomifensine-pretreated rats: Behavioral evidence for postsynaptic supersensitivity

The behavioral syndrome induced by l-5-hydroxytryptophan (l-5-HTP) in rats was used to study the supersensitivity to l-5-HTP and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) which develops after unilateral intracerebroventricular (ICV) injections of 200 g 5,7-dihydroxytryptamine (5,7-DHT). Pretreatment of the animals with a combination of desipramine and nomifensine was found to protect dopamine neurones better than desipramine alone. Maximal behavioral supersensitivity to l-5-HTP and 5-MeODMT was found as early as 24 h after injection of the neurotoxin, even in the presence of the specific 5-HT uptake inhibitor CGP 6085 A, or the MAO-A inhibitor clorgyline. The results indicate that a quickly occurring postsynaptic event contributes to the development of behavioral supersensitivity after ICV injections of 5,7-DHT.     

Prenatal Drug Exposure: Neurodevelopmental Outcome and Parenting Environment

Examined neurodevelopmental patterns and caregiving environmentamong 20 infants prenatally exposed to cocaine and 20 drug-freeinfants. The Brazelton Scale was administered 4 times. Drugexposedinfants had less optimal neurodevelopment than comparison infantsat birth, but by 6 weeks only differences in autonomic stabilitywere apparent. Neurodevelopmental performance was related positivelyto the child-centered quality of the environment. Though supportbuffered stress in both groups, the effect was more robust amongdrug-free mothers. Findings support the need to consider neurodevelopmentalrecovery and the caregiving environment in evaluations of developmentaloutcome among drug-exposed infants.     

Regional hippocampal lesions alter matching by monkeys: an anorexiant effect

Findings showed that monkeys with middle, but not anterior or posterior hippocampal damage, are impaired in ability to acquire matching-to-sample, if training is conducted without error correction. All groups except this middle hippocampal lesion group abandoned the spatial strategy and achieved above-chance levels of matching within 6,000 trials. Although monkeys with anterior and posterior hippocampal lesions abandoned spatial strategies of responding at the normal rate, they, along with the middle hippocampal lesion group began to show a short-session-effect which coincided with just-above-chance matching performance. Affected monkeys, although able to correctly match, would not consume the food pellet reward, showed signs of anxiety, and performed only 25 of the usual 200 problems offered each day. None of the surgical control or unoperated control monkeys exhibited the short-session-effect. The untreated short-session-effect continued for as long as two months, but was always quickly alleviated by oxazepam, diazepam, or chlordazepoxide hydrochloride.     

Electrodermal activity and temperament in preschool children

This study had two objectives: To examine poorly understood patterns of young children's electrodermal reactivity and to test the hypothesis that this reactivity reflects individual differences in the behavioral inhibition system (BIS). We recorded skin conductance responses (SCRs) from 92 4-year-old children during a laboratory session that encompassed physiological and psychological stimuli. Physiological stimuli (breaths), moderately loud to loud sounds (expected and unexpected) and, to a lesser extent, stimuli with psychological significance elicited clear SCRs. Induction of psychological conflict and exposure to emotional film clips for the most part did not elicit increases in skin conductance (SC). Children's temperament dimensions of fearfulness and effortful (or inhibitory) control--two components of the BIS--were assessed using robust observational batteries at age 2 and 4 years. The theoretically expected correlations between overall SC lability (reflecting SC levels) and both dimensions of temperament were significant, albeit modest and limited to the contemporaneous measures at age 4.