Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine

Experiments examined how learning processes modulate tolerance to discriminative stimulus effects of morphine. Rats were trained to discriminate saline and 3.2 mg/kg morphine, and the doses of morphine required to mimic the training dose were determined before, during and after repeated treatment with saline or high doses of morphine (10 mg/kg, b.i.d.). In one set of experiments, training was either suspended or continued with saline and the original training dose during a 2-week treatment regimen. When training was suspended, high-dose morphine treatment increased the dose of morphine required for stimulus effects approximately 3-fold. Tolerance persisted 2 days after treatment ended, but disappeared within 7 days. In contrast, continued training with saline and 3.2 mg/kg morphine during high-dose treatment both attenuated development of tolerance and transferred control to lower doses. Transfer of control to lower doses appeared conditional upon recent termination of high-dose treatment, as it disappeared within 7 days. Treatment with saline did not change the doses of morphine required for stimulus effects under either training condition. A final experiment examined whether high-dose treatment could transfer control to higher doses of morphine. The treatment dose of 10 mg/kg morphine itself was used as the training dose during a 2-week treatment regimen. The dose of morphine required for stimulus effects increased 2- to 4-fold during treatment, but quickly returned to control values when treatment ended. These results extend previous findings that conditioning and pharmacodynamic processes jointly regulate development of tolerance to discriminative effects of morphine.     

Binge cocaine self-administration by humans: smoked cocaine

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.     

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats

Salicylate-kodein is a widely used analgesic agent, particularly in outpatient practice. Salicylates have been incriminated in hepatic injury while kodein may induce biliary spasm. We report here a case of granulomatous hepatitis attributed to prolonged intake of this combination, which has never been reported previously to our knowledge.     

Behavioral contingencies and self-mutilation in Lesch-Nyhan disease.

Lesch-Nyhan syndrome is a rare, sex-linked, recessive disease that is accompanied by severe self-mutilation, especially finger biting. Evidence is presented suggesting that parental response patterns may contribute to the genesis of the self-injurious behavior (SIB). The therapeutic effectiveness of punishment, positive reinforcement of either SIB or non-SIB, and time-out learning paradigms were evaluated in 5 Ss aged 3–13 yrs. Electric skin shock failed to suppress the behavior. Positive reinforcement of non-self-injury and time-out from social reinforcement were consistently and rapidly effective, indicating a complex interaction of genetic and environmental factors in the production of SIB. Elimination or major reductions in incidence of SIB was maintained during follow-up periods of 2 yrs. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Caffeine self-administration in humans: 1. Efficacy of cola vehicle

Eight exclusive cola drinkers in Experiment 1 (mean caffeine intake = 157 +/- 74 mg/day) and 16 drinkers of both cola and coffee in Experiment 2 (mean caffeine intake = 579 +/- 201 mg/day) underwent 6 independent, double-blind weekly trials. Each trial began with a randomized cross-over sampling period of 1 day of access to noncaffeinated cola and 1 day of access to caffeinated (33 mg/8 oz) cola. During the subsequent 1- or 2-day test period, participants had unlimited concurrent access to the 2 colas. Reliable caffeine self-administration occurred in 2 of 8 participants in Experiment 1 and in 4 of 16 participants in Experiment 2. Self-reported drowsiness, fatigue, and headache were higher when participants received only placebo colas in Experiment 2, but not Experiment 1. Caffeine self-administration via cola occurs both among people whose primary source of caffeine is cola and among those whose primary source of caffeine is coffee.     

Attributions modulate immunization against learned helplessness in humans.

Conducted 3 experiments to determine the effect of global and internal attributions on immunization against learned helplessness. Exp 1 replicated the helplessness effect and its immunization. This immunization effect was weakened in Ss with global internal attributions about negative events and strengthened in Ss with specific and external attributions. In Exp 2, previous attributional style did not produce any effect on either immunization or helplessness. However, instructions to induce global internal attributions produced an enhanced helplessness effect. In Exp 3, global internal attributions induced by instructions during uncontrollability, but not during controllability, produced significant differences in the immunization effect. Immunization against helplessness was a function of a previous controllable experience, and attributions represented a vulnerability factor that modulated the actual influence of previous experiences on new tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

America's angriest home videos: Behavioral contingencies observed in home reenactments of marital conflict.

Sequential analysis was used to compare the conflictual marital interactions of 17 physically aggressive (PAG), 15 verbally aggressive, 18 withdrawing, and 15 nondistressed, low-conflict (NDLC) couples to describe behavior patterns characteristic of couples who report different marital conflict styles. Videotapes of couples enacting typical conflicts in their own homes were coded with a system designed to capture the affective aspects of communication. PAG couples were characterized by the reciprocity of hostile affect and by rigid, highly contingent behavior patterns that were both stronger and longer lasting than those of other conflictual, but nonviolent, couples. In a limited way, NDLC couples demonstrated some of the same negative behavior patterns as the conflictual couples, but they were able to exit these negative interaction cycles quickly, which underscores the importance of further research into the de-escalation of conflict. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

Cocaine self-administration increased by compounding discriminative stimuli

Presenting independently established discriminative stimuli in compound can substantially increase response rates under food and shock-avoidance schedules. To determine whether this effect extends to drug self-administration, rats were trained to press a lever to receive cocaine intravenously. A tone and a light were independently established as discriminative stimuli for cocaine self-administration, then presented in combination in a stimulus-compounding test. Compared to tone and light alone, the tone-plus-light compound stimulus increased responding approximately three-fold when cocaine was withheld during testing, and it increased drug intake approximately two-fold when cocaine was made available during testing. Compounding did not increase responding after training in a truly random control condition where tone and light were presented uncorrelated with the availability of cocaine. The results obtained with this animal model of drug abuse define conditions under which combinations of environmental stimuli might substantially increase human drug use.     

Caffeine self-administration in humans: 2. A within-subjects comparison of coffee and cola vehicles.

The reinforcing effects of caffeine ingested in coffee versus cola were studied. Eleven participants who drank both coffee and cola (3–10 cups of coffee and 1–6 cans of cola daily; M?=?632 mg caffeine/day) were tested in 4 conditions: cola at 33 mg/serving (the usual dose), coffee at 33 mg/serving, cola at 100 mg/serving, and coffee at 100 mg/serving (the usual dose). Each condition consisted of 6 double-blind weekly trials. In each trial, participants sampled caffeinated and noncaffeinated beverages and then had concurrent access to the 2 beverages. Relative use of these beverages was used to assess caffeine reinforcement. Across the 4 conditions (24 weeks), reliable caffeine reinforcement occurred in 5 participants (45%). Caffeine reinforcement did not differ as a function of vehicle or serving dose, and no vehicle-dose interactions were found. With both cola and coffee at the commonly used doses, self-reported motivation to work was greater and drowsiness and laziness smaller with caffeinated than noncaffeinated beverages. Results indicate that, among users of both coffee and cola, caffeine self-administration and subjective effects occur with both vehicles. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional guidance by salient feature singletons depends on intertrial contingencies.

Evidence that salient feature singletons guide attention only when the target and the singleton frequently coincide has been taken to suggest that selection of singletons is under top-down control: Observers strategically use an attentional set sensitive to the singleton being a target. Changing the singleton-target (or singleton-distractor) coincidence also changes the opportunity for facilitative and disruptive intertrial effects to occur. The authors show that benefits and costs associated with certain singletons depend at least partly on the preceding trial type. Results are in line with dimensional weighting and perceptual priming accounts, which propose a (semi-) automatic transfer of dimensional activity from one trial to the next. Results also indicate that priming is set independently for each dimension. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term alcohol self-administration and alcohol withdrawal differentially modulate microtubule-associated protein 2 (MAP2) gene expression in the rat brain

Chronic alcohol intoxication is known to produce neuronal degeneration in the central and peripheral nervous system of experimental animals and of humans. It is suggested that various components of the cytoskeleton undergo profound changes following chronic alcohol use and misuse. Here we studied the expression of the neuronal cytoskeletal microtubule-associated protein 2 (MAP2) following long-term alcohol consumption and subsequent alcohol withdrawal. Alcohol-preferring AA (Alko Alkohol) rats with a high voluntary alcohol consumption for a period of 16 months were compared with age-matched control rats without prior experience with alcohol. For comparison, in a second experiment, heterogeneous Wistar rats that also had voluntary access to alcohol for 8 months were examined following alcohol consumption and withdrawal. In situ hybridization and subsequent dot blot and Northern blot analysis for further quantification revealed that chronically alcoholized animals exhibit markedly decreased MAP2 mRNA levels in several parts of the extrapyramidal system (mainly in the caudate putamen, the substantia nigra pars compacta and the globus pallidus), the mesolimbic system, in several hypothalamic nuclei and in the nucleus inferior colliculus. Other areas such as the hippocampus, frontoparietal cortex and cerebellum were less affected by chronic alcohol intake, however, in these regions the MAP2 mRNA levels were increased during alcohol withdrawal. These results suggest that long-term alcohol self-administration affects central neurons involved in motor control via the influence on the integrity of the cytoskeleton and may thus induce motor dysfunction.     

Intravenous preparations for self-administration of drugs by animals.

Describes the construction of the 5 components of iv drug self-administration preparations: (a) a chronically implanted venous catheter; (b) a harness worn by the animal; (c) a flexible leash, providing catheter protection, which is at tached at either end to the harness and to the cage wall; (d) a swivel joint in the leash allowing the animal to turn in the cage; and (e) an infusion pump. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral tolerance and sensitization to alcohol in humans: The contribution of learning.

This experiment tested the hypothesis that tolerance or sensitization to repeated alcohol doses is predicted by the particular response (diminished or augmented impairment) that is reinforced under drug. Twelve male social drinkers were assigned to a tolerance (T) or sensitization (S) group (n?=?6) and performed a psychomotor task under 0.62 g/kg of alcohol on 5 separate sessions. The 1st session preceded training and determined that the groups' drugged performance did not differ. On 3 subsequent sessions verbal feedback reinforced diminished impairment in Group T and augmented impairment in Group S. During these sessions, Groups T and S displayed tolerance and sensitization, respectively. The final session showed that training effects were retained without reinforcement. The results extend the evidence on the effect of reinforcement to show that it can enhance sensitization as well as tolerance. The findings demonstrate that behavioral variables modulate the response to alcohol and imply that tolerance and sensitization may be affected by a common learning process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral measurement of thermal pain sensitivity in humans: Effects of stimulus intensity and instructions.

This study validated a human behavioral model of thermal nociception analogous to the rodent tail-flick assay. Effects of instructions and stimulus intensity on behavior (i.e., finger withdrawal latency) were evaluated. Using a repeated measures randomized crossover design, the authors exposed 10 volunteers to varying radiant heat intensities (from 42.2 to 52.2 degrees Celsius) during each of 4 sessions. In the different sessions, participants were told to remove their finger when they felt heat, felt unpleasant, felt pain, or could no longer tolerate pain. Withdrawal latencies significantly decreased as stimulus intensity increased and significantly increased for sensory, affective, pain, and intolerance instructions. Instruction set differences were significantly larger at higher stimulus intensities. this technique may be useful in human psychopharmacological research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: Locomotion, cocaine self-administration, and prepulse inhibition of startle.

Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Negligible tolerance produced by chronic intravenous alprazolam administration: A low serum drug concentration effect.

In 3-hr sessions, the authors investigated the onset, peak, and disappearance of the effects of alprazolam on performance under a differential reinforcement of low rate 45-s schedule in rats. Alprazolam was administered chronically as a daily bolus dose (2 mg/kg) via the intravenous route. Alprazolam decreased the reinforcement rate and increased the shorter response (nonreinforced) rate in a dose- and time-related fashion. Tolerance did not develop to the decreases in reinforcement rate; tolerance to increases in shorter response rate was negligible, occurring only at the low-concentration range. Clinically, an optimal dose regimen should be designed to avoid the tolerance development that occurs in the low serum benzodiazepine concentration range. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory monitoring by animals and humans

The authors asked whether animals and humans would use similarly an uncertain response to escape indeterminate memories. Monkeys and humans performed serial probe recognition tasks that produced differential memory difficulty across serial positions (e.g., primacy and recency effects). Participants were given an escape option that let them avoid any trials they wished and receive a hint to the trial's answer. Across species, across tasks, and even across conspecifics with sharper or duller memories, monkeys and humans used the escape option selectively when more indeterminate memory traces were probed. Their pattern of escaping always mirrored the pattern of their primary memory performance across serial positions. Signal-detection analyses confirm the similarity of the animals' and humans' performances. Optimality analyses assess their efficiency. Several aspects of monkeys' performance suggest the cognitive sophistication of their decisions to escape.     

Determination of alprazolam and alpha-hydroxyalprazolam in human plasma by gas chromatography/negative-ion chemical ionization mass spectrometry

A sensitive and specific method was developed for the determination of alprazolam and its major metabolite alpha-hydroxyalprazolam in plasma. After the addition of deuterium-labeled internal standards, plasma samples were buffered to pH 9 with 1 ml of saturated sodium borate buffer, extracted with toluene-methylene chloride (7:3) and evaporated to dryness. The residues were treated with N,O-bis(trimethylsilyl)trifluoroacetamide containing 1% of trimethylchlorosilane and analyzed on a Finnigan-MAT mass spectrometer operated in the negative-ion chemical ionization mode with methane as the reagent gas. Chromatographic separation was achieved on a Restek-200 capillary column using hydrogen as the carrier gas. The assay was linear from 0.25 to 50 ng ml-1 for both compounds. The intra-assay precision for alprazolam was 16.1% at 0.5 ng ml-1 and 4.6% at 50 ng ml-1 and that for alpha-hydroxyalprazolam was 15.8% at 0.5 ng ml-1 and 4.2% at 50 ng ml-1. The method was used to determine alprazolam and alpha-hydroxyalprazolam in human plasma samples collected after a single 2 mg oral does of alprazolam. A peak concentration of 32.9 ng ml-1 of alprazolam was detected at 1 h following the dose.     

Locomotion and self-administration induced by cocaine in 129/OlaHsd mice lacking galanin.

Previous studies have demonstrated that the galanin system modulates responses to drugs of abuse such as morphine. The current study examined whether genetic deletion of galanin could affect the locomotor and reinforcing effects of cocaine in mice. We analyzed spontaneous motor activity and cocaine-induced hyperactivity in wild-type (GAL-WT) and knockout mice lacking galanin (GAL-KO) maintained on the 129/OlaHsd background. Our results indicate that cocaine enhanced locomotion (defined as moving more than 5 cm) dose-dependently in GAL-WT and GAL-KO mice. However, general activity (total beam breaks) was increased by cocaine only in GAL-WT mice. An additional experiment indicated that galnon, a nonselective galanin receptor agonist, did not affect cocaine-induced hyperactivity. In a second set of experiments, mice of both genotypes were trained to self-administer cocaine under a fixed ratio schedule, tested with various doses of cocaine and under different schedules of reinforcement. This set of experiments showed that cocaine self-administration did not differ markedly between genotypes. However, while GAL-WT mice acquired cocaine self-administration, a median split analysis showed that mice could be divided into large and small drug takers, whereas all GAL-KO mice behaved as small drug takers. Our results indicate that wild-type and galanin knockout mice on a congenic 129/OlaHsd background are responsive to the locomotor effects of cocaine and can acquire intravenous cocaine self-administration. However, the phenotype observed in GAL-KO mice does not support a major role for galanin in cocaine-induced hyperlocomotion and self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)