Psychopharmacology

Miczek, Klaus; Johanson, Chris-Ellyn; Dykstra, Linda

doi: 10.1007/s00213-002-1014-5pmid: 11919659

Escarabajal, Dolores; Aragon, Carlos

doi: 10.1007/s00213-001-0991-0pmid: 11919660

Rationale: It has been proposed that brain aldehyde dehydrogenase (ALDH) plays a role in the modulation of some psychopharmacological effects of ethanol. Diethyldithiocarbamate (DDTC), an ALDH inhibitor, elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by DDTC. Objective: To investigate the effects of concurrent DDTC and 4-MP administration on ethanol-induced locomotor activity in mice. Methods: Mice were pretreated IP with saline (S+S) or 4-MP (10 mg/kg) (S+4-MP), then received IP injections of ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg) prior to testing in the open field. Results: Pretreatment with 4-MP does not modify the spontaneous or ethanol-induced locomotor activity. In the second experiment, the DDTC (114, 228 and 456 mg/kg) and 4-MP (DDTC+4-MP) were administered 8 h prior to testing locomotor activity in the open field. Animals were then treated with ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg), and placed in open field chambers. The locomotor activity of animals pretreated with DDTC and 4-MP was significantly enhanced here compared to groups S+S and S+4-MP. These effects cannot be attributed to elevated blood acetaldehyde levels, as pretreatment with 4-MP prevented peripheral accumulation of acetaldehyde. Conclusions: These data suggest that brain ALDH may contribute to the effects of ethanol on locomotor activity. This role of the enzyme ALDH in some of the psychopharmacological effects of ethanol may be a result of its ability to regulate levels of acetaldehyde in brain.

Greenwald, Mark; Schuh, Kory; Hopper, John; Schuster, Charles; Johanson, Chris-Ellyn

doi: 10.1007/s00213-001-0975-0pmid: 11919661

Rationale: Buprenorphine can decrease opioid self-administration by humans and animals, but its ability to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers using clinically relevant dosing schedules has not been extensively studied. Objectives: We investigated whether daily versus alternating-day administration of high versus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. Methods: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200, ...12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. Results: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternate-day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high-dose buprenorphine. Conclusions: High-dose buprenorphine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days.

Bymaster, Frank; Zhang, Wei; Carter, Petra; Shaw, Janice; Chernet, Eyassu; Phebus, Lee; Wong, David; Perry, Kenneth

doi: 10.1007/s00213-001-0986-xpmid: 11919662

Rationale: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. Objective: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. Methods: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. Results: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT2C receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. Conclusion: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

Mutschler, Nicole; Bergman, Jack

doi: 10.1007/s00213-001-0976-zpmid: 11919663

Rationale: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. Objective: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. Methods: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. Results: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2–5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. Conclusions: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.

Salamone, J.; Arizzi, M.; Sandoval, M.; Cervone, K.; Aberman, J.

doi: 10.1007/s00213-001-0994-xpmid: 11919664

Rationale: Dopamine is important for enabling organisms to overcome work-related response costs. One way of investigating this function has been with concurrent choice procedures using food reinforcement. In the present study, rats were given a choice between pressing a lever for preferred Bioserve pellets, or approaching and consuming a less-preferred laboratory chow that was concurrently available. In previous work with this task, dopamine antagonists and accumbens dopamine depletions decreased lever pressing but increased chow consumption. Objective: The present study assessed three drugs (two dopamine antagonists and one appetite suppressant) using the lever pressing/chow feeding task. Results: Under baseline conditions, rats pressed the lever at high rates (1,300–1,500 responses) to obtain the preferred food, and little of the laboratory chow was eaten (1–2 g). Selective D1 and D2 antagonists (SKF 83566 and raclopride) reduced fixed ratio 5 lever pressing, but substantially increased chow consumption. In contrast, the serotonergic appetite suppressant fenfluramine reduced both lever pressing and chow consumption. With the dopamine antagonists, lever pressing and chow consumption were inversely correlated across treatments, while these two measures were unrelated in the fenfluramine experiment. Conclusions: Dopamine antagonists and accumbens dopamine depletions do not simply reduce appetite. Rats with accumbens dopamine depletions, or rats treated with low doses of selective or non-selective dopamine antagonists, remain directed toward the acquisition and consumption of food. These results demonstrate that fundamental aspects of food reinforcement are left intact after treatment with low doses of dopamine antagonists.

Schmitt, Jeroen; Riedel, Wim; Vuurman, Eric; Kruizinga, Monique; Ramaekers, Johannes

doi: 10.1007/s00213-001-0993-ypmid: 11919665

Rationale: Serotonin reuptake inhibitors (SSRIs) have been attributed CNS-activating properties based on their ability to elevate the Critical Flicker Fusion (CFF) threshold. However, such an interpretation may be questioned since CFF elevations may also be due to SSRI-induced increases in pupil diameter. Objectives: The effect of pupillary changes on CFF assessment following SSRI administration was investigated in a double blind, crossover study. Methods: During three periods of 15 days, 21 healthy men and women (30–50 years) received sertraline (50 mg on days 1–8, 100 mg on days 9–15), citalopram (20 mg on days 1–8, 40 mg on days 9–15) and placebo. Assessments were done on days 1, 8 and 15 and consisted of pupillary measurements and CFF assessments with and without pupillary control (a 2-mm artificial pupil) using the Leeds Psychomotor Tester. Results: Both SSRIs induced an acute and steady increase in pupil diameters. CFF thresholds were depressed following acute administration of sertraline and citalopram, but this was only apparent when a control was made for the pupillary changes. No CFF effects were seen at day 8, but CFF was again reduced at day 15, with and without control for pupil size. Conclusions: Mydriasis masked the detrimental effects of both SSRIs on CFF during the acute assessments. Our results raise questions regarding the validity of the assessment of the behavioural toxicity of SSRIs based on CFF measurements without ample control for pupil size, especially when these concern acute measurements.

Sünram-Lea, Sandra; Foster, Jonathan; Durlach, Paula; Perez, Catalina

doi: 10.1007/s00213-001-0987-9pmid: 11919666

Rationale: Memory for a list of 20 words can be enhanced by preceding learning with consumption of 25 g glucose rather than an equally sweet aspartame solution. In previous studies, participants performed a secondary hand-movement task during the list-learning phase. Objective: The present placebo-controlled, double-blind study examined whether the additional cognitive load created by a secondary task is a crucial feature of the glucose memory facilitation effect. Methods: The effect of glucose administration on word recall performance in healthy young participants was examined under conditions where the primary memory task and a secondary task were competing for cognitive resources (across a range of secondary tasks), and where task difficulty was increased but dual task-mediated competition for cognitive resources did not exist. Measures of non-verbal and working memory performance were also compared under the different glycaemic conditions (glucose versus aspartame drinks). Results: In the present study, a beneficial effect of glucose on memory was detected after participants encoded a 20-word list while performing a secondary task, but not when participants encoded the list without a secondary task, nor when the 20 target words were intermixed with 20 non-target words (distinguished by gender of speaker). In addition, glucose significantly enhanced performance on spatial and working memory tasks. Conclusion: The data indicate that possible "depletion" of episodic memory capacity and/or glucose-mediated resources in the brain due to performing a concomitant cognitive task might be crucial to the demonstration of a glucose facilitation effect. Possible implications regarding underlying cognitive and physiological mechanisms are discussed in this article.

Buck, Kari; Rademacher, Brooks; Metten, Pamela; Crabbe, John

doi: 10.1007/s00213-001-0988-8pmid: 11919667

Rationale: Alcoholism is associated with withdrawal (physical dependence), tolerance, or a maladaptive pattern of alcohol (ethanol) use. The well-documented difference in susceptibility to withdrawal after chronic ethanol exposure between the C57BL/6J and DBA/2J mouse strains provides an excellent starting point for dissecting genetic influences involved in physical dependence on ethanol. A quantitative trait locus (QTL) identifies the genomic location of a gene (or genes) affecting a trait of interest. Objectives: A genome-wide QTL mapping study was carried out to dissect the multifactorial nature of withdrawal after chronic ethanol exposure using 400 B6D2F2 mice. Methods: To induce physical dependence, we used a standard paradigm in which mice were exposed to ethanol vapor for 72 h. The mice were then tested hourly for handling-induced convulsions (HICs) for 10 h and at hours 24 and 25. Ethanol withdrawal severity was first computed as the area under the 25-h HIC curve. Separate regression residuals were then calculated that corrected for individual differences in blood ethanol concentration at the time of withdrawal and baseline HIC severity (i.e. before ethanol exposure). Results: Statistical mapping yielded significant evidence (P<0.00005) for QTLs on chromosomes 19 and distal 1 that account for 45% of the genetic variance in ethanol withdrawal severity. The F2 results also provide supporting evidence for a sex-limited QTL on chromosome 13, and QTLs on chromosomes 4 and proximal 1, which may account for an additional 38% of the genetic variance. The distal chromosome 1 QTL is a locus of major effect, accounting for 26% of the genetic variance. Experiments using two congenic strains more precisely mapped this QTL. Conclusions: The QTLs map near candidate genes involved in neurosteroid biosynthesis and signal transduction. Syntenic homology between human and mouse chromosomes suggests that genes related to physical dependence on ethanol may localize to human chromosome regions 10q23-q26, 1q21-q43, 2q11-q32, 5p15/5q14-q21, and 9p24-p22.

Johnson, Bankole; Roache, John; Ait-Daoud, Nassima; Zanca, Nursen; Velazquez, Madeline

doi: 10.1007/s00213-002-1002-9pmid: 11919668

Rationale: Early onset alcoholics (EOA) differ from late onset alcoholics (LOA) by having greater serotonergic abnormality, familial history, and a range of antisocial behaviors. Previously, we showed that ondansetron, a selective 5-HT3 antagonist, effectively treated EOA. Proximate motivational drives such as craving could have determined drinking behavior. We therefore investigated whether ondansetron treatment would reduce alcohol craving significantly among EOA. Objectives: We tested the hypothesis that the craving outcomes of EOA, compared with LOA, would be differentially improved by ondansetron. We also tested the prediction that craving would be significantly correlated with drinking behavior. Methods: We studied a cohort of 253 out of 321 enrolled alcohol dependent subjects. These 253 subjects were entered into a 1-week lead-in single-blind placebo period followed by 11 weeks of double-blind outpatient treatment. Study design was a 2 (EOA versus LOA)×4 medication dose (placebo, or ondansetron 1, 4, or 16 µg/kg b.i.d)×13 (visits) factorial analysis of variance. Craving was measured at each visit using seven visual analogue scales. Subjects received 12 weekly sessions of standardized group cognitive behavioral therapy. Results: Data reduction by factor analysis of the visual analog scale items yielded one dimension, overall craving. Ondansetron 4 µg/kg b.i.d. reduced overall craving significantly among EOA. In contrast, ondansetron (1 µg/kg b.i.d.) increased craving significantly in LOA. Decreased overall craving was positively correlated with reduced drinking and negatively associated with increased abstinence. Conclusions: Compared with placebo, ondansetron (4 µg/kg b.i.d.) was associated with significant reductions in overall craving in EOA but not LOA, presumably by ameliorating serotonergic abnormality.