A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency.In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA](n)) are linked to alcohol addiction and craving.We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p < 0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p < 0.05) and lower levels of craving (p < 0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p < 0.05). No effects were found for A49T or (TA)(n).These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies.

Relapse is an important problem in substance dependence treatment. When drug users try to abstain from drug use, they often report strong temptations to use drugs. Temptation episodes have commonalities with relapse episodes, and assessment of temptation episodes may help to identify individuals at risk of relapse.This study aims to examine affect and cognition prior to and during temptation episodes by administering self-report and implicit cognitive assessments on a handheld computer (PDA) using Ecological Momentary Assessment.Heroin-dependent patients (N = 68) attending a drug detoxification unit completed up to four random assessments (RAs) per day on a PDA for 1 week. They also completed an assessment when they experienced a temptation to use drugs (temptation assessment; TA).Participants completed 1,482 assessments (353 TAs, 1,129 RAs). The rate of TAs was maximal during the first 2 days. Participants reported higher levels of negative affect, anxiety, and difficulty concentrating, and more positive explicit attitudes to drugs, at TAs compared to RAs. In addition, they exhibited elevated attentional bias to drug cues (assessed using the modified Stroop task) at TAs compared to RAs. Implicit affective associations with drug cues (assessed using the Implicit Association Test) were not different at TAs compared to RAs. Attentional bias was elevated in the 1 h prior to the entry of a temptation episode.Elevated attentional bias may be a harbinger of temptation episodes. Interventions that target cognitions prior to or during temptation episodes may reduce the probability or severity of a temptation episode.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans.The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR).Sprague-Dawley rats with telemetry implants were administered 40 micromol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (TA) (HOT; 30+/-1 degrees C) or an area at room temperature (ROOM; 21.5+/-1.5 degrees C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation.HOT rats showed higher core temperature (TC), HR, and locomotor activity than ROOM rats during confinement to a set TA (P<0.001). HR responses to MDMA over 6 weeks at both TAs progressively decreased with repeated dosing (P<0.05). TC was significantly higher in both 6-week groups compared to the 1-week groups (P<0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P<0.05) and 5-hydroxyindole acetic acid (5-HIAA; P<0.001) decreased significantly irrespective of TA, while concentrations of dopamine and 5-HT did not change.Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of TC in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants.We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(-)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters.F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50 = 1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED50 = 530.3 microg/kg i.v.), an effect completely abolished by the 5-HT(1A) antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED) = 10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED50 = 2 mg/kg) and reduced the immobility in the tail suspension test (MED = 10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg(-1) day(-1), p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine.F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities.

Traumatic life events can induce long-term alterations in neuronal substrates, which may ultimately lead to the development of anxiety disorders. It has been postulated that corticotropin-releasing hormone (CRH) plays an important role in anxiety-like behavior.(1) To study the long-term effects of a single foot-shock experience on defensive withdrawal (DW) behavior in rats. (2) To examine the effects of the benzodiazepine anxiolytic drug chlordiazepoxide on the behavior of preshocked and control rats in the DW test. (3) To study the role of endogenous CRH in the long-term stress-induced increase in DW behavior.(1) Rats were exposed to a single session of foot shocks or exposed to the grid cage without receiving any shocks. Two, six and ten weeks later, rats were tested in the DW tests (2, 3). In subsequent experiments, rats were exposed to foot shocks or exposed to the grid cage without receiving any shocks, and 2 weeks later the effect of pharmacological treatments on the behavioral response in the DW test was investigated. Chlordiazepoxide (1, 5, 10 mg/kg BW, i.p.) and the CRH antagonists D-Phe CRH(12-41) (0.2, 1, 5 microg per rat, i.c.v.) and alpha-helical CRH(9-41) (5 microg per rat, i.c.v.) were injected 30 min before the test.A single session of foot shocks induced a long-term increase in DW behavior, which persisted after repeated testing for at least 10 weeks. Chlordiazepoxide decreased the latency but did not affect time spent in light, distance moved, or the number of entries in the open field. D-Phe CRH(12-41) had no behavioral effects. alpha-Helical CRH(9-41) increased the time spent outside the box, primarily as a result of effects of alpha-helical CRH(9-41) in controls.These data demonstrate that preshocked rats display long-term increased anxiety-like behavior in the DW test but that CRH is unlikely to be involved in its expression.

We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule 3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses required for a reinforcer eventually exceeded its value, termed the "break point", a sensitive measure of food motivated behavior. Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P = 0.01) but not for sweet pellets (51.6 versus 38.5, P = 0.31). We determined if naloxone (0.01-3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free access to food than in rats working for food.

Using radio-biotelemetry, the timecourse of recovery and sensitivity to ambient temperature (Ta) of the thermogenic response of methylenedioxymethamphetamine (MDMA or "Ecstasy") was examined. Ambient temperatures of 17 and 22 degrees C produced very different response profiles, with the lower temperature producing a hypothermic response to 10 and 15 mg/kg doses of MDMA, and the higher temperature producing a profound hyperthermia to the same doses. Although the peak responses to the drug had subsided within 5 h of administration, residual effects, in the form of an elevation of body temperature during the "low" phase of the diurnal cycle, were present for a further 48 h. Long-lasting disruption of the thermoregulatory system following a short series of MDMA administrations (10 mg/kg once per day for 4 days) was shown by exposing the rats in the undrugged state to a thermoregulatory challenge, consisting of 60-min exposure to a Ta of 30 degrees C, at 1 week before, and at 4 weeks and 14 weeks after the drug administration. MDMA-treated rats showed a prolonged hyperthermic response to the challenge at both post-drug intervals compared with fenfluramine-treated rats and saline-treated controls. Thus, the results indicate both that MDMA's thermogenic effects are more sensitive to Ta than previously demonstrated, and that the serotonergic neurotoxicity of the drug may produce long-lasting changes in thermoregulatory mechanisms.

A stress-free, biotelemetric monitoring technique was used to investigate the effects of ambient temperature (Ta) on the hyperthermic and hyperkinetic effects of 3,4-methylenedioxymethamphetamine. In the first experiment a single injection of 5.0 or 7.5 mg/kg MDMA produced hyperthermia in rats maintained at a Ta of 24 degrees C but hypothermia in rats maintained at a Ta of 11 degrees C for 24 h prior to the injection. In contrast, hyperkinesis was induced at both Tas. In the second experiment, the effects of acute MDMA administration was compared in rats maintained at a standard Ta of 24 degrees C and in rats which were placed in a cool (11 degrees C) room for a brief (90-min) period commencing 30 min after the injection. The brief exposure to the cool environment produced significant attenuation of MDMA-induced hyperthermia but did not affect the magnitude of hyperkinesis. The implications of the results for the understanding of the thermotoxic effects of MDMA in human drug users are discussed.

We challenged five patients suffering from tardive akathisia (TA) with intravenous benztropine (2 mg), propranolol (1 mg) and placebo (saline) using a random, double-blind cross-over design to examine the effects of the drugs on the subjective, objective and global manifestations of neuroleptic-induced akathisia. Benztropine produced a marginally significant, and propranolol a significant improvement in the overall manifestations of the disorder. The patients demonstrated a considerable placebo effect and marked variation in their responses to the drugs. The implications of these findings for the pathophysiology of TA in relation to acute akathisia and tardive dyskinesia are discussed.

Two novel agents, tandamine (TA; a thiopyrano (3,4-b) indole) and pirandamine (PA; an indeno (2,1-c)pyran), and the tricyclic antidepressants desimipramine (DMI), imipramine (I) and amitriptyline (A) were compared in various in vivo pharmacological tests and for norepinephrine (NE) and 5-hydroxytryptamine (5-HT) neuronal uptake inhibition. TA was found to be equivalent, or greater, in activity to DMI in blocking brain NE uptake, antagonizing reserpine-induced effects and potentiating the behavioural effects of l-Dopa. Similarly to DMI, TA did not appreciably block brain 5-HT uptake; unlike DMI, TA did potentiate central 5-HT activity at high doses. PA exerted an opposite profile to TA, being equivalent to A and greater than I as a 5-HT uptake blocker and central 5-HT potentiator; PA was not effective as a NE uptake blocker or potentiator. Neither TA or PA exhibited in vivo MAO inhibition, and in contrast to DMI, I and A, exhibited no central anticholinergic effects. TA, but not PA, potentiated apomorphine-induced gnawing. These findings indicate that TA is a relatively specific blocker of neuronal NE uptake and PA is a selective 5-HT uptake blocker.