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Biomedical subjects

D N Stephens

Publications and source records attributed to D N Stephens.

At least 19 recordsLinked to original sources
PubMed2000

Previous experience of withdrawal from chronic diazepam ameliorates the aversiveness of precipitated withdrawal and reduces withdrawal-induced c-fos expression in nucleus accumbens.

Flumazenil (20 mg/kg, i.p.)-precipitated withdrawal from chronic treatment with diazepam (DZP, 15 mg/kg, s.c. in sesame oil for 21 days) resulted in a decreased seizure threshold to the convulsant, pentylenetetrazole (PTZ), infused into the tail vein; withdrawal from 21-day chronic diazepam treatment, interspersed with two periods of drug withdrawal, resulted in a greater decrease in convulsant threshold. A separate experiment showed that consumption of a sucrose solution immediately prior to precipitated withdrawal resulted in a decreased subsequent consumption of the sucrose solution; no such evidence of a conditioned taste aversion (CTA) was seen in mice given prior experience of withdrawal. Thus, prior experience of withdrawal enhanced the effects of a subsequent precipitated withdrawal in increasing seizure sensitivity, but weakened the ability of this withdrawal to serve as an aversive unconditioned stimulus (US). The weakening of the aversive properties of precipitated withdrawal may reflect habituation to the withdrawal stimulus, and was accompanied by a loss of the ability of withdrawal to induce c-fos expression in the shell of the nucleus accumbens, an area sensitive to both novel, and stressful, as well as rewarding stimuli.

Amygdala↗
PubMed2000

State-dependent behavioural sensitization: evidence from a chlordiazepoxide state.

The present study investigated the hypothesis that behavioural sensitization to psychomotor stimulants is expressed only if the internal state of the animal is the same as it was at the time of sensitization development. This state-dependency hypothesis has previously been put forward to explain the apparent blockade of sensitization by N-methyl-D-aspartate (NMDA) receptor antagonists. The present study used amphetamine (0.375 mg/kg) as the stimulant and chlordiazepoxide (CDP) as a secondary stimulus. Mice were given double injections of either amphetamine + CDP, amphetamine + saline, CDP + saline, or saline + saline daily over 8 days. On the ninth and tenth days, all mice were challenged with amphetamine + saline and with CDP + saline, in a counterbalanced design. CDP does not show evidence of locomotor sensitization and does not act at NMDA receptors, but in other studies it has been shown to give rise to state-dependent-like effects. Thus any progressive augmentation of the response to repeated amphetamine + CDP treatment would be attributable to amphetamine sensitization, and any blockade of sensitization would not be due to NMDA receptor antagonism. Both groups receiving amphetamine became sensitized over the first 8 days (shown by progressive increases in locomotion). When challenged with amphetamine alone, the amphetamine + CDP group failed to show a sensitized response. This observation supports the state-dependency hypothesis and emphasizes the importance of considering the context provided by drug-induced internal states in studies of sensitization.

Animals↗
PubMed1999

Increased sensitivity to cocaine, and over-responding during cocaine self-administration in tPA knockout mice.

Tissue plasminogen activator, tPA, is induced in the brain by electrical activity leading to synaptic remodeling. It is also induced in the prefrontal cortex (PFC) by acute cocaine. We investigated cocaine-induced locomotor activity, the development of sensitisation to cocaine and cocaine self-administration in mice lacking the gene encoding tPA. Mice lacking tPA (tPA knockout mice, tPA-/-) showed normal spontaneous activity, exhibited cocaine-induced locomotor activity at lower doses than wild-type (WT) control mice and showed a greater degree of cocaine-induced locomotor activity following repeated administration. tPA-/- and WT mice did not differ significantly in the time to acquire self-administration of cocaine (20 microg/i.v. infusion) under an FR2 schedule. Following acquisition of this behavior, these groups also did not differ significantly in the rate of cocaine self-administration across the next three sessions. However, WT mice decreased responses on the active lever during signaled periods when reinforcer was not available; in contrast, tPA-/- mice did not. The emission of non-reinforced responses was most marked at the beginning of each 90 min daily session. This pattern of responding was not seen in tPA-/- mice pressing for food under an FR2 schedule of reinforcement. These results suggest that tPA may play a specific role either in retention of information between sessions or in behavioural inhibition in cocaine self-administration.

Animals↗
PubMed1999

Relationship of components of an alcohol interoceptive stimulus to induction of desire for alcohol in social drinkers.

The ability of a low (0.2 g/kg) oral dose of ethanol to provide a drug discriminative stimulus was studied in young healthy human volunteers, who were social drinkers. Seventeen of 24 subjects acquired the discrimination following 10 trials in which they received aliquots of ethanol or of placebo drink (tonic water mixed with Tabasco sauce). In generalization studies, in which the dose of ethanol was varied, discrimination performance was dose dependent; doses greater than 0.05 g/kg gave rise to significant ethanol-appropriate responding. Concurrent estimates of the subjective effects of doses administered as discriminative stimuli revealed that two factors--taste and light-headedness--were associated with discrimination: at the training dose, 0.2 g/kg, although both the factors taste and light-headedness were significantly increased, only taste predicted discrimination performance. At lower doses, taste did not contribute to discrimination, but the subjective rating light-headedness correlated significantly with discrimination accuracy. Post hoc analyses of the influence of the amount of alcohol regularly drunk by the volunteers, on discrimination performance suggested light-headedness correlated with discriminative performance only in social drinkers drinking more than 20 units per week. In a second experiment, groups of "high" (mean 40 units per week) and "low" (mean 10 units per week) social drinkers were prospectively identified. Discrimination performance of 0.2 g/kg ethanol in orange juice vs. orange juice vehicle indicated that both groups were able to perform the discrimination following a single training trial, and that generalization curves over the range 0.05-0.2 g/kg were dose dependent, and not different between the groups. At the lowest dose, discrimination performance was predicted by taste, stimulation, and light-headedness in the "high" group, but not in the "low" group. The ability of these ethanol doses to induce feelings of craving for ethanol were assessed in parallel, using the Desire for Alcohol Questionnaire (DAQ). "High" drinkers showed higher desire for ethanol on all factors of the DAQ except the "positive negative reinforcement" factor, and sampling ethanol tended to increase desire in these measures. However, at each dose, the induction of feelings of desire for ethanol showed a negative correlation with discrimination performance. These findings are discussed in the context of the ability of animals and humans to use several components of drug-induced stimuli in the performance of drug discrimination, and the role of such discriminative stimuli in priming of ethanol drinking.

Alcohol Drinking↗
PubMed1999

AMPA-receptor involvement in c-fos expression in the medial prefrontal cortex and amygdala dissociates neural substrates of conditioned activity and conditioned reward.

Exposure to an environment, previously conditioned to amphetamine (1 mg/kg, i.p.), induced locomotor activity and c-fos expression (a marker for neuronal activation) in the mouse medial prefrontal cortex (mPFC) and amygdala; acute or repeated amphetamine (1 mg/kg, i.p.) administration induced c-fos expression additionally in the nucleus accumbens. An alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor antagonist, 2, 3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)quinoxaline (NBQX), blocked expression of conditioned activity, and prevented the increase in c-fos expression in mPFC, implicating mPFC AMPAergic transmission in the conditioned component of behavioural sensitization to amphetamine. NBQX failed to block the expression of amphetamine-conditioned place preference, a measure of conditioned reward, or conditioned c-fos expression in the amygdala, an area implicated in the expression of conditioned place preference. These findings indicate that the conditioned components of behavioural sensitization depend on AMPA-receptor-mediated activation in mPFC, but that conditioned reward does not.

Amygdala↗
PubMed1999

The calcium channel antagonist, nimodipine, decreases operant self-administration of low concentrations of ethanol.

This study examined effects of the dihydropyridine calcium channel antagonist, nimodipine, on operant self-administration of ethanol, under a progressive-ratio schedule of reinforcement, by hooded Lister rats. Calcium channel antagonists have been reported to decrease the ethanol withdrawal syndrome, the development of tolerance to ethanol and ethanol consumption; and dihydropyridine binding site density in the central nervous system (CNS) is increased by chronic alcohol treatment. In addition, these drugs decrease reinforcing effects of psychostimulants. In the present studies, nimodipine was administered, once weekly, at either 10 or 50 mg/kg intraperitoneally (i.p.). At 10 mg/kg, nimodipine decreased the break point, and number of reinforcers obtained, for ethanol concentrations of 5, 10 and 15%. At 50mg/kg, nimodipine only decreased the break point, and number of reinforcers, for 5% ethanol. Responding for higher concentrations of ethanol was unaffected by nimodipine, as was responding when ethanol was replaced by water. The break point for 10% sucrose, but not for 1% or 0.1%, was decreased by 50 mg/kg nimodipine, but 10 mg/kg nimodipine had no effect on sucrose-reinforced responding. The 50 mg/kg dose of nimodipine decreased motor activity, but 10 mg/kg nimodipine only slightly decreased static activity counts. The results suggest that nimodipine, at the lower dose tested, decreased the reinforcing properties of low concentrations of ethanol.

Alcohol Deterrents↗
PubMed1999

CNQX but not NBQX prevents expression of amphetamine-induced place preference conditioning: a role for the glycine site of the NMDA receptor, but not AMPA receptors.

We investigated the role of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the induction and expression of an amphetamine-induced conditioned place preference (CPP) in mice. The selective AMPA-receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) failed to prevent the induction of a CPP, except at a dose (30 mg/kg) that also produced a conditioned place aversion. NBQX also failed to affect the expression of a CPP at a dose high enough to reduce activity levels. In contrast, the less selective AMPA receptor antagonist 6-cyano-7-nitroquinoxalone-2,3-dione (CNQX) prevented the expression of a CPP at doses (1-10 mg/kg) that had no effect on activity levels. We therefore tested the possibility that CNQX exerted its effects due to antagonism at the glycine site of the N-methyl-D-aspartate receptor. The glycine-site antagonist 7-chloro-4-hydroxy-3-(2-phenoxy)phenyl-2(1H)-quinolone also prevented the expression of a CPP at doses that had no effect on activity levels (0.1-0.3 mg/kg). These results suggest that neither the induction nor the expression of an amphetamine-induced CPP requires AMPA receptor-mediated transmission and that effects found in previous studies using the less selective AMPA receptor antagonists may be due to the effects of these compounds at the glycine site of the N-methyl-D-aspartate receptor.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Disruption of operant oral self-administration of ethanol, sucrose, and saccharin by the AMPA/kainate antagonist, NBQX, but not the AMPA antagonist, GYKI 52466.

BACKGROUND: AMPAergic transmission has been suggested to be important in mediating the rewarding effects of drugs. We therefore examined the role of non-NMDA glutamate-receptors in mediating the reinforcing properties of ethanol in an oral self-administration paradigm. METHODS: The competitive antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline) and the non-competitive antagonist, GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H2,3- be nzodiazepine), were administered to animals previously trained to self-administer ethanol, sucrose, or saccharin, on a progressive ratio schedule. RESULTS: GYKI 52466 (5 & 10 mg/kg) had no effect on operant responding for ethanol, but increased spontaneous locomotor activity, whereas the highest doses of NBQX (3 & 6 mg/kg) significantly decreased operant responding and correspondingly decreased the breaking point in responding for ethanol on a progressive ratio schedule. NBQX (but not GYKI 52466) also significantly decreased operant responding for a food reinforcer (sucrose) as well as for a sweet tasting reinforcer (saccharin). Doses of NBQX that disrupted operant performance caused a significant reduction in locomotor activity, indicating that NBQX decreased ethanol self-administration only at doses which disrupt motor activity. CONCLUSIONS: These results suggest non-NMDA glutamate-receptors may not have a specific role in the maintenance of responding for an ethanol reinforcer, but may generally disrupt operant performance. Because, unlike GYKI 52466, NBQX possesses an action at central kainate receptors, these results suggest that kainate, but not AMPA (alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionate) receptors may be important in mediating the reinforcing effects of ethanol.

Animals↗
PubMed1998

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity.

Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety.

Animals↗
PubMed1998

Sensitisation to repeated withdrawal, in mice treated chronically with diazepam, is blocked by an NMDA receptor antagonist.

Mice were treated either with diazepam (15 mg/kg s.c. in oil), for 21 days, or for 3x7-day periods interspersed with two 72-h drug-free periods. Convulsant thresholds to pentylentetrazole infused into the tail vein 72 h following the final chronic treatment were lower in multiple-withdrawal mice than in mice which had experienced the same drug load, but only a single withdrawal, consistent with sensitisation of withdrawal events following previous withdrawal experience. The increase in seizure sensitivity of repeatedly withdrawn mice was prevented by treatment with the NMDA receptor antagonist CGP 39551 (20 mg/kg, i.p.) given once daily during the 3-day breaks in diazepam treatment, suggesting a role of glutamatergic transmission in the sensitisation process.

2-Amino-5-phosphonovalerate↗
PubMed1998

Discriminative stimulus properties of low doses of ethanol in humans.

Discriminative stimulus properties of low doses of ethanol were evaluated in humans using established behavioural drug discrimination procedures. Twenty-five moderate drinkers (12 females and 13 males) were trained to discriminate placebo from 0.2 g/kg ethanol in 200 ml tonic water mixed with Tabasco sauce and drunk in portions of 50 ml every 15 s. Seventeen of the subjects (ten females and seven males) were able to reach criterion performance (at least 80% correct responses). Generalisation responding across ethanol doses of 0 (placebo), 0.025, 0.05, 0.1 and 0.2 g/kg was examined the day after training using a procedure in which subjects reported the extent to which the test stimulus resembled the training dose. At the end of each generalisation session, self ratings of mood changes, physiological responses and performance in a working memory and a time estimation task were evaluated. Subjects were able to distinguish the three higher doses of ethanol from placebo. Self ratings indicated that subjects' ability to distinguish ethanol from placebo was related, at the highest dose, to change of taste, but to feelings of light-headedness at the lower doses. Ethanol administration influenced skin conductance measurements but there was no relationship found between changes in skin conductance and the ethanol discriminative stimulus. These data suggest a difference in the nature of the discriminative stimulus of ethanol between high (training) and low (generalising) doses as indicated in the subjective reports.

Adolescent↗
PubMed1998

AMPA-receptors are involved in the expression of amphetamine-induced behavioural sensitisation, but not in the expression of amphetamine-induced conditioned activity in mice.

We investigated the role of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) in the expression of amphetamine-induced behavioural sensitisation and amphetamine-induced conditioned activity in mice. Repeated weekly administration of amphetamine (0.375 mg/kg) for 7 weeks led to an increased locomotor response when challenged with amphetamine 1 week later. NBQX attenuated this increased response at doses (3 and 30 mg/kg) which had no effect on the acute locomotor response to amphetamine. In a separate experiment, mice given amphetamine (1 mg/kg) in a distinctive environment, showed an increased locomotor response within this environment following a subsequent saline administration. NBQX (5-20 mg/kg) had no effect on the expression of this conditioned response. These results suggest that AMPA receptors are involved in the expression of amphetamine-induced behavioural sensitisation in mice, and that this involvement is limited to either the neurobiological effects of amphetamine or the effects of amphetamine on conditioned associations, rather than drug environment conditioned associations.

Amphetamine↗
PubMed1998

AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice.

A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.

Animals↗
PubMed1998

Alcohol choice and outcome expectancies in social drinkers.

Eighteen male social drinkers underwent four training sessions during which they ingested two colour-coded drinks (red or blue, balanced for drink type); one containing alcohol (aliquots of 0.1 g/kg) and the other placebo (aliquots of orangeade). Following the training sessions, subjects were presented with both drinks, and instructed to choose the drink they felt like consuming and to indicate their preference for their chosen drink over the other drink. In addition, they were instructed to consume the first drink but that all subsequent drinks (total of six drinks), offered at 10-min intervals, were optional. A number of trait characteristics were assessed including alcohol outcome expectancies, drinking habits and personality traits. The acute effects of alcohol on mood was also evaluated by comparing subjective ratings following alcohol and placebo during the training sessions. Of the 18 subjects, 12 chose alcohol at least once ('samplers'), whereas six never chose alcohol ('non-samplers'). Over the three sessions, however, alcohol and placebo were chosen equally. When alcohol was chosen, subjects drank significantly more than when placebo was chosen, which may be consistent with a priming effect of drinking alcohol. The amount of alcohol drunk was seen to correlate with the alcohol expectancy factor 'sociability'. Subjective reports of feeling 'alert', 'clear-headed', 'quick-witted', and 'attentive' all showed a main effect of choosing behaviour (i.e. 'samplers'/'non-samplers'). Further analysis indicated that this effect was due to 'samplers' reporting increased subjective ratings of these mood states following the ingestion of alcohol compared to 'non-samplers'. These increased subjective ratings were also positively correlated with the amount of alcohol consumed by the subjects during the choice procedure. No other relationships were found between the amount of alcohol consumed and any of the other state or trait measures. These data suggest that social drinkers who sample alcohol in a laboratory setting can be primed by alcohol to consume more. The results also indicated that the amount drunk was related to the degree to which subjects expected alcohol to increase sociability and to reports of subjective stimulant effects of alcohol (e.g., 'alert', 'clear-headed', 'quick-witted', and 'attentive').

Adult↗
PubMed1998

Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule.

Male hooded Lister rats were trained using a sucrose-fading technique, to perform an operant lever press response to obtain ethanol. Initial training, using an FR4 schedule in which each reinforcement required four lever presses, included varying the concentration of ethanol in the liquid reinforcer. Changes in reinforcer concentration between 7 and 15% (vol/vol) had little effect on either numbers of lever pressing responses, or reinforcers obtained during the 3h session. Increasing the reinforcer concentration to 20% caused a decline in responding. The effects of varying reinforcer concentration (0-20% ethanol) were also studied in the same animals performing a progressive ratio schedule, in which the number of responses required to obtain a reinforcer was successively increased during the session. In these experiments the point at which rats ceased to respond (breaking point) was taken as a measure of their motivation to obtain ethanol. The function describing the relationship between ethanol concentration and number of responses, and number of reinforcers obtained in a session was an inverted U, with the maximum values occurring at an ethanol concentration of 10%. The value of the breaking point (highest ratio achieved) depended on the criterion used to define cessation of responding, but was between 15 and 22. Rats performing for ethanol showed higher breaking points than when responding for water, but there was no statistically reliable effect of ethanol concentration on the breaking point parameter. The effects of feeding the rats a liquid diet containing ethanol, and its subsequent withdrawal, on progressive ratio responding for 5% ethanol, were studied over four cycles of exposure and withdrawal. Intakes of ethanol of 11 g/kg/day had no effect on the animals' breaking point on the progressive ratio schedule, but withdrawal from the ethanol diet resulted in breaking points significantly higher than those in a control group pair-fed a nutritionally equivalent, ethanol-free diet. Although there was no further effect of repeated exposure and withdrawal on responding during the acute withdrawal phase, baseline levels of responding were elevated in the animals which had received multiple cycles of ethanol diet and withdrawal. These results are discussed in the context of the consequences of sensitization to repeated withdrawal from ethanol in dependent animals and humans.

Administration, Oral↗
PubMed1998

Discriminative stimulus properties of nicotine at low doses: the effects of caffeine preload.

Discriminative stimulus properties of low nicotine doses administered in the form of chewing gum in combination with caffeine have been evaluated in humans, using established behavioural drug discrimination procedures. Twenty-one smokers who were also regular coffee drinkers were trained to discriminate 0 versus 1 mg nicotine chewing gum. Twenty subjects (11 men and nine women) were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 0.25, 0.5 and 1 mg was then examined. Subjects were randomly allocated to receive either 50 mg caffeine or placebo before testing. Nicotine-appropriate responding was linearly related to dose, demonstrating that smokers can accurately discriminate nicotine from placebo and between relatively small doses of nicotine. Nicotine-appropriate responding was high at the 0 mg nicotine dose in the caffeine group demonstrating a partial generalization. Subjective effects assessed concurrently with behavioural discrimination revealed that nicotine discrimination was guided by the interoceptive cues of 'sensations in mouth', 'taste', 'heart rate', 'stimulated', 'alert' 'jittery' and 'nausea'. Caffeine increased self-ratings of 'stimulated' and 'alert' (at the 0 mg nicotine dose) and 'jittery' at the 0.5 and 1.0 mg nicotine dose. Relationships between nicotine-appropriate responding and subjective feelings induced by caffeine suggested that feelings of 'stimulated' and 'alert' were guiding discrimination behaviour. These data are discussed in terms of interoceptive nicotine cues and their importance at different doses and after caffeine preload.

Adult↗
PubMed1997

Alprazolam dependence prevented by substituting with the beta-carboline abecarnil.

Abrupt termination of the treatment of humans with benzodiazepines (BDZs) leads to a rapid onset of discontinuation syndrome characterized by anxiety, muscle spasms, and occasionally convulsions. For this reason, it is recommended in clinical practice to reduce the dose of the BDZs gradually at the end of treatment. Nevertheless, many clinicians report signs of dependence even during gradual reduction of doses (tapering) of the BDZs in a large proportion of patients. Thus, there is considerable interest in discovering means of weaning patients away from BDZs without the risk of discontinuation syndrome. In the present study, mice withdrawn from chronic treatment with alprazolam showed anxiety, muscle rigidity, and seizures between days 1 and 28 after termination of the treatment. Replacement of alprazolam with the beta-carboline abecarnil for 7 days prevented the occurrence of the signs of dependence. In contrast, substitution of the beta-carboline antagonist ethyl-5-isopropoxy-4-methyl-beta-carboline-3-carboxylate (ZK93426) for alprazolam worsened the discontinuation syndrome. Replacement therapy with abecarnil after long-term treatment with the BDZs offers a novel method for rapid tapering.

Alprazolam↗