Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence.

Recent scientific advances have led to a greater understanding of the neurobiological processes that underlie drug abuse and addiction. These suggest that multiple neurotransmitter systems may play a key role in the development and expression of drug dependence. These advances in our knowledge promise not only to help us identify the underlying cause of drug abuse and dependence, but also to aid the development of effective treatment strategies.

Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats.

Recent evidence suggests that 5-HT(1B) receptor activation modifies ethanol's reinforcing, intoxicating and discriminative stimulus effects. The present study further explored the role played by 5-HT(1A/1B) receptors by examining their influence on oral ethanol self-administration. Male Wistar rats were trained on an FR 4 schedule to obtain a reinforcer of 0.1 12% w/v ethanol solution. Once responding was stable, the effect of the 5-HT(1A/1B) agonist RU24969 alone and in combination with the 5-HT(1B) antagonist GR127935 or the 5-HT(1A) antagonists (+) WAY100135 and (+) WAY100635 was assessed. The effect of RU24969 on ethanol's pharmacokinetic profile and on operant oral saline self-administration was also examined to assess if alterations in oral ethanol self-administration were due to nonspecific effects on level pressing. For comparison, we examined the effect of another 5-HT(1A/1B) agonist, CGS12066B, on oral ethanol self-administration. Both RU24969 (0.1 to 1 mg/kg) and CGS12066B (0.1 to 1 mg/kg) significantly suppressed oral ethanol self-administration. Administration of GR127935 (1 mg/kg), significantly reversed the effects elicited by RU24969, whereas neither WAY100635 (1 mg/kg) nor (+)WAY100135 (1 mg/kg) had any effect. The effects of lower doses of RU24969 on oral ethanol self-administration were selective as oral saline self-administration and blood ethanol levels were not altered by these doses. These data demonstrate that 5-HT(1B) receptor activation suppresses oral ethanol self-administration. These studies provide further evidence that 5-HT(1B) receptors play a modulatory role in ethanol's behavioral effects.

Differences in propensity for drinking alcohol are reflected in subunit- and region-specific GABA(A) receptor levels.

Enhancement of GABA(A) receptor activity within certain discrete brain areas can elicit increased ethanol consumption, supporting a regionally specific role for GABAergic mechanisms in modulating ethanol reinforcement. The present study investigated if rats, which were in the highest (HES) or lowest (LES) 15th percentile of ethanol self-administration, had different GABA(A) receptor levels. MaleWistar rats (n=30) were trained to self-administer ethanol for 8 weeks followed by assessment of GABA(A) receptor mRNAs. In the last operant session the HES rats (4/group) were consuming significantly more ethanol than the LES rats (1.31+/--0.31 g/kg versus 0.02+/-0.02 g/kg; p<0.001). Significant GABA(A) receptor mRNA differences were found between the groups, which were subunit- and brain region-specific, with higher mRNA levels in the HES rats in the dorsal raphe (α2, α3, γ1), medial raphe (α3, α, ß1, ß3, γ1), cerebellum (α1, α6, ß3, γ2long) and hippocampus (ß1, ß3, γ1 and γ2long). The elevated cerebellum alpha1 mRNA level in the HES rats was confirmed using Western blotting (mean density units +/-SEM; LES rats 0.460 +/-0.005 versus HES rats 0.610 +/- 0.006, p=0.03). These data suggest that the differences in GABA receptors were due either to the different propensities of the groups to consume ethanol or were caused by their differing ethanol exposure.

Effect of pentylenetetrazole on ethanol intake, ethanol kinetics, and social behavior in male Wistar rats.

Stress and anxiety are often implicated in excessive alcohol use. The nature of this interaction, however, is not understood. The aim of this study was to examine the effect of the anxiogenic agent, pentylenetetrazole (PTZ), on the acquisition and maintenance of ethanol drinking behavior in male Wistar rats. In rats maintained on a limited access procedure, with a choice between a 12% w/v ethanol (ETOH) solution and water available for 30 min each day, acute PTZ administration (1.5 to 15.0 mg/kg) did not modify ETOH intake. Chronic PTZ administration elicited a significant suppression in ETOH intake; however, this effect developed gradually over time. During the acquisition phase, chronic PTZ treatment also suppressed ETOH consumption. Chronic, but not acute, treatment with PTZ seemed to enhance water consumption. To assess whether the effect of PTZ on ETOH intake was due to either alterations in ETOH kinetics or behavior, blood ETOH levels and social interaction behaviour were examined. PTZ (15.0 mg/kg) produced a significant suppression in social interaction behavior, although tolerance developed to this effect on chronic PTZ administration. Both acute and chronic PTZ treatment (15 mg/kg) resulted in lower blood ETOH levels achieved after administration of 1.0 g/kg po of ETOH. Because the anxiogenic effect of PTZ was not maintained on repeated administration, yet the suppression of ETOH intake was only observed after chronic treatment, this suggests a dissociation between the processes regulating these behaviors.

Effect of CYP2D1 inhibition on the behavioural effects of d-amphetamine.

In rats, amphetamine (AMP) conversion to 4-OH-AMP is metabolized by CYP2D1, the rat equivalent of the human enzyme CYP2D6. To determine the impact of impaired AMP metabolism on its behavioural effects, AMP-induced hyperactivity, AMP discrimination and AMP self-administration were examined in male Wistar rats with or without pretreatment with the CYP2D1 inhibitors quinine and budipine. In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) increased the plasma area under the curve of AMP 4-fold and 3.6-fold respectively, and decreased the plasma levels of 4-OH-AMP, 3-fold and 8.6-fold, confirming that the doses used suppressed CYP2D1 activity. Both inhibitors prolonged AMP-induced hyperactivity (0.3 mg/kg) and prolonged the duration of AMP-appropriate responding for periods of up to 90 min post-AMP administration in a drug discrimination procedure. In rats given a preload dose of AMP (0.8 mg/kg) 3 h prior to the self-administration test session, CYP2D1 inhibition resulted in fewer AMP infusions being taken compared with rats receiving the AMP preload dose alone. These studies indicate that AMP is responsible for the behavioural effects seen in rats and that a rat phenocopy model of the human CYP2D6 deficiency state can be produced by CYP2D1 inhibitors.

Effect of cytochrome P450 2D1 inhibition on hydrocodone metabolism and its behavioral consequences in rats.

Humans that lack cytochrome P450 2D6 (CYP2D6) activity may have an altered risk of drug dependence or abuse because this enzyme is important in the metabolism of some drugs of abuse, including hydrocodone. In rats, hydrocodone conversion to hydromorphone is catalyzed by CYP2D1, the rat homolog of the human CYP2D6. To determine the impact of impaired hydromorphone formation on the behavioral effects of the parent compound, hydrocodone-induced analgesia and hyperactivity, hydrocodone discrimination and self-administration were examined in male Wistar rats, with or without pretreatment with CYP2D1 inhibitors (quinine and budipine). In vivo, quinine (20 mg/kg) and budipine (10 mg/kg) produced a marked suppression in brain and plasma hydromorphone levels detected after the peripheral administration of hydrocodone, thus confirming that the doses used suppressed CYP2D1 activity. In contrast, CYP2D1 inhibition had no impact on the analgesic or discriminative stimulus effects of hydrocodone, nor did this type of manipulation alter hydrocodone self-administration. The effects of quinine on the locomotor activating effects of hydrocodone were subtle at best. Because inhibition of CYP2D1 in this rat strain is proposed to be a useful animal counterpart for studying the impact of CYP2D6 polymorphism in humans, these data suggest that differences in CYP2D6 phenotype will have limited influence on the drug response to hydrocodone after nonoral administration. This has recently been verified in a study showing that inhibition of hydrocodone biotransformation to hydromorphone does not affect measures of abuse liability. Therefore, hydrocodone's behavioral effects are most likely attributable to its own intrinsic effects at mu opioid receptors.

Effect of naltrexone and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and saccharin intake in rats.

Drug craving, the desire to re-experience the effects of a psychoactive substance, may be an important influence on drug-seeking and drug-taking behaviour. In rats, drug-seeking behaviour can be operationalized as conditioned anticipatory behaviour, evidenced by frequent visits to, and an increased time spent and distance travelled in, the drug administration area prior to the availability of the reinforcer. The effects of the opioid antagonist, naltrexone, and its derivatives, nalmefene and naltrindole, on conditioned anticipatory behaviour and drinking-associated behaviour and fluid intake during the access phase were examined. Male Wistar rats were trained to consume 0.1% saccharin and water in a distinct environment in a free-choice limited-access procedure. Naltrexone (0.3, 1 mg/kg) decreased conditioned anticipatory behaviour and drinking-associated behaviour in the saccharin zone without affecting the corresponding behaviour in the water zone. Its derivatives had different effects. Nalmefene (0.1 mg/kg) increased drinking-associated behaviour but not conditioned anticipatory behaviour, whereas naltrindole (1, 2 mg/kg) modestly decreased conditioned anticipatory behaviour but not drinking-associated behaviour. Naltrexone (0.3, 1 mg/kg) and naltrindole (1, 2 mg/kg), but not nalmefene, selectively decreased saccharin intake. These findings suggest that the blockade of selective opioid receptors may differentially alter conditioned anticipatory behaviour, drinking-associated behaviour and consumption levels, and that these behaviours can be modified separately.

Opposite effects of Ro 15-4513 on acquisition and maintenance of ethanol drinking behavior in male Wistar rats.

Acute treatment with Ro 15-4513, a benzodiazepine receptor inverse agonist, has been consistently shown to suppress ethanol self administration behavior by rats. The aim of the present study was to examine the effect of Ro 15-4513 on the acquisition and maintenance of ethanol drinking behavior in male Wistar rats. In rats maintained on a limited access procedure with a choice of 12% w/v ethanol solution and water, acute treatment with Ro 15-4513 (0.1 to 3.0 mg/kg) suppressed ethanol intake in a selective and dose-related manner (p < 0.01). However, by the fourth day of chronic Ro 15-4513 treatment, ethanol intake had returned to baseline levels. In contrast, chronic administration of Ro 15-4513 during the acquisition phase increased ethanol drinking behavior, compared with vehicle (p < 0.05). To assess whether the effects of Ro 15-4513 on ethanol intake were due to an alteration in ethanol kinetics or on behavior, blood ethanol levels and rat social interaction behavior were also assessed. Neither acute nor chronic Ro 15-4513 treatment significantly altered ethanol kinetics after oral administration of ethanol (1.0 g/kg), but did suppress locomotor activity and time spent engaged in active social interaction at the 1.0 and 3.0 mg/kg doses. These results show that Ro 15-4513 has opposite effects on ethanol consumption during the acquisition and maintenance phases of ethanol drinking behavior, suggesting that different mechanisms regulate Ro 15-4513's effects on acquisition and maintenance of ethanol intake. Ro 15-4513's reported anxiogenic or memory enhancing properties may be responsible for its effects on acquisition.

Use of serotonin (5-HT) and opiate-based drugs in the pharmacotherapy of alcohol dependence: an overview of the preclinical data.

Numerous neurotransmitter systems [e.g. dopamine, gamma-aminobutyric acid (GABA), the endogenous opioids, and serotonin (5-hydroxytryptamine, 5-HT)] are involved in the regulation of alcohol consumption. Because 5-HT reuptake inhibitors and opioid antagonists modify the activity of neurotransmitters, it has been hypothesized that they may also mediate the desire to drink alcohol by acting on specific receptors in the brain. Animal studies have shown that concomitant administration of 5-HT and opioid antagonists reduces alcohol consumption; therefore, the combined use of several pharmacotherapies may be the most effective treatment for alcohol dependence.

Use of serotonin (5-HT) and opiate-based drugs in the pharmacotherapy of alcohol dependence: an overview of the preclinical data.

Numerous neurotransmitter systems [e.g. dopamine, gamma-aminobutyric acid (GABA), the endogenous opioids, and serotonin (5-hydroxytryptamine, 5-HT)] are involved in the regulation of alcohol consumption. Because 5-HT reuptake inhibitors and opioid antagonists modify the activity of neurotransmitters, it has been hypothesized that they may also mediate the desire to drink alcohol by acting on specific receptors in the brain. Animal studies have shown that concomitant administration of 5-HT and opioid antagonists reduces alcohol consumption; therefore, the combined use of several pharmacotherapies may be the most effective treatment for alcohol dependence.

Evidence that GABA(A) but not GABA(B) receptor activation in the dorsal raphe nucleus modulates ethanol intake in Wistar rats.

Injection of the GABA(A) agonist muscimol into the dorsal raphe nucleus produces a marked and selective increase in voluntary ethanol intake. The purpose of the present study was threefold: first, to demonstrate that the effect of muscimol on ethanol consumption is mediated by GABA(A) receptors; secondly, to test the generalizability of this effect by examining the effects of another GABA(A) agonist, THIP, on ethanol drinking; and finally, to examine whether GABA(B) receptors within the dorsal raphe also play a role in modifying voluntary ethanol consumption under the same experimental conditions. Rats were trained to drink a 12% ethanol solution in a limited access paradigm with water concurrently available. Muscimol (50ng) injected into the dorsal raphe enhanced intake by at least 100%. Peripheral administration of the GABA(A) antagonist bicuculline (4mg/kg), but not the 5-HT(1A) antagonist (+)- WAY100135 (1 and 3mg/kg), antagonized the stimulatory effect of muscimol at a dose which, when administered alone, did not alter ethanol intake. This supports the suggestion that the effect of muscimol is mediated via GABA(A) receptors. This conclusion was further supported by the finding that another GABA(A) agonist, THIP (500ng), also selectively increased ethanol intake in this paradigm. Injection of bicuculline (60ng) into the dorsal raphe reduced ethanol intake, but also appeared to reduce water intake. Finally, intra-dorsal raphe injection of the GABA(B) agonist baclofen (62.5 and 125ng) did not produce any change in ethanol or water consumption. Together, these findings suggest that enhancement of GABAergic activity in the dorsal raphe increased voluntary ethanol intake via activation of GABA(A) but not GABA(B) receptors.

Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure.

The effect of the 5-HT3 antagonist ondansetron on ethanol self-administration was examined in a limited access paradigm. Acute administration of ondansetron (0.01 and 0.1 mg/kg) reduced ethanol intake in male Wistar rats by 35%, whilst water intake was unaffected. Both a lower (0.001 mg/kg) and higher dose (1 mg/kg) of ondansetron failed to modify ethanol consumption. Ondansetron did not, however, alter the pharmacokinetic profile of an orally administered dose of ethanol (1 g/kg) over the same dose range. To examine the generality of these findings and to determine if tolerance would develop to the suppressant effects of ondansetron on ethanol intake, male C57BL/6 mice were treated with ondansetron (0.001, 0.01 and 0.1 mg/kg) over 22 days, 30 min prior to scheduled access to ethanol. Both 0.01 and 0.1 mg/kg doses reduced ethanol intake; however, water intake was not altered by either dose. This finding confirms and extends the generality of the effects of 5-HT3 receptor antagonists on ethanol intake across different species and different paradigms of ethanol consumption. More importantly, the present study shows that the reduction in ethanol intake induced by ondansetron was maintained even after a prolonged period of treatment and is not due to an alteration in the absorption or metabolism of ethanol.

Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion.

Recent evidence shows that rats exhibit individual differences in their locomotor response to amphetamine (AMP). Moreover, evidence has accumulated showing that high-AMP responders exhibit more mesolimbic dopaminergic (DAergic) activation in response to AMP treatment than low-AMP responders. Cholecystokinin (CCK) is a peptide that is colocalised with mesolimbic DA and exerts complex modulatory actions on DA function. Two CCK receptor subtypes have been identified and selective antagonists have been developed. To examine the possible contribution of endogenous CCK mechanisms to individual differences in responsivity to AMP treatment, male Wistar rats were divided into low- and high-AMP responders based on a median split of their locomotor response to AMP and the effects of the selective CCK antagonists L365-260 (CCKB; 0.01, 0.1, 0.5 mg/kg; n = 16) and devazepide (CCKA; 0.001, 0.01, 0.1 mg/kg; n = 23) were determined. Results showed that L365-260 (0.1 mg/kg) potentiated AMP-induced hyperactivity in low-AMP responders but did not affect AMP-induced hyperactivity in high-AMP responders. Devazepide was without effect in both groups of animals. This pattern of results suggests that CCKB, but not CCKA, receptor mechanisms contribute to interindividual variation in responsivity to AMP.

Dissociation of serotonergic regulation of anxiety and ethanol self-administration: a study with mCPP.

Alcohol dependence frequently co-exists with anxiety disorders, although it is unclear how these disorders functionally or neurochemically relate. Central serotonergic dysfunction may be one common factor. The aim of this study was to compare the effects of the mixed 5-HT agonist m-chlorophenylpiperazine (mCPP) on both anxiety-related (hole board/plus maze) and ethanol self-administration (limited access procedure) behaviours in male Wistar rats. mCPP was selected because it is known to be anxiogenic in both animals and humans, and to induce "craving" in abstinent alcoholics. For comparative purposes pentylenetetrazole (PTZ), a non-serotonergic anxiogenic agent, was also examined. mCPP (0.3 and 1.0mg/kg s.c.) decreased exploratory behaviour in both the hole board and plus maze, which is indicative of anxiogenesis. At comparable doses, mCPP reduced ethanol and water intake during a limited access procedure where rats were presented with both a 12% ethanol solution and water. mCPP-induced anxiogenesis was reversed by two antagonists, metergoline (5-HT(1/2) receptor antagonist) and ritanserin (5-HT(2A/2C) receptor antagonist). However, the effect of mCPP on ethanol was modified only by metergoline, which suggests that different 5-HT receptor subtypes are involved in regulating these behaviours. Furthermore, there was no evidence of tolerance to the anxiogenic effect of mCPP (0.3mg/kg) following chronic (8 days) treatment. However, tolerance developed to its effect on ethanol intake. Upon discontinuation ethanol intake increased (by 41%). In contrast, PTZ (15.0mg/kg i.p.) induced anxiogenesis in the plus maze and also increased ethanol intake on chronic administration. Since mCPP and PTZ had opposite effects on ethanol intake, the effect of mCPP may not be related to its anxiogenic properties but rather reflect its non-selective pharmacology. This non-selectivity of mCPP makes it an unsatisfactory pharmacological tool with which to investigate the functional relationship between anxiety and alcohol dependence.

Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake.

Previous work has reported that the 5-hydroxytryptamine (5-HT)1A agonist, 8-hydroxy 2-(di-n-propylamino)tetralin (8-OH DPAT), reduces ethanol intake by rats. However, as 8-OH DPAT reduces 5-HT neurotransmission, these findings are inconsistent with the proposed inhibitory role of central 5-HT neurons on ethanol intake. We examined the effect of 8-OH DPAT on ethanol, water and food intake in rats maintained on a limited access schedule using a lower dose range (6-250 micrograms/kg) and by assessing concomitant changes in behaviour. Low doses of 8-OH DPAT enhanced ethanol intake even when food and water were offered as alternatives. Suppression in ethanol intake was observed at higher doses where elements of the 5-HT syndrome were apparent. Similar observations were made in both fluid and non-fluid deprived water drinking rats, suggesting the latter effect is non-selective. Therefore 8-OH DPAT may both increase or decrease ethanol consumption in the rat depending on the dose used.

Median and dorsal raphe injections of the 5-HT1A agonist, 8-OH-DPAT, and the GABAA agonist, muscimol, increase voluntary ethanol intake in Wistar rats.

Low doses of the selective 5-HT1A agonist 8-OH-DPAT increase ethanol intake in a limited access paradigm following peripheral injection. This may be due to a reduction in 5-HT neurotransmission following activation of raphe somatodendritic autoreceptors. In order to test this hypothesis, and to determine the effects of selective reductions in raphe 5-HT activity, experiments examined the effects of injecting 8-OH-DPAT into the dorsal raphe (0, 0.02, 0.1, 1 and 2.5 micrograms) or the median raphe (0, 0.1, 1 and 5 micrograms) in rats trained to drink 12% ethanol for 40 min each day. The effects of the GABAA agonist, muscimol, on ethanol intake were also examined. Ethanol intake was increased at the highest dose of 8-OH-DPAT following injection into either site, with no change in water intake. Thus, the effects of 8-OH-DPAT are selective for ethanol. The selective 5-HT1A antagonist, (+)-WAY100135 (0.3, 1 and 3 mg/kg), blocked the effect of 8-OH-DPAT, showing that activation of 5-HT1A receptors underlies the ethanol drinking induced by 8-OH-DPAT. These results are consistent with the idea that reduced 5-HT function increases ethanol intake. Several behavioral mechanisms for this effect are discussed. Muscimol (50-100 ng) also increased ethanol drinking. Following injection into the median raphe, muscimol also stimulated water intake. These effects are probably due to non-specific behavioural activation induced by this treatment. However, the effect of muscimol in the dorsal raphe was specific for ethanol since water intake was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dexfenfluramine on saccharin drinking: behavioural and pharmacological studies.

We have previously reported that the 5-hydroxytryptamine (5-HT) releaser/reuptake blocker dexfenfluramine suppresses voluntary ethanol intake. To further analyse the generality of these findings, in the present study we examined the effect of equivalent doses of dexfenfluramine (0.5-2.5 mg/kg) on the intake of another preferred fluid, saccharin. Saccharin was made available for 2 h daily across a wide concentration range chosen to promote varying degrees of intake. Following stable levels of intake, the behaviour of vehicle-pretreated rats was assessed immediately prior to (anticipatory/preparatory phase) and during (consumatory phase) saccharin access. These behaviours were compared and contrasted with those produced following dexfenfluramine pretreatment at the optimally preferred saccharin concentration (0.2%). In a preliminary study the effects of various 5-HT antagonists were also examined against the dexfenfluramine response. The present results suggest that dexfenfluramine produced a dose-related suppression of saccharin intake at doses similar to those which reduced ethanol intake. However, the magnitude of this suppression was similar across each saccharin concentration. Behavioural analysis indicated that the profile of the dexfenfluramine (0.5- and 1-mg/kg doses only) suppression of the 0.2% solution was similar to that observed in vehicle-pretreated rats presented with saccharin solutions of lesser palatability to this concentration. Pharmacological studies indicated a 5-HT1 (non-5-HT1C) receptor involvement in the dexfenfluramine response. These studies imply that at certain doses dexfenfluramine may produce a subtle alteration in the motivation to consume a preferred fluid.

Effect of dorsal raphe injections of the GABAA agonist, muscimol, on ethanol intake and measures of intoxication in Wistar rats.

Peripheral administration of selective agents for GABAA receptors have been reported to modify ethanol self-administration behaviour. Recently, it has been reported that the dorsal and median raphe may represent potential brain sites for mediating these effects since injection of the GABAA agonist, muscimol, into these sites increased ethanol intake. The aim of the present study was to extend these findings and assess the effect of muscimol, injected into either the dorsal or median raphe, on a range of parameters including ethanol intake, ethanol-induced hypothermia and ethanol-induced suppression of high rates of responding. Wistar rats trained to drink 12% ethanol for 40 mins each day, increased their ethanol consumption, but not water consumption, following injection of 50 ng muscimol into the dorsal raphe. Ethanol intakes returned to baseline levels the day following drug treatment. The same dose injected into the median raphe has been shown to produce a non-selective increase in both water and ethanol intake. Further analysis of this data revealed that the rats tended to avoid the ethanol solution on the day following treatment. A further difference between the dorsal and median raphe was revealed in the ethanol-induced hypothermia experiment. Thus, 10 ng muscimol injected into the median raphe potentiated the hypothermic response induced by intraperitoneal injection of 1.5 g/kg ethanol, whereas injection into the dorsal raphe had no significant effect on this measure. Intraperitoneal injection of 0.5 g/kg ethanol suppressed operant responding for water intake and this behaviour was not altered by dorsal raphe injection of muscimol. Together these results suggest that GABAergic mechanisms within the dorsal raphe represent an important neural site for controlling the ingestion of ethanol, but not that of ethanol intoxication.

The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety.

The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.