Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Diazepam and buspirone alter neuropeptide Y-like immunoreactivity in rat brain

Neuropeptide Y-like immunoreactivity (NPY-LI) was investigated in naIve Sprague-Dawley rats subjected to acute, subchronic (7 days) or chronic (21 days) intraperitoneal treatment with diazepam (1 or 3 mg/kg once daily) or buspirone (1.5 or 5 mg/kg twice daily). NPY-LI was determined by radioimmunoassay in the amygdala, nucleus accumbens, hypothalamus and frontal cortex 24 h after the last dose of the drugs. Amygdala NPY-LI decreased after acute diazepam (3 mg/kg) or buspirone (1.5 mg/kg) and increased after subchronic treatment with both doses of diazepam and after chronic buspirone (1.5 mg/kg) treatment. Both diazepam and buspirone given in subchronic and chronic doses decreased NPY-LI levels in the nucleus accumbens. Hypothalamic NPY-LI changed only after chronic treatment: it decreased after diazepam and increased after buspirone (5 mg/kg). NPY-LI content in the frontal cortex decreased after subchronic diazepam (3 mg/kg) treatment and slightly increased after buspirone. The study has shown that both diazepam and buspirone affect NPY-LI levels in rats. These results suggest that the NPY system in the amygdala and nucleus accumbens is implicated in the anxiolytic effects of the drugs studied.     

Phase I study of a new antianxiety drug, buspirone

1. A phase I study of buspirone was conducted in 7 healthy male volunteers. 2. Diazepam was selected as the control drug and administered in equipotent doses to buspirone. Dosage was initiated at 2.5mg and doubled until a maximum dosage of 20mg was attained. Subsequently, 10mg was administered once a day for three consecutive days. 3. Clinico-pharmacologically both drugs produced sleepiness/drowsiness, but dizziness, light-headed feeling and feeling of drunkenness were marked only in the diazepam group. 4. No drug-related abnormalities were observed in clinical laboratory test values, endocrinological tests and ECG. 5. On the Uchida-Kraepelin test, no change with the control values was observed under buspirone but subjects administered diazepam exhibited marked deterioration during the latter half of the test. Moreover, in the tapping test, significant impairment was observed in the diazepam group whereas buspirone had no effect. 6. On the EEG some fast waves were observed with diazepam whereas buspirone exhibited slow waves.     

The comparative efficacy of buspirone and diazepam in the treatment of anxiety.

In this double-blind study, 56 adult psychoneurotic outpatients with a primary diagnosis of anxiety neurosis were randomly assigned to receive buspirone (N = 18), diazepam (N = 20), or placebo (N = 18) over a four-week period. A battery of tests administered weekly indicated that buspirone, a new agent not chemically related to any currently marketed drugs, was as effective an antianxiety agent as diazepam and produced no more and perhaps fewer side effects. Buspirone showed excellent antidepressant effects as well. If further studies confirm the authors' findings and determine that buspirone does not result in tolerance and addiction, it would be more advantageous than the benzodiazepines in the treatment of anxiety.     

Pharmacokinetic and pharmacodynamic drug interactions during treatment with vigabatrin

Pharmacokinetic drug interactions take place when one drug interacts with another at the level of metabolism, absorption or excretion. Pharmacodynamic interactions take place at the level of receptor sites, where they may have additive or potentiating effects. Vigabatrin is relatively free of pharmacokinetic interactions, and though it is associated with about a 20% decrease in serum levels of concomitantly administered phenytoin, the reduction is of little clinical significance. The mechanism underlying this effect is unknown. Because vigabatrin increases GABA-mediated inhibition in the brain (an action that is believed to account for its anticonvulsant effects), it might be expected to potentiate the CNS effects of benzodiazepines and alcohol. However, very sensitive eye movement studies have failed to detect any evidence of such an interaction. Overall, vigabatrin appears to be remarkably free of drug interactions. As a result, it is easier to use in clinical practice than older anti-epilepsy agents. Perhaps the most important finding of the interaction studies with vigabatrin is that there is no need for patients receiving the drug to be told to avoid alcohol.     

Interactions Between Anticonvulsants and Other Commonly Prescribed Drugs

Summary: Many drug interactions can be demonstrated, but only a few are so clinically significant that they necessitate adjusting drug dosages. The same drug combination may produce changes of variable extent or direction in different individuals. The reasons for this variability include genetic control of the rate and inducibility of drug metabolism, and environmental factors such as contact with chemicals. Among antimicrobial agents, chloramphenicol may cause accumulation of phenytoin (PHT) and phenobarbital (PB), and isoniazid may cause PHT, carbamazepine (CBZ), and primidone (PRM) to accumulate. Erythromycin may cause accumulation of CBZ. Among antiulcer agents, antacids may reduce PHT concentration while cimetidine may cause accumulation of PHT, CBZ, and diazepam (DZP). Salicylates displace strongly binding drugs such as PHT, DZP, or valproate (VPA) from the binding sites in plasma proteins, which may lead to some decline of the total plasma level with an increase in the unbound drug percentage. Conversely, anticonvulsants may influence the dosage requirements of oral anticoagulants by inducing their metabolism. Failures of oral contraceptives have been attributed to anticonvulsants in some patients. Probably the most predictable interaction that necessitates dosage adjustment is accumulation of PB caused by VPA. Intentional inhibition of PRM metabolism by nicotinamide serves as an example of attempts to utilize an interaction for improved therapeutic effect.     

Cognition and vigilance: differential effects of diazepam and buspirone on memory and psychomotor performance.

Effects of a single dose of the anxiolytic buspirone (15 mg) on memory and psychomotor performance were studied in healthy volunteers and compared to those of the classic benzodiazepine anxiolytic diazepam (15 mg). The study was performed in a double-blind, placebo-controlled way. Three groups of 12 subjects were exposed to an extended test battery before and after intake of drug or placebo. Next to this, an evaluation session took place 1 week later. Immediately after intake, diazepam exerted major effects on memory, impaired psychomotor performance and decreased alertness. In particular, long-term memory had deteriorated, which was interpreted as anterograde amnesia. One week later, more items were recalled from the predrug session compared to the number of items from the postdrug session; this was interpreted as retrograde facilitation. After intake of buspirone, there were no effects of alertness and vigilance, on psychomotor performance and on memory. One week later, a small memory decrement was noticed for verbal material, which was considered as a sign of anterograde amnesia. These results indicate that effects of anxiolytics on memory can be more easily demonstrated 1 week later than immediately after drug intake and, furthermore, that the disruptive effects of diazepam outweight the small effects of buspirone. Finally, it was established that the effects of diazepam on cognition might be mediated by its effects on alertness and vigilance and that cognitive effects are not related to the anxiolytic properties of the drug.     

Buspirone: Anxiolytic?

1. Sixty (60) out-patients with DSM III generalized anxiety disorder were treated after a 1-week placebo washout in a 4-week double-blind study with buspirone, diazepam and placebo; after which they were withdrawn abruptly from medication or assigned to a 2-week period of placebo.

2. The HAM-A score was significantly lower in the diazepam group at week 2 (p < .02) and the buspirone group at week 3 (p <.04) as compared to the placebo group. A similar pattern was evident in the female group, but not in the male group.

3. Dizziness was the most prominent adverse effect in the buspirone group, whereas the diazepam group had more adverse effects including sedation, fatigue, dizziness and impaired concentration.

4. Withdrawal symptoms were more evident in the diazepam group than the buspirone group.     

The effects of benzodiazepine and non-benzodiazepine anxiolytics on locus coeruleus unit activity

Two theories have been put forth concerning the anxiolytic actions of the anti-anxiety drugs. One theory maintains that these drugs decrease locus coeruleus output, and the other maintains that they facilitate gamma-aminobutyric acid (GABA) neurotransmission at benzodiazepine (BZ)-linked GABA receptors. The BZ-anxiolytic diazepam does decrease locus coeruleus neuronal impulse flow. However, this decrease is not due to effects on BZ-linked GABA receptors in the locus coeruleus. Furthermore, the non-BZ anxiolytic buspirone, its metabolite and its analog all slightly increase locus coeruleus neuronal impulse flow. This increase, in the case of the metabolite, appears to be due, in part, to blockade of alpha 2-adrenoceptors. Finally, buspirone, unlike diazepam, did not potentiate GABA inhibition at BZ-linked GABA receptor sites (i.e. cerebellar Purkinje cells). These data suggest that the non-BZ anxiolytic buspirone produces its anti-anxiety effects by unconventional mechanisms.     

Comparative study on the behavioral and EEG changes induced by diazepam, buspirone and a novel anxioselective anxiolytic, DN-2327, in the cat.

Behavioral and EEG effects of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4)-dioxa-8-(azas piro-[4.5]dec-8- yl)carbonylmethyl]isoindolin-1-one (DN-2327; 1, 5 and 20 mg/kg p.o.) were compared to those of diazepam (0.2 and 1 mg/kg p.o.) and buspirone (1 and 5 mg/kg p.o.) in freely moving cats. DN-2327 did not affect motor coordination or the relative percentages of the three sleep-wakefulness stages. Diazepam (1 mg/kg) increased wakefulness and non-REM sleep, and buspirone (5 mg/kg) also increased wakefulness and decreased REM sleep. In addition, diazepam (1 mg/kg) caused severe motor disturbance, but buspirone did not. The cortical EEG power density spectra during wakefulness were changed almost dose-dependently by DN-2327 (decreased: 2-7.75 Hz; increased: 20-49.75 Hz), and dose-dependently by diazepam (decreased: 2-7.75 Hz; increased 13-49.75 Hz) and buspirone (decreased: 4-9.75 and 13-19.75 Hz). The effect of DN-2327 on the cortical EEG varied with the sleep-wakefulness stage. The power of the 4- to 7.75-Hz frequency (theta) band of the hippocampal EEG during wakefulness was decreased by diazepam and buspirone but not by DN-2327, while the peak frequency of its spectra was decreased only by diazepam. On the other hand, during non-REM sleep, DN-2327 decreased the power of the theta band as did diazepam. These results indicate that the behavioral and EEG effects of DN-2327 differ completely from those of buspirone and considerably from those of diazepam and that the EEG effect of DN-2327 varies with the sleep-wakefulness stage.     

Anxiety in primary care: Is short-term drug treatment appropriate?

Thirty-six patients with generalised anxiety disorder, panic disorder or agoraphobia with panic attacks, diagnosed by DSM-III criteria, were treated with a new non-benzodiazepine anti-anxiety drug, buspirone, and with diazepam and placebo, in a cross-over design. Each patient took buspirone, diazepam and placebo for one week each in flexible dosage and balanced order. Ratings of symptomatology using the Comprehensive Psychopathological Rating Scale were made after each week's treatment and a sub-scale used for measuring anxiety change alone was used separately. There was no overall difference in efficacy between the drugs, but when the scores for individual symptoms were analysed, diazepam was significantly superior to the other treatments for the symptom of muscle tension only. The results suggest that the common practice of giving short-term therapy with tranquilising drugs for anxiety in primary care is pharmacologically suspect.     

Issues in the pharmacological modification of cocaine conditioning: evidence that the stimulus properties of drugs can interact with contextual cues to activate or inactivate cocaine conditioned stimuli.

Cocaine conditioned stimuli are capable of eliciting cocaine craving in individuals with a history of cocaine use. As a consequence, there have been a number of attempts using animal models to identify pharmacological treatments which can attenuate cocaine conditioned effects. The emphasis in these studies has been to employ drug doses which do not have response effects that could directly alter the conditioned drug response. A drug treatment may not have a response effect but still have drug stimulus effects which could interact with and modify the cocaine conditioned stimulus. In order to experimentally investigate this important issue, two experiments are reported. In one experiment, rats were co-administered 0.1 mg/kg MK-801 either with cocaine (10 mg/kg) or with saline; in the other experiment 3.0 mg/kg buspirone was co-administered with either cocaine (10 mg/kg) or with saline. The MK-801 and buspirone treatments did not affect spontaneous activity levels or alter the unconditioned cocaine stimulant effect. In tests for conditioning, however, the effects of buspirone and MK-801 depended upon their association with cocaine. If MK-801 and buspirone had no association with cocaine then these drugs inactivated the cocaine conditioned stimulant response. If MK-801 and buspirone had been co-administered with cocaine, then, in saline conditioning tests, no cocaine conditioning was observed. If the conditioning tests were conducted following MK-801 or buspirone treatment, however, cocaine conditioning was elicited. Altogether, these studies demonstrate that the stimulus properties of drugs can interact with contextual stimuli to inactivate or activate cocaine conditioned stimuli. In the search for drugs which may prevent cocaine craving, therefore, the stimulus properties of drugs provide an important mechanism for the modification of cocaine conditioned stimuli.     

Antiepileptic drugs and the immune system

Data on the effects of antiepileptic drugs on the immune system are frequently inconsistent and sometimes conflicting because the effects of drugs cannot be separated from those of seizures, first-generation drugs have been most intensively investigated, the patient's genetic background, the mechanism of action and the pharmacokinetic profile of AEDs and the concurrent use of immunosuppressant drugs may act as confounders. Valproate, carbamazepine, phenytoin, vigabatrin, levetiracetam, and diazepam have been found to modulate the immune system activity by affecting humoral and cellular immunity. AEDs are associated with pharmacokinetic interactions (most frequently occurring with carbamazepine, phenytoin, phenobarbital and valproate). Hepatic metabolism is the primary site of interaction for both AEDs and immunotherapies (ACTH, dexamethasone, hydrocortisone, methylprednisolone, cyclophosphamide, methotrexate, rituximab), which entail induction or inhibition of drug effects. However, the clinical importance of these drug interactions is still far from defined. An important adverse effect of the action of AEDs on the immune system is antiepileptic hypersensitivity syndrome (AHS), a life-threatening, idiosyncratic cutaneous reaction to aromatic AEDs resulting in end organ damage. Phenytoin, carbamazepine, phenobarbital, lamotrigine, oxcarbazepine, felbamate, and zonisamide have been implicated. The pathogenic mechanisms of AHS are incompletely understood.     

The long-term effects of diazepam, lorazepam, and buspirone on behavioral suppression by a shock signal

1. Two experiments examined the long-term effects of treatment with buspirone (a nonbenzodiazepine anxiolytic), diazepam, or Lorazepam (two pharmacokinetically distinct benzodiazepines) on the capacity of a shock cue to disrupt appetitively conditioned behavior. 2. In Experiment 1, rats were injected with diazepam (5 mg/kg), buspirone (1.5 mg/kg or .75 mg/kg), or saline shortly before each of 12 bar press training sessions. Injections were suspended and three days later the rats received five days of Pavlovian fear conditioning (bars removed) in which a tone signaled shock. The capacity of the tone to disrupt bar pressing was then assessed. 3. Bar pressing of rats previously injected with diazepam was more suppressed by the shock cue than that of rats previously injected with buspirone or saline. The long-term effects of buspirone and saline did not differ. 4. In Experiment 2, Lorazepam had effects different from diazepam during bar press training. Nonetheless, rats previously injected with Lorazepam were also more disrupted by a shock cue than were controls. 5. The results suggest that one long-term consequence of treatment with benzodiazepines may be hypersensitivity to behavioral disruption by stimuli that presumably elicit fear or anxiety.     

Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy

OBJECTIVE: Patients with generalized anxiety disorder (N=107) who had been long-term benzodiazepine users (average duration of use=8.5 years) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine (180 mg/day) and buspirone (38 mg/day) compared to placebo in facilitating benzodiazepine discontinuation. METHOD: After a benzodiazepine stabilization period taking either diazepam, lorazepam, or alprazolam, patients were treated for 4 weeks with imipramine, buspirone, or placebo under double-blind conditions while benzodiazepine intake was kept stable (treatment phase). Patients then entered a 4-6 week benzodiazepine taper and a 5-week posttaper phase with imipramine, buspirone, and placebo treatment being continued until 3 weeks into the posttaper phase, at which time all patients were switched to placebo for 2 weeks. Benzodiazepine plasma levels were assayed weekly. Benzodiazepine-free status was assessed 3 and 12 months posttaper. RESULTS: Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts. The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy. CONCLUSIONS: Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper. Daily benzodiazepine dose, severity of baseline symptoms of anxiety and depression, and duration of benzodiazepine use were additional significant predictors of successful taper outcome.     

Comparative neuropharmacology of buspirone and MJ-13805, a potential anti-anxiety drug

Buspirone is a clinically efficacious anti-anxiety drug without any other benzodiazepine-like activity. Although buspirone can displace ligands for dopamine (DA) receptors, its equipotent analog, MJ-13805, cannot. Buspirone can potently increase dopaminergic impulse flow and metabolism, primarily due to inhibition of DA autoreceptors. However, MJ-13805 does not block striatal nerve ending DA autoreceptors and slightly increases striatal DA metabolism. Both drugs potently reverse catalepsy due to either DA receptor blockade or DA depletion which indicates an effect within the extrapyramidal system efferent from the DA neuron. Amantadine is at least ten fold less potent than these drugs for reversal of catalepsy. These data indicate that altered dopaminergic neurotransmission may not be important for the anti-anxiety effect of buspirone and that buspirone should be tested for efficacy in various models of movement disorders. The site and mechanism of action for buspirone and MJ-13805 remains obscure. A metabolite of buspirone, 1-piperazinylpyrimidine, does not reverse catalepsy although this drug is known to be active in anti-anxiety screening tests. Thus, buspirone may have separate mechanisms of action for reduction of anxiety and reversal of catalepsy.     

Frequency domain source localization shows state-dependent diazepam effects in 47-channel EEG

Summary The topic of this study was to evaluate state-dependent effects of diazepam on the frequency characteristics of 47-channel spontaneous EEG maps. A novel method, the FFT-Dipole-Approximation (Lehmann and Michel, 1990), was used to study effects on the strength and the topography of the maps in the different frequency bands. Map topography was characterized by the 3-dimensional location of the equivalent dipole source and map strength was defined as the spatial standard deviation (the Global Field Power) of the maps of each frequency point. The Global Field Power can be considered as a measure of the amount of energy produced by the system, while the source location gives an estimate of the center of gravity of all sources in the brain that were active at a certain frequency. State-dependency was studied by evaluating the drug effects before and after a continuous performance task of 25 min duration. Clear interactions between drug (diazepam vs. placebo) and time after drug intake (before and after the task) were found, especially in the inferior-superior location of the dipole sources. It supports the hypothesis that diazepam, like other drugs, has different effects on brain functions depending on the momentary functional state of the brain. In addition to the drug effects, clearly different source locations and Global Field Power were found for the different frequency bands, replicating earlier reports (Michel et al., 1992).     

A clinical trial of buspirone and diazepam in the treatment of generalized anxiety disorder

In double-blind trials with hundreds of patients, buspirone has proven to be as effective an anxiolytic as the benzodiazepines. It causes less sedation and motor impairment than diazepam, and may be particularly useful in geriatric patients. We conducted a 4 week double-blind, randomized trial of buspirone versus diazepam and placebo in thirty adult outpatients with generalized anxiety disorder. Maximum doses were 40 mg of diazepam or buspirone or eight placebo tablets a day. There were no significant differences in outcome between the three groups on any physician or subject measures. Some implications of this finding are discussed.     

Contingent tolerance to the anticonvulsant effects of carbamazepine: Relationship to loss of endogenous adaptive mechanisms

Contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala kindled seizures develops when the drug is repeatedly given prior to but not after the electrical stimulation. Such tolerance can be reversed by kindling the rats for several days without drug or even by continuing to give the drug but after each seizure has occurred. Contingent tolerance can be slowed by reducing the electrical stimulus intensity and by chronic continuous (as opposed to repeated paired) drug administration. Contingent cross-tolerance has been demonstrated from carbamazepine to PK11195 (a drug active at peripheral-type benzodiazepine receptors) and valproate, but not to clonazepam and diazepam (two drugs active at central-type benzodiazepine receptors) or phenytoin. Endogenous physiological changes occur in conjunction with contingent tolerance, exemplified by the decrease in seizure threshold that returns to normal upon reversal of tolerance. We suggest that contingent tolerance is associated with a loss of seizure-induced adaptations, since many biochemical changes that occur following seizures (or in non-tolerant animals given drug after seizures) are not observed in tolerant animals. These include a loss of seizure-induced up-regulation of GABA_A receptors and a loss of increases in mRNA expression for corticotropin-releasing-factor (CRF), thyrotropin-releasing-hormone (TRH), neuropeptide Y (NPY), glucocorticoid receptors and brain-derived neurotrophic factor (BDNF). Thus, several putative seizure-induced anticonvulsant adaptations, such as increases in GABA_A receptors and TRH and NPY mRNA fail to occur in tolerant animals. These findings are consistent with the novel observations that, paradoxically, seizures themselves appear to facilitate the anticonvulsant effects of carbamazepine or diazepam on amygdala kindled seizures. That is, animals given a ‘vacation’ from seizures show a decreased response to these agents, a phenomenon we have called the ‘time-off seizure’ effect. Thus, seizures are postulated to induce adaptive changes that influence seizure thresholds and potentiate the anticonvulsant effects of exogenously administered drugs such as carbamazepine and diazepam. Taken together, these data suggest that seizures are associated with endogenous adaptations lasting days to weeks and that a selective failure of some of these to occur during contingent drug administration may underlie the development of contingent tolerance. These observations suggest that endogenous, illness-related mechanisms may participate both in the therapeutic responses of some agents and that their failure to occur could relate to loss of drug efficacy via tolerance; these processes may reveal new potential targets for therapeutic intervention.     

Evidence that conditioned stress enhances outflow of dopamine in rat prefrontal cortex: A search for the influence of diazepam and 5-HT1A agonists

We evaluated the impact of conditioned stress on outflow of dopamine in the rat prefrontal cortex. Exposure of rats to an environment associated with aversive stimuli-foot shock enhanced outflow of dopamine in a similar way as seen during the conditioning session when foot shocks were applied. Diazepam (2.5 and 10 mg/kg) dose-dependently decreased outflow of dopamine and, when given in a dose of 10 mg/kg, but not 2.5 mg/kg, decreased enhanced dopamine outflow evoked by conditioned stress. On the other hand, ipsapirone (10 mg/kg, but not 2.5 mg/kg) and buspirone (2.5 mg/kg) enhanced basal outflow of dopamine. When ipsapirone (10 mg/kg) and buspirone (2.5 mg/kg) were given to rats exposed to conditioned stress, the stress-evoked elevation in dopamine outflow was abolished. Ipsapirone in a dose of 2.5 mg/kg was ineffective in the stress paradigm tested. It is concluded that conditioned stress in vivo enhances dopaminergic neurotransmission in the rat prefrontal cortex, this effect being attenuated by diazepam, a classic anxiolytic drug, and by such novel anxiolytics as ipsapirone and buspirone, which operate via serotonergic 5-HT_1A receptors. Although ipsapirone and buspirone blocked stress-induced enhancement of dopamine outflow, this effect seems to result from their influence on the basal outflow of dopamine. Differential effects of diazepam and 5-HT_1A agonists on basal and stress-induced alterations in dopamine outflow are discussed in terms of their possible effectiveness in various types of general anxiety disorders. © 1996 Wiley-Liss, Inc.