The pharmacology of latent inhibition as an animal model of schizophrenia.

The nature of the primary symptoms of schizophrenia and our lack of knowledge of its underlying cause both contribute to the difficulty of generating convincing animal models of schizophrenia. A more recent approach to investigating the biological basis of schizophrenia has been to use information processing models of the disease to link psychotic phenomena to their neural basis. Schizophrenics are impaired in a number of experimental cognitive tasks that support this approach, including sensory gating tasks and models of selective attention such as latent inhibition (LI). LI refers to a process in which noncontingent presentation of a stimulus attenuates its ability to enter into subsequent associations, and it has received much attention because it is widely considered to relate to the cognitive abnormalities that characterise acute schizophrenia. Several claims have been made for LI having face and construct validity for schizophrenia. In this review of the pharmacological studies carried out with LI we examine its claim to predictive validity and the role of methodological considerations in drug effects. The data reviewed demonstrate that facilitation of low levels of LI is strongly related to demonstrated antipsychotic activity in man and all major antipsychotic drugs, both typical and atypical, have been shown to potentiate LI using a variety of protocols. Very few compounds without antipsychotic activity are active in this model. In contrast, disruption of LI occurs with a wide range of drugs and the relationship with psychotomimetic potential is less clear. Although reversal of disrupted LI has also been used as a model for antipsychotic acticity, mostly using amphetamine-induced disruption, insufficient studies have been carried out to evaluate its claim to predictive validity. However, like facilitation, it is sensitive to both typical and atypical antipsychotic agents. The data we have reviewed here demonstrate that facilitation of LI and, perhaps to a lesser extent, reversal of disrupted LI fulfil the criteria for predictive validity.

Characterisation of the effects of nicotine in the five-choice serial reaction time task in rats: antagonist studies.

RATIONALE: Nicotine has been shown to decrease reaction time and increase anticipatory responses in a five-choice serial reaction time task (5-CSRTT) in rats, but the receptor mechanisms mediating this effect remain unknown. OBJECTIVES: To evaluate further the effects of nicotine in this task and to characterise the receptors mediating these effects. METHODS: Using a standard 5-CSRTT protocol, rats were trained to respond to a 0.5-s visual stimulus, which was reduced to 0.25 s for experimental sessions to induce a performance decrement. The effects of acute (0.03-0.3 mg/kg IP) and repeated (0.1 and 0.3 mg/kg IP for 5 days) nicotine were studied, as was the ability of mecamylamine (1 mg/kg IP), hexamethonium (5 mg/kg IP), dihydro-beta-erythroidine (6 mg/kg IP) and methyllycaconitine (10 mg/kg IP) to antagonise the effects of acute nicotine. RESULTS: Nicotine had no effect on accuracy, but decreased response latencies, improved performance in the less-well attended stimulus locations and increased inappropriate responding after both acute and repeated treatment. The data suggest that nicotine improves readiness to respond and improves target scanning, and decreases the ability to withhold premature responses (i.e. increased impulsivity). Except for the reduction in error latency, all of the effects of nicotine were antagonised by the non-selective, centrally acting antagonist mecamylamine, whereas the peripheral antagonist hexamethonium had no effect, demonstrating that nicotine's actions are central in origin. Dihydro-beta-erythroidine, a competitive nicotinic antagonist, antagonised all of the effects of nicotine. In contrast, the alpha7 antagonist methyllycaconitine had no significant effects against nicotine. CONCLUSIONS: These results demonstrate that the alpha7 receptor subtype is not involved in the effects of nicotine in the 5-CSRTT and that its effects are more likely to be mediated by a receptor(s) such as alpha4beta2, alpha4beta4 and/or alpha3beta2 which is sensitive to antagonism by dihydro-beta-erythroidine.

5-HT1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats.

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT1A receptors using the forced swim test in rats using both (+/-)-pindolol and the selective 5-HT1A receptor antagonist WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125-1 mg/kg s.c.), used as a reference for 5-HT1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01-0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (+/-)-pindolol (1-16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10-80 mg/kg p.o.) and befloxatone (0.03-1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (+/-)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (+/-)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.

Effects of mild traumatic brain injury on immunoreactivity for the inducible transcription factors c-Fos, c-Jun, JunB, and Krox-24 in cerebral regions associated with conditioned fear responding.

We have previously demonstrated that mild traumatic brain injury (TBI) of the right parietal cortex results in a relatively selective deficit in conditioned fear responding. However, this behavioural deficit is very consistent and unrelated to the extent of the cortical necrotic lesion. We were therefore interested in determining if other brain regions might show a consistent response to mild TBI, and therefore, more reliably relate to the behavioural change. Increased expression of inducible transcription factors (ITFs) has been used to study which brain regions respond to a variety of events. In the present study, we examined the expression patterns of immunoreactivity (IR) for four ITFs (c-Fos, c-Jun, JunB, and Krox-24) at 3 h after mild fluid percussion TBI. Changes in ITF expression were only observed ipsilateral to the side of TBI. The clearest changes were observed in brain regions known to be involved in conditioned fear responding, such as the amygdala complex and hippocampal formation and several cortical regions. In contrast, no changes in IR for any of the ITFs were observed in the striatum, nucleus accumbens, nucleus basalis magnocellularis, septum or periacqueductal grey. Unlike the extent of visible damage to the cortex at the site of impact, the overexpression of ITFs showed a notable consistency between animals subjected to TBI. This consistency in regions known to be involved in conditioned fear responding (i.e., amygdala complex and hippocampal formation) lead us to suggest that it is these changes, rather than the more variable cortical necrotic lesion, that is responsible for the behavioural deficits we observe following mild TBI. Importantly, our results demonstrate that like the hippocampus, the amygdala is a sub-cortical structure particularly sensitive to the effects of mild brain trauma and underline the fact that cerebral regions distant from the location of the fluid impact can be affected.

Mild traumatic lesion of the right parietal cortex of the rat: selective behavioural deficits in the absence of neurological impairment.

Fluid impact models are widely used to study the histological and neurochemical consequences of traumatic brain injury and although behavioural consequences have also been studied, behavioural changes are often confounded by non-specific neurological deficits. In the present study we investigated behavioural effects of a unilateral mild traumatic lesion of the right lateral parietal cortex. This region is implicated in a number of basic and complex behaviors, and we therefore analyzed the performance of rats in a diverse range of behavioural procedures. The lesion had no effects on general neurological function, motor activity (activity boxes, rota-rod and paw reaching tests), habituation to a novel environment (holeboard), spatial learning ability (Morris water maze) or anxiety (elevated plus-maze). However, the lesioned animals demonstrated lower levels of exploration than the control group when novel objects were placed beneath some of the holes in the holeboard. Lesioned animals also differed from controls in their performance in passive and active avoidance procedures. In a step-through passive avoidance test the lesioned rats performed worse than the sham-operated controls, i.e. they had significantly lower entry latencies on the 2nd day. In contrast, in the active avoidance task the lesioned animals performed better than sham-operated rats, demonstrating a better ability to learn to avoid and escape from the shock. These diverse results in different tests of learning and memory, in particular the impairment in passive avoidance and the improvement in active avoidance behavior, are difficult to reconcile with a simple effect of the lesion on cognitive performance per se. The complete absence of general neurological deficits following the mild traumatic injury rules out the possibility that the observed behavioural changes reflect a non-specific impairment. These results demonstrate that mild traumatic lesion of the right parietal cortex can induce relatively selective behavioural changes that may serve to study functional recovery after trauma. However further work is required to establish the underlying deficit(s) that has led to the behavioural effects described here.

Mild traumatic lesion of the right parietal cortex in the rat: characterisation of a conditioned freezing deficit and its reversal by dizocilpine.

We have previously demonstrated that traumatic injury of the lateral aspect of the right parietal cortex results in reduced acquisition of the passive avoidance task but enhanced learning in an active avoidance procedure. In order to try to explain the apparent dichotomy between these findings a series of experiments examined the effect of fluid percussion-induced traumatic brain injury (FP-TBI) on the conditioned freezing response to a context previously paired with an aversive stimulus. Rats subjected to FP-TBI displayed less conditioned freezing than the sham-operated controls. This effect was particularly marked when the delay between context exposure and footshock was short (< or = 30 s) and was no longer significant when this delay was 3 min, indicating that the injured animals did not have an impaired freezing response per se. This phenomenon was enduring such that it could still be observed 2 months following the surgery. There was no significant freezing deficit after FP-TBI of the motor cortex, demonstrating that the site of injury is important and that the freezing deficit is not a general response to CNS trauma. The NMDA receptor antagonist dizocilpine (MK-801, 1 mg/kg i.v.) significantly reduced the trauma-induced freezing deficit when administered as a single bolus 15 min prior to the surgery, or as three repeated treatments (3 x 0.33 mg/kg) 15 min, and 6 and 24 h following lesion. The trauma-induced deficit in conditioned freezing can explain the differences in active and passive avoidance behaviours and appears to be specific to lesion of the lateral parietal cortex. In addition, the behavioural deficit can be attenuated using the neuroprotective agent dizocilpine, suggesting that it may prove useful as a sensitive and specific measure of cortical damage following traumatic injury.

Neuroprotective effect of eliprodil: attenuation of a conditioned freezing deficit induced by traumatic injury of the right parietal cortex in the rat.

We have previously demonstrated that a lateral fluid percussion-induced traumatic lesion of the right parietal cortex can lead to a deficit in a conditioned freezing response and that this deficit can be attenuated by both pre- and postlesion administration of the NMDA receptor antagonist dizocilpine. In the present study, we investigated the effects of eliprodil, a noncompetitive NMDA receptor antagonist acting at the polyamine modulatory site, which also acts as a Ca2+ channel blocker, on the trauma-induced conditioned freezing deficit. Eliprodil produced a 50% reduction in this deficit when administered as three 1 mg/kg injections i.v. at 15 min, 6 h, and 24 h following the lesion. Approximately the same degree of protection was afforded when 2 x 1.5 mg/kg were administered 6 and 24 h and equally at 12 and 24 h after surgery (56% and 59%, respectively). A single treatment (3 mg/kg) at 24 h was ineffective against the deficit. The protection afforded with treatment at 6 and 24 h after lesion was dose dependent, with a minimal active dose of 2 x 0.75 mg/kg. These data complement those previously published on the ability of eliprodil to reduce lesion volume following traumatic brain injury and show, in addition, that the neuroprotective effect has functional consequences.

Effects of clozapine on latent inhibition in the rat.

In the present study we have examined the effect of clozapine, an atypical antipsychotic drug, on latent inhibition (LI) using the conditioned emotional response (CER) procedure. In this procedure, ten pre-exposures to the to-be-conditioned stimulus result in weak or no LI whereas 30 pre-exposures produce robust LI. Three different experimental protocols were used to study the effects of clozapine: facilitation of LI in animals subjected to ten pre-exposures to the to-be-conditioned stimulus; antagonism of the disruptive effect of amphetamine (1mg/kg, s.c.) on LI in animals receiving 30 pre-exposures; antagonism of the disruptive effect of nicotine (0.6mg/kg, s.c.) on LI in animals receiving 30 pre-exposures. High doses of clozapine (3 and 10mg/kg, s.c.) disrupted the CER in non pre-exposed animals. Despite this, clozapine significantly facilitated the development of LI at 1 and 10mg/kg and significantly attenuated the disruptive effects of nicotine at 0.3 and 1mg/kg and of amphetamine at 2 and 5mg/kg. These results demonstrate that clozapine is active in the LI model and further support the utility of this model in the study of mechanisms of action of antipsychotic drugs.

Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT2A antagonist.

MDL 100,907 is a potent and selective antagonist of the 5-HT2A receptor which, unlike other antagonists at this receptor, has little affinity for the 5-HT2C receptor. We have investigated the antipsychotic potential of MDL 100,907 by examining its ability to antagonise different behavioural effects of amphetamine in rats. MDL 100,907 reversed the locomotor stimulant effects of amphetamine in rats without itself having any effect on locomotor activity. It also antagonised the disruptive effects of amphetamine on the development of latent inhibition. In contrast, MDL 100,907 had no effect on the discriminative stimulus properties of amphetamine, nor did it affect the ability of amphetamine to reduce the threshold required to sustain rewarding brain stimulation in the ventral tegmental area. This profile is different from that of typical and atypical neuroleptics, and also from other 5-HT2 receptor antagonists, which lack the selectivity of MDL 100,907. These results suggest that MDL 100,907 may have a unique interaction with dopaminergic systems and support the further development of selective 5-HT2 receptor antagonists as a novel therapeutic strategy for schizophrenia.

The effect of 5-HT3 receptor antagonists on the writhing response in mice.

1. The ability of several 5-HT3 receptor antagonists (MDL 72,222EF, the methyl quaternary ammonium salt of MDL 72,222, dolasetron, tropisetron, granisetron and ondansetron) to inhibit writhing induced in the mouse by either 5-hydroxytryptamine (5-HT), acetylcholine or acetic acid was examined. 2. All of the 5-HT3 receptor antagonists were able to inhibit writhing induced by acetylcholine. MDL 72,222EF and tropisetron were also able to inhibit writhing induced by 5-HT and acetic acid but higher doses were required to have the same effect as against acetylcholine. Dolasetron inhibited writhes induced by 5-HT but failed to significantly affect writhes induced by acetic acid. 3. MDL 72,222EF and its quaternary salt were more potent and had a more rapid onset of action after i.p. than after s.c. administration. 4. 2-Methyl-5-HT did not induce writhing at doses up to 4 mg/kg i.p., whereas 5-HT dose-dependently induced writhing over the range 0.5-2 mg/kg. 5. These results show that 5-HT3 receptor antagonists can inhibit writhes induced by a variety of compounds and this appears to be a local action. However, the inability of 2-methyl-5-HT to induce writhing and the high doses of antagonist required indicate that further studies are required to establish a role for 5-HT3 receptors in this effect.

Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein.

The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.

MDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat.

Latent inhibition (LI) is a behavioral model of selective attention that has been used to study the attentional deficits seen in schizophrenia. In the present study, we examined the effect of 5-hydroxytryptamine3 (5-HT3) receptor blockade on LI using the conditioned emotional response (CER) procedure. Prior exposure to 20, 30, or 40 stimulus presentations significantly, and almost completely, inhibited the CER to that stimulus. This LI effect was much weaker when only 10 preexposures were given. 1H-indole-3-carboxylic acid, trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester methanesulfonate (MDL 73,147EF), a selective 5-HT3 receptor antagonist, significantly facilitated the LI effect observed after 10 preexposures at 0.1 mg/kg but not at 0.01 mg/kg. The magnitude of this effect was comparable to that observed with the classical neuroleptic haloperidol (0.1 mg/kg). Neither MDL 73,147EF nor haloperidol affected the CER in animals not preexposed to the stimulus. These results strongly corroborate suggestions that 5-HT3 receptor antagonists will be of use in the treatment of schizophrenia.

The effect of 5-HT3 receptor antagonists on the discriminative stimulus effects of amphetamine.

The discriminative stimulus induced in rats by amphetamine has previously been shown to be due to raised mesolimbic dopamine levels. As 5-HT3 receptor antagonists have been shown to inhibit hyperactivity resulting from raised mesolimbic dopamine levels, the present study examined their effects against the amphetamine discriminative stimulus. None of the 5-HT3 receptor antagonists tested (MDL 72,222EF, 0.3-10 mg/kg s.c.; MDL 73,147EF, 0.3-10 mg/kg s.c.; ICS 205-930, 0.01-10.0 mg/kg s.c.; ondansetron, 0.1-1000 micrograms/kg s.c.) antagonised the effects of amphetamine in this test. This suggests that 5-HT3 receptors cannot modulate the effects of raised mesolimbic dopamine in pathways involved in the interoceptive effects of amphetamine.

Enhancement of working memory performance in the rat by MDL 26,479, a novel compound with activity at the GABAA receptor complex.

MDL 26,479, a novel triazole compound with action at the GABAA receptor complex, was examined in 2 models of working memory deficit in the rat. MDL 26,479 attenuated a scopolamine-induced acquisition deficit in a T-maze reinforced alternation task. MDL 26,479 also reversed a performance deficit induced by increased delay between sample and choice trials in the same task, suggesting that the compound may have memory enhancing potential. This finding further supports claims that drugs acting at the GABAA receptor complex are of potential use in the treatment of memory disorder.

The effect of putative 5-HT1A receptor antagonists on 8-OH-DPAT-induced hypothermia in rats and mice.

The effects of three putative 5-HT1A receptor antagonists (NAN-190, BMY 7378 and WB 4101) were studied on the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In order to control for the alpha 1-adrenoceptor antagonist activity of NAN-190 and WB 4101, the effects of prazosin were also examined. Both NAN-190 and WB 4101 lowered body temperature in the mouse. This effect appeared to be due to their alpha 1-adrenoceptor antagonist effects as prazosin had a similar profile. Neither NAN-190, WB 4101 nor prazosin antagonised the hypothermic effects of 8-OH-DPAT. BMY 7378 slightly lowered body temperature but to a lesser extent than 8-OH-DPAT and, in contrast to the other compounds studied, also prevented a fall in body temperature on injection of 8-OH-DPAT. In the rat there was much less interference from alpha 1-adrenoceptor antagonist activity as both NAN-190 and prazosin only slightly reduced body temperature. In this species, however, NAN-190 showed marked antagonist activity against 8-OH-DPAT hypothermia. This was not due to alpha 1-adrenoceptor antagonist activity as prazosin had no effect. In the rat, as in the mouse, BMY 7378 had a partial agonist profile, whereas WB 4101 behaved essentially as an agonist. These results suggest that NAN-190 is a pure antagonist of 8-OH-DPAT-induced hypothermia in rats and that BMY 7378 and WB 4101 are, respectively, a partial agonist and an agonist in this test.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam.

1. With radioligand binding techniques, MDL 73005 EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-az aspiro[4, 5]decane-7,9-dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (greater than 100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5-hydroxytryptamine (5-HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2. In rats pretreated with reserpine, 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8-OH-DPAT. 3. In rats trained to discriminate 8-OH-DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose-dependently and completely to the 8-OH-DPAT cue. 4. To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus-maze test and in the water-lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water-lick conflict test but opposite effects in the elevated plus-maze. 8-OH-DPAT also had opposite effects in the elevated plus-maze test to MDL 73005EF and diazepam. 5. The anti-conflict effects of MDL 73005EF were reversed by low doses of the 5-HT1A receptor agonist, 8-OH-DPAT; those of buspirone were neither antagonised nor mimicked by 8-OH-DPAT. 6. These results suggest that an interaction with 5-HTIA receptors is the basis of the anxiolytic-like activity of MDL 73005EF. However, its mechanism of action is clearly different from that of buspirone, possibly reflecting a greater selectivity for the 5-HTlA receptors located presynaptically on central 5- hydroxytryptaminergic neurones.

Yawning induced by apomorphine, physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers.

Previous studies have shown that dihydropyridine (DHP) calcium channel blockers can potentiate yawning induced by apomorphine in rats. The present study was undertaken to examine whether or not this interaction was seen with other compounds that induce yawning or if it represented a specific interaction with dopaminergic mechanisms. Yawning induced by apomorphine (40 micrograms/kg SC), physostigmine (50 micrograms/kg SC) or pilocarpine (1 mg/kg SC) was dose-dependently potentiated by the DHP calcium channel blocker nifedipine (1.25-10 mg/kg IP). Nimodipine (1.25-5 mg/kg IP) and nitrendipine (1.25-5 mg/kg IP) also significantly increased the yawning response. The DHP calcium channel blockers alone induced only a low incidence of yawning. The effects of nifedipine on physostigmine-induced yawning were reversed by the DHP calcium channel activator BAY K 8644 which also inhibited yawning induced by physostigmine (100 micrograms/kg SC) and pilocarpine (2 mg/kg SC). In contrast to the DHP compounds, diltiazem (2.5-10 mg/kg IP) and verapamil (2.5-10 mg/kg IP) failed to potentiate yawning. Sulpiride (10 mg/kg SC) antagonised the nifedipine potentiation of apomorphine-induced yawning but not that of physostigmine-induced yawning; atropine (2.5 mg/kg SC) antagonised both effects. These results support the hypothesis that this effect of dihydropyridine compounds is not dependent on, nor mediated through, dopaminergic mechanisms.

The effects of dihydropyridine compounds in behavioural tests of dopaminergic activity.

1. The effects of the dihydropyridine calcium channel blocker nifedipine and the activator Bay K 8644 were investigated in different behavioural tests involving dopaminergic systems. These were the discriminative stimulus induced by amphetamine, rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions and apomorphine-induced yawning in rats. 2. The yawning induced by apomorphine (40 micrograms kg-1 s.c.) was significantly potentiated by nifedipine (5-10 mgkg-1 i.p.). Bay K 8644 (0.05-0.5 mgkg-1 i.p.) dose-dependently inhibited yawning induced by apomorphine (80 micrograms kg-1 s.c.) and, at 0.4 mgkg-1, inhibited the nifedipine potentiation of apomorphine-induced yawning. In contrast to their effects on apomorphine-induced yawning, nifedipine and Bay K 8644 had no effect on apomorphine-induced penile erection. 3. Bay K 8644 (0.06-0.5 mgkg-1 i.p.) and nifedipine (5-20 mgkg-1 i.p.) had no dose-related effect on the discrimination performance of rats trained to discriminate amphetamine from saline. However, nifedipine dose-dependently reduced the response rate of amphetamine-treated rats. Bay K 8644 had no effect on this measure except at high doses that also caused disruption. 4. Neither nifedipine (5-10 mgkg-1 i.p.) nor Bay K 8644 (0.06-0.5 mgkg-1 i.p.) affected the turning behaviour induced by amphetamine (1 mgkg-1 i.p.) in rats with unilateral 6-OHDA lesion of the medial forebrain bundle, and did not induce turning themselves. 5. As the dihydropyridine compounds affected apomorphine-induced yawning but not penile erection, and did not affect amphetamine-induced rotation or drug discrimination, it seems unlikely that they are affecting dopamine release in vivo.

The effect of pre- and postoperative procedures on physostigmine- and apomorphine-induced yawning in rats.

Previous experiments have shown that the potentiation of physostigmine-induced yawning by nifedipine is abolished by sham-lesioning procedures in rats, whereas the nifedipine potentiation of apomorphine-induced yawning is unaffected. The present results demonstrate that either the presurgical drug treatment (desmethylimipramine and pentobarbital) or 7 days isolation was alone sufficient to reduce the yawning response to physostigmine and abolish its potentiation by nifedipine. The sham-lesioned rats responded normally to a combination of apomorphine and nifedipine. These results suggest that the stress associated with standard operative procedures can differentially affect drug interactions with yawning induced by either apomorphine or physostigmine and that caution should be exercised when interpreting results from animals that have been similarly stressed.