Two-way Avoidance Conditioning Research Articles

Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model

Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug-drug interactions. However, the pharmacological and behavioral mechanisms underlying drug-drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug-drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia.

Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning

Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Well-trained Sprague-Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D(2/3) agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT(2A/2C) agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D(2) receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT(2A) receptors. The repeated haloperidol effect may be mediated by 5-HT(2A/2C) blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D(2/3) blockade-initiated neural processes.

Anxiolytic-like property of risperidone and olanzapine as examined in multiple measures of fear in rats

Atypical antipsychotics are also used in the treatment of anxiety-related disorders. Clinical and preclinical evidence regarding their intrinsic anxiolytic efficacy has been mixed. In this study, we examined the potential anxiolytic-like effects of risperidone and olanzapine, and compared them with haloperidol, chlordiazepoxide (a prototype of sedative–anxiolytic drug) or citalopram (a selective serotonin reuptake inhibitor). We used a composite of two-way avoidance conditioning and acoustic startle reflex model and examined the effects of drug treatments during the acquisition phase (Experiment 1) or extinction phase (Experiments 2 and 3) on multiple measures of conditioned and unconditioned fear/anxiety-like responses. In Experiment 4, we further compared risperidone, olanzapine, haloperidol, citalopram and chlordiazepoxide in a standard elevated plus maze test. Results revealed three distinct anxiolytic-like profiles associated with risperidone, olanzapine and chlordiazepoxide. Risperidone, especially at 1.0 mg/kg, significantly decreased the number of avoidance responses, 22 kHz ultrasonic vocalization, avoidance conditioning-induced hyperthermia and startle reactivity, but did not affect defecations or time spent on the open arms. Olanzapine (2.0 mg/kg, sc) significantly decreased the number of avoidance responses, 22 kHz vocalization and amount of defecations, but it did not inhibit startle reactivity and time spent on the open arms. Chlordiazepoxide (10 mg/kg, ip) significantly decreased the number of 22 kHz vocalization, avoidance conditioning-induced hyperthermia and amount of defecations, and increased time spent on the open arms, but did not decrease avoidance responses or startle reactivity. Haloperidol and citalopram did not display any anxiolytic-like property in these tests. The results highlight the importance of using multiple measures of fear-related responses to delineate behavioral profiles of psychotherapeutic drugs.

1-(Benzofuran-2-yl)-2-(3,3,3-trifluoropropyl)aminopentane HCl, 3-F-BPAP, antagonizes the enhancer effect of (−)-BPAP in the shuttle box and leaves the effect of (−)-deprenyl unchanged

The subcutaneous administration of 1 mg/kg tetrabenazine, once daily for 5 days, which depletes the catecholamine stores in the brain, significantly inhibits in rats the acquisition of a two-way conditioned avoidance reflex in the shuttle box. Enhancer substances, the tryptamine-derived selective and highly potent enhancer, R-(−)-1-(benzofuran-2-yl)-2-propylaminopentane HCl [(−)-BPAP] (0.05–10 mg/kg), the β-phenylethylamine (PEA)-derived enhancer, (−)-deprenyl (1–5 mg/kg) and the (−)-deprenyl analogue, free of MAO-B inhibitory potency, (−)-1-phenyl-2-propylaminopentane HCl [(−)-PPAP], (1–5 mg/kg), antagonize in a dose-dependent manner the inhibition of learning caused by tetrabenazine. 1-(Benzofuran 2 yl)-2-(3,3,3-trifluoropropyl)aminopentane HCl [3 F BPAP], a newly synthetized analogue of (−)-BPAP with low specific activity, significantly antagonized the enhancer effect of (−)-BPAP but left the effect of (−)-deprenyl and (−)-PPAP unchanged. This is the first proof for a difference in the mechanism of action between a PEA-derived enhancer substance and its tryptamine-derived peer.

A new computer-assisted two-way avoidance conditioning equipment for rats: Behavioral and pharmacological validation

A new PC-controlled two-way avoidance conditioning equipment for rats is described. The position of the rat within the two-compartment shuttle-box is monitored by means of 4 + 4 horizontal photocell beams. Experimental conditions and procedures, such as CS-UCS interval, photocell operations, shock strength, and so on, can conveniently be preset by the experimenter. The successful operation of the shuttle-box is evidenced by rapid and efficient acquisition of the avoidance behavior, and approximately 100% median avoidance performance was obtained within 5 successive days of training (20–25 trials per day). In a separate experiment, different groups of rats received avoidance training (0–5 sessions) at 8 weeks of age, and a retention avoidance performance was weak ( r = 0.33, NS), and performance during the acquisition process appears to be a poor predictor of final performance. As expected, a number of dopamine (DA) receptor blocking agents (DA D 1 and/or D 2 selective) produced a selective suppression of the avoidance behavior, that is, the suppression of avoidance responding was matched by a corresponding increase in escape responding (with no escape failures).

Roman strains as a psychogenetic model for the study of working memory: Behavioral and biochemical data

Performances of male rats of the Roman High- (RHA), Roman Control- (RCA) and Roman Low- (RLA) Avoidance strains were compared in two working memory tests, a spatial one, the radial maze, and a nonspatial one, an object recognition test. The same rats were subjected to measures of emotional reactivity and of different forms of motoractivity and finally to measures of cholinergic and aminergic activities in the hippocampus, frontal cortex and striatum. Compared to RHA, RLA performed better in the two working memory tests, displayed “anxiety” and had also lower levels of exploratory locomotor activity. Hippocampal ChAT activity was higher in RLA than in RHA. Levels of DA and DOPAC in the striatum were higher in RLA compared to RHA, whereas in the frontal cortex they were lower. For most of these measures, RCA were intermediate between RLA and RHA. These results confirm and extend the finding that the Roman strains are not only a genetic model for two-way avoidance conditioning but also for working memory.

The effect of LHRH on rat conditioned avoidance behavior: Interaction with brain catecholamines

LHRH (100 micrograms/kg. SC) impairs the acquisition of two-way avoidance conditioning. This is partially potentiated by pretreatment with alpha-methyltyrosine (alpha-MT; 250 mg/kg IP) or fusaric acid (10 mg/kg IP). L-DOPA (100 mg/kg IP) administered 5 h after alpha-MT partially reversed its effects. The possible roles of brain catecholamines on the behavioral effects of LHRH are analysed. Other tentative mechanisms of action are also discussed.

Effect of combined or separate administration of piracetam and choline on learning and memory in the rat.

Different groups of rats received combined or separate administration of different doses of piracetam (P1:100, P2:200, and P4:400 mg/kg) and choline (C1:100 and C2:200 mg/kg). Compared to control treatment, C1 significantly improved performance in a delayed alternation (DA) task, while P1, P2, P4 or P1C1 had no effect. Moreover, rats receiving P2C1 and P4C1 were significantly inferior in acquiring DA to rats receiving the vehicle or separate administration of P1, P2 or C1. The different treatments with combined or separate administration of P and C had no effect on spontaneous locomotor activity and two-way avoidance conditioning. In a recognition-task only groups C1 and P4 were able to discriminate between familiar and new objects. The combined or separate administration of P1 and C1 on NA, DA, DOPAC, 5-HT, 5-HIAA levels, CAT activity and choline uptake were measured in frontal cortex and hippocampus: the only significant effect was a 5-HT increase in the hippocampus of rats treated with C1.

Repeated testing of rats markedly enhances the duration of effects induced by haloperidol on treadmill locomotion, catalepsy, and a conditioned avoidance response

In the present experiments we have investigated the duration of haloperidol-induced effects in rats tested repeatedly, and in rats tested on a single occasion after drug administration. The behavioral test situations used include treadmill locomotion (speed 4 m/min), inclined grid catalepsy, two-way conditioned avoidance behavior and open field spontaneous locomotor activity. It was found that the duration of haloperidol-induced effects on treadmill locomotion, spontaneous locomotor activity, catalepsy and a conditioned avoidance response (doses: 0.32, 0.32, 1.25 and 0.2 mg/kg IP, respectively) was about 2 hr or less in animals observed once only (“independent procedure”). With the possible exception for locomotor activity, the duration of haloperidol-induced effects was considerably prolonged, up to 8 hr depending on the test situation, in animals observed repeatedly after the administration of haloperidol in the same doses (“dependent procedure”). The enhanced duration by the dependent procedure is probably not caused by handling stress since the enhanced duration of haloperidol-induced effects in some of the behavioral tests were only noted in animals tested repeatedly in one particular test, and not in animals given the repeated pretests in another situation. Furthermore, it was not possible to relate the enhanced duration of haloperidol-induced effects by repeated testing to changes in striatal DA metabolism as evaluated by measurements of DOPAC, HVA and DA. It was found that the treadmill test 2–4 hr after haloperidol (0.12–0.32 mg/kg IP), at certain doses and time intervals produced an increase in DA turnover [(DOPAC + HVA)/DA], but this increase was the same in both procedures (dependent and independent). Our findings that the time-course of action of haloperidol is dependent on the test procedures used may be of importance when interpreting interaction studies and the relationship between pharmacokinetics and behavioral effects of this, and possible other, psychotropic drugs.

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amtiriptyline, (−) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.

Brain octopamine and strain differences in avoidance behavior

According to recent research, a significant relationship seems to exist between brain contents of p-octopamine and two-way avoidance responding in rats. Levels of this amine in hypothalamus and brainstem are higher in rats from the Roman High Avoidance (RHA) strain than in rats from the Roman Low Avoidance (RLA) strain. Intracerebroventricular administration of p-octopamine facilitates avoidance responding. The present paper reports the behavioral and neurochemical effects of p-octopamine administration on rats from the Roman strains. This treatment has no significant effect on cerebral levels of catecholamines, but it temporarily suppresses the strain differences in p-octopamine levels. In parallel, it also suppresses the strain differences in two-way avoidance conditioning, its facilitatory effect being much greater in RLA than in RHA rats. Avoidance behavior appears to be a useful model for the study of octopamine functions in the mammalian brain.

Hyponeophagia in the Roman rat strains: Effects of 5-methoxy-N,N-dimethyltryptamine, diazepam, methysergide and the stereoisomers of propranolol

The effects of 5-MeODMT (2.5 mg/kg), diazepam (1 mg/kg), methysergide and the stereoisomers of propranolol (6 mg/kg) on hyponeophagia were studied in both sexes of the Roman strains of rats, selectively bred for acquisition of a two-way conditioned avoidance response. Diazepam, methysergide and 1-propranolol increased feeding in a novel environment whilst 5-MeODMT decreased it and d-propranolol was inactive. Several strain differences in drug responsiveness occurred, the Roman Low Avoidance subjects being most sensitive to all drugs tested as well as being most neophobic. A sex difference in 5-MeODMT sensitivity was also found, female rats of the Roman High and Control Avoidance strains being more sensitive than males. The findings are discussed in connection with differences in arousal and biochemical parameters between these strains.

An association between granule cell density in the dentate gyrus and two-way avoidance conditioning in the house mouse.

Mice with genetically associated variations in the number and density of granule cells in the dentate gyrus were tested for open-field activity, spatial maze learning, and two-way avoidance conditioning. The number of granule cells was not associated with any behavior measured. Only avoidance conditioning was related to granule cell density, which had a negative correlation with performance on the shuttle box task. This result was replicated in two genetically different stocks of mice. Density of the more caudal portion of the dentate was associated with early stages of avoidance learning, whereas the more rostral portion was associated with later stages. The results are discussed in relation to theories of functional dissociation within the hippocampus.

An association between granule cell density in the dentate gyrus and two-way avoidance conditioning in the house mouse.

An association between granule cell density in the dentate gyrus and two-way avoidance conditioning in the house mouse.

TRH on rat conditioned avoidance behavior: Interaction with brain catecholamines

TRH (10 μg) intracerebroventricularly injected improves the acquisition of a two-way avoidance conditioning. This effect is partially antagonized by pretreatment IP with α-methyltyrosine (60 mg/kg) or disulfiram (300 mg/kg). L-DOPA (100 mg/kg) administered IP 2 hr after α-MT partially restores the facilitatory effect of the hormone. The possible roles of brain catecholamines on the behavioral effect of TRH are analysed. Other tentative mechanisms of action are also discussed.

Effects of diazepam-infrasounds combination on locomotor activity and avoidance behavior of rats

The locomotor activity, the two-way conditioned avoidance response, the norepinephrine and dopamine brain levels, were simultaneously studied in rats, under the influence of Diazepam alone or in combination with infrasound environment. Diazepam decreased the spontaneous activity and facilitated the retention of an avoidance behaviour of rats subjected to four shuttle box sessions. These effects were reversed when Diazepam was administered to rats exposed to infrasound environment. The norepinephrine and dopamine levels, determined in whole brain homogenate, were slightly affected in both cases.

Implication of the estrous cycle on conditioned avoidance behavior in the rat

The two-way conditioned avoidance response, serum estradiol, food daily consumption, water intake and urine output were simultaneously studied in rats during the various stages of the estrous cycle. Rats in proestrus exhibited: (a) a significant facilitation of conditioned avoidance response in relation to the intervening stages of the cycle (diestrus and estrus), (b) a highly significant rise in serum estradiol concentration, and (c) a significant depression in food intake and urine output. An impairment of conditioned avoidance response occurred at diestrus when compared with metestrous rats and castrated rats. Rats in metestrus exhibited a significant decrease of serum estradiol concentrations. The rise in serum estradiol at proestrus suggests a negative control upon food intake, a decrease in urine output and involvement in the facilitation of conditioned avoidance response.

Effect of septal lesions, required response, and shock on the acquisition of a two-way conditioned avoidance response in rats

Normal albino rats and rats with septal lesions were trained to a criterion of 9/10 avoidance responses in a two-way conditioned avoidance response (CAR) task. The animals were required to run through a doorway or climb over a hurdle, and were motivated by continuous shock or intermittent shock. The subjects showed facilitated acquisition of the CAR if they sustained a septal lesion and/or were trained in the hurdle condition. The type of shock had no effect on learning. Lesioned subjects made more intertrial responses than normals. It is suggested that rats with septal lesions learn faster because they are more fearful, and that response requirement is an important variable in shuttlebox avoidance conditioning.

Open field activity and avoidance behavior following serotonin depletion: A comparison of the effects of parachlorophenylalanine and electrolytic midbrain raphe lesions

Three experiments were performed in order to compare the behavioral effects of electrolytic destruction of the dorsal and median mesencephalic raphe nuclei (MR lesion) and parachlorophenylalanine (pCPA; 300 mg/kg, IP) administration. Forebrain 5-hydroxytryptamine (5-HT) was measured in all animals following completion of behavioral testing. In the first experiment open field behavior (one 50 min session) and two-way (shuttle) conditioned avoidance acquisition (50 massed trials) were examined 68–72 hr after vehicle or pCPA administration in rats which had received control operations or MR lesions two weeks earlier. Only the MR lesion and the MR lesion + pCPA groups evidenced increased open field activity and facilitated two-way avoidance learning. Although the reduction in forebrain 5-HT of the pCPA group (85%) was greater than in the MR lesion group (55%), the pCPA treated animals did not differ from the control group. In the second experiment animals were tested in the open field 24, 48 or 72 hr after pCPA treatment to determine its effects on activity level as a function of the time after injection. No differences between the vehicle and pCPA groups, however, were found. In the third experiment, the effects of pCPA (72 hr postinjection) on the acquisition of an unsignalled one-way avoidance response was examined. MR lesion rats tested in the same apparatus and with the same procedure repeatedly have been shown to be impaired in this task. The pCPA and vehicle animals, however, did not differ. Reductions in 5-HT following electrolytic MR lesions and pCPA administration, thus, produce different behavioral effects. MR lesions, but not pCPA treatment, result in (1) increased activity in a novel environment, (2) facilitated two-way conditioned avoidance learning, and (3) impaired acquisition of an unsignalled one-way avoidance response. These data support earlier studies suggesting that the behavioral effects of electrolytic MR lesions are not due primarily to their disruption of ascending 5-HT pathways. The role of 5-HT in avoidance conditioning and the regulation of activity level, furthermore, remains to be elucidated.

Avoidance conditioning and Hebb-Williams maze performance in rats treated prenatally with alcohol.

Throughout gestation pregnant Wistar rats consumed a nutritious liquid diet containing 35% ethanol-derived calories. Control mothers were fed lab chow. Subsequently, the offspring of the ethanol-fed mothers were found to be impaired on two-way avoidance conditioning when compared to control offspring, but did not differ from controls in their performance on the Hebb-Williams maze. Fostering and cross-fostering procedures indicated that the effect was due to prenatal influences arising from the drug treatment.