Potentiation of the haloperidol-induced blockade of a conditioned avoidance response by alpha-methyltyrosine

The influence of haloperidol and of pretreatment with α-methyltyrosine on a conditioned avoidance response were studied in rats.Haloperidol produced a dose—response-related disruption of avoidance behavior, which was significantly potentiated by α-methyltyrosine. Subsequent administration of Dopa reversed the behavioral impairment.     

Acquisition of conditioned avoidance response in rats under the influence of addicting drugs

Four groups of white rats, aged 8–12 weeks, were treated with morphine, d-lysergic acid diethylamide, dl-amphetamine and ethanol, respectively, while being trained in a conditioned avoidance response (CAR) schedule. Morphine caused deterioration in the acquisition of CAR, as manifested by significant increases in the number of training sessions required for 100% correct CAR and in the reaction time (RT), when compared to those of a control group. The RT decreased after withdrawal of morphine and was associated with a revival of the conditioned emotional responses (CER). LSD and ethanol insignificantly retarded the acquisition of CAR, while withdrawal of LSD caused significant increases in the RT, error and CER. Amphetamine facilitated the acquisition rate associated with increased CER; during withdrawal, the CER was negligible whereas the error increased significantly. In another series of rats, tolerance was seen to morphine and, to a less extent, to ethanol and amphetamine after 8–12 days of continued treatment; whereas the withdrawal effects lasted for 3–4 days only. These effects of the addicting drugs on conditioned learning are discussed in the light of their influence on the emotional responses of the animals and the degree of development of drug-dependence.     

The effect of various antidepressant drugs upon the tetrabenazine-suppressed conditioned avoidance response in rats

Rats were trained in a three-chambered discrimination box to avoid an electric shock which was preceded by the presentation of light. Tetrabenazine, at a subcutaneous dose of 6 mg/kg suppressed this conditioned avoidance response (CAR) without abolishing the unconditioned escape response (UER). The three classes of antidepressant drugs affected differently the tetrabenazine-induced suppression of CAR. The tricyclic antidepressants, imipramine and desmethylimipramine (DMI), did not prevent the suppression of the CAR while the monoamine oxidase (MAO) inhibitors, iproniazid and pargyline did. The stimulant drugs d-amphetamine and methylphenidate, in addition to preventing also reversed the effect of tetrabenazine. The action of two experimental compounds, butriptyline and Lu3-010 was also investigated.The results are discussed in view of a possible relationship between the maintenance of the CAR and the availability of both norepinephrine (NE) and dopamine (DA) in the central nervous system.Abbreviations 5-HT 5-hydroxytryptamine, serotonin - NE norepinephrine - DA dopamine - DMI desmethylimipramine - MAO monoamine oxidase - CAR conditioned avoidance response - UER unconditioned escape response     

Acute effects of morphine and chlorpromazine on the acquisition of shuttle box conditioned avoidance response

Morphine sulfate, 0.25–24.0 mg/kg, or chlorpromazine hydrochloride, 0.0625–4.0 mg/kg, were administered subcutaneously to naive rats 30 min prior to the start of massed-trials conditioned avoidance response (CAR) testing. The graded doses of both drugs were applied in each of three CAR task difficulty levels created by manipulation of the duration of conditioned and unconditioned stimuli, intertrial interval and shock intensity. Chlorpromazine, in a dose-related manner, caused a decrement in CAR acquisition in all tasks. Morphine, in comparison, produced a biphasic dose response. For a given task difficulty, low doses of morphine enhanced acquisition, whereas higher doses inhibited acquisition. With increasing task difficulty, relatively larger doses of morphine were required to inhibit or facilitate acquisition of CAR. These results emphasize the need to consider not only drug dosage levels, but also the interaction of task difficulty in the application of drugs in learning paradigms.     

Effect of aluminum upon conditioned avoidance response acquisition in the absence of neurofibrillary degeneration.

Aluminum induces neurofibrillary degeneration in cats but not rats. Cats develop a progressive encephalopathy in which an early manifestation is impaired learning-memory performance. At brain aluminum concentrations of 5 to 6 times that found in cat, rats demonstrate an initial transient weight loss and acquisition deficit immediately following intracranial injection. However, rats do not develop a progressive encephalopathy or a chronic learning deficit.     

Factors inflencing tolerance to the effects of Δ9-THC on a conditioned avoidance response

Male, Fischer strain rats were resistant to the impairing effects of Δ⁹-THC (15–60 mg/kg, IG) on performance of a conditioned pole-climb avoidance response (CAR) after daily subacute pretreatment for 4 or 6 days. A single administration of 20 mg/kg Δ⁹-THC independent of the performance test did not attenuate the subsequent impairment caused by Δ⁹-THC when tested 1–6 days later; however, administration 2 hr before each test attenuated the effect on subsequent tests given at intervals of 1–5 weeks. Similarly, subacute treatment with 20 mg/kg Δ⁹-THC for 4 days independent of the performance test attenuated the impairment caused by Δ⁹-THC during tests given to separate groups of rats 1 or 6, but not 14 days later. However, when the tests for tolerance were conducted repeatedly in the same rats, the attenuation appeared to persist for intervals up to 5 weeks. The results are discussed in terms of metabolic, functional and compensatory (behavioral) tolerance.     

The effects of fenfluramine and fluoxetine on the acquisition of a conditioned avoidance response in rats

This study tested a behavior-suppressing punishment system and how its activity may be altered by agents known to interrupt or enhance serotonergic (5-HT) transmission. Holtzman male albino rats were tested for shuttle box avoidance acquisition and intertrial responding either 1 or 8 h following daily injections of fenfluramine (FEN) or fluoxetine (FXT). When the drug-test interval was 1 h, a time when both drugs are presumably potentiating 5-HT activity, avoidance acquisition and intertrial responding were impaired. When testing occurred 8 h after drug treatment, a time when 5-HT levels are unaltered by FXT and are maximally reduced by FEN, these drugs had no effect on avoidance acquisition, but FEN produced an increase in intertrial responses whereas FXT did not. These results support the proposal of an inhibitory 5-HT system. Furthermore, these data demonstrate that FEN is capable of exerting a biphasic action on intertrial responding and suggest that the time interval between drug administration and behavioural testing is a crucial variable when investigating FEN.     

Effects of electrical stimulation of the reticular formation and chlorpromazine on performance of trace conditioned avoidance response in the rat

The effects of electrical stimulation to the mesencephalic reticular formation and chlorpromazine on the performance of a trace conditioned avoidance response by rats were studied. Either treatment alone impaired the performance; this impairment was a function of level of stimulation or dose of the drug, respectively. The performance deficit was not present when a high intensity of stimulation of the reticular formation was combined with a moderate dose of chlorpromazine. However, the combination of a high dose of the drug with a low stimulation intensity interfered with the avoidance responding more than any other condition tested. These effects appeared to be independent of neutral or negative reinforcement effects of the stimulation, as tested in an independent situation.     

Effects of (-)3-PPP on acquisition and retention of a conditioned avoidance response in the rat

The administration of (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) was found to partially, but significantly, suppress the acquisition (4–8 mg/kg IP) and performance (8–16 mg/kg IP) of a conditioned avoidance response (CAR) in male Sprague-Dawley rats. All statistically significant effects were observed within 2 h of injection. Furthermore, using a situation in which the CAR was dependent on a visual successive discrimination, it was shown that discriminative performance was unaffected, and that (-)3-PPP (12.5–25 mg/kg IP) but not (+)3-PPP, suppressed the CAR. When (-)3-PPP (6.25 mg/kg IP) was combined with haloperidol (0.1–0.4 mg/kg IP), additive effects on the CAR performance were observed. Considering these effects, and the doses of (-)3-PPP required to suppress the CAR performance, it is concluded that the effects obtained in the present experiments are primarily due to a blockade of postsynaptic DA receptors.     

MAO inhibition and the effects of centrally administered LSD,serotonin, and 5-methoxytryptamine on the conditioned avoidance response in rats

Pretreatment with the MAO-inhibitors iproniazid, clorgyline, or deprenyl abolishes the effects of LSD on the conditioned avoidance response (CAR) in rats. The effects of serotonin (5-HT) and 5-methoxytryptamine (5-MT) are greatly potentiated by these substances. Brain levels of LSD are not affected by MAO inhibition whereas levels of 5-HT and 5-MT are significantly elevated. It is postulated that the decreased behavioral response to LSD is the result of MAO inhibitor-induced changes whereas the increased response of 5-HT and 5-MT results from increased brain levels of these compounds.     

Effects of 5-HT1A receptor agonists,partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat

In the present study, the effects of 5-HT_1A receptor ligands with varying degrees of intrinsic activity at the 5-HT_1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT_1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever pressing. The 5-HT_1A receptor partial agonist, buspirone (0.1–1.0 mg/kg), the 5-HT_1A receptor agonist, 8-OH-DPAT (0.01– 0.10 mg/kg), and the 5-HT_1A receptor antagonist, WAY-100635 (0.03–3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT_1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats. Received: 13 March 1996/Final version: 8 July 1996     

Effect of Atomoxetine on the Cognitive Functions in Treatment of Attention Deficit Hyperactivity Disorder in Children with Congenital Hypothyroidism: A Pilot Study

Background:

With early initiation of thyroxine supplementation, children with congenital hypothyroidism (CH) retain some subtle deficits, such as attention and inhibitory control problems. This study assessed the effects of atomoxetine on cognitive functions in treatment of attention deficit hyperactivity disorder (ADHD) symptoms in children with CH.

Methods:

In a 6-month, open-labeled pilot study, 12 children were recruited and received atomoxetine. The measures of efficacy were scores on the Swanson, Nolan and Pelham Teacher and Parent Rating Scale, version IV (SNAP-IV) and Clinical Global Impression-Severity scale (CGI-S). The cognitive functions were evaluated with the Wechsler Intelligence Scale for Chinese Children, Digit Span, Wisconsin Card Sorting Test, and Stroop test.

Results:

A statistically significant difference was found between the mean CGI-S and SNAP-IV scores before and after treatment (p < 0.01). All the indicators of cognitive functions at the endpoint were improved compared with those at baseline. No serious adverse events were reported.

Conclusion:

Atomoxetine appears to be useful in improving ADHD symptoms, as well as cognitive functions, in children with CH. Larger, randomized, double-blinded, clinical trials are required to replicate these results.     

Effects ofd-fenfluramine and metergoline on responding for conditioned reward and the response potentiating effect of nucleus accumbensd-amphetamine

These studies investigated the effects of the 5-hydroxytryptamine (5-HT) releaser, and re-uptake inhibitor,d-fenfluramine, and the non-selective 5-HT receptor antagonist metergoline, on responding for conditioned reward (CR), and on the potentiation of responding for CR following amphetamine injected into the nucleus accumbens. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase, water was not delivered but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers; responding on the other lever was not reinforced. Overall, rats responded at a higher rate on the lever delivering the CR.d-Amphetamine (1, 3 and 10 µg) injected into the nucleus accumbens dose-dependently enhanced responding on the CR lever. Treatment withd-fenfluramine (0.5 and 1 mg/kg) reduced responding for the CR, and abolished the potentiating effect ofd-amphetamine. Responding on the inactive lever was also reduced by 1 mg/kg but not 0.5 mg/kgd-fenfluramine. The reduction ofd-amphetamine's effect on responding for CR was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Control experiments showed that changes in thirst and motor performance, as well as deficits in learning ability, cannot account for the effects ofd-fenfluramine in this paradigm. In a separate experiment, 1 mg/kg metergoline failed to enhance responding for CR, and to augment the response potentiating effect of a low dose (2 µg) ofd-amphetamine injected into the nucleus accumbens. Thus, elevating brain 5-HT activity appears to reduce the ability of secondary reinforcing stimuli to elicit and maintain behaviour, and antagonizes the effects of enhanced dopamine activity within the nucleus accumbens. However, reduced 5-HT function induced by blockade of 5-HT_1/2 receptors does not appear to influence responding for CR, or the response potentiating effect ofd-amphetamine. These results suggest that 5-HT may play an important role in mediating incentive motivation.     

Physiological disposition of isoergine [from Argyreia nervosa (Burm. f.) Bojer Convolvulaceae] and its effect on the conditioned avoidance response in rats

Physiological disposition of isoergine (d-isolysergamide, iso-LA) obtained from the seeds of Argyreia nervosa (Burm. f.) Bojer were determined in rat liver, brain and plasma. Method of determination involved the extraction of the drug from biological samples and quantitation of the compound by fluorometric analysis. The injection of 5 mg/kg, i.p., of iso-LA resulted after 5 min in peak levels in the liver (7.2 g/g) and after 15 min in peak levels in the brain (1.2 g/g) and plasma (1.9 g/ml). After 120 min, 90% of the compound had disappeared from the tissues and plasma. The minimal dose required to produce a significant decrease in the conditioned avoidance response (CAR) was somewhat less than 5 mg/kg. The minimal brain level which interfered with the CAR was approximately 1 g/g. Brain levels of iso-LA seem to correlate directly with changes in behavior suggesting that iso-LA, and not a metabolite, is the psychoactive agent.     

Effects of a positive allosteric modulator of mGluR5 ADX47273 on conditioned avoidance response and PCP-induced hyperlocomotion in the rat as models for schizophrenia

Metabotropic glutamate receptors of the subtype 5 (mGluR₅) are located in brain regions implicated in schizophrenia such as the cerebral cortex or the nucleus accumbens. They may therefore provide an interesting target for the treatment of psychoses. Currently available agonists of mGluR₅ are not selective, do not penetrate the brain and induce a tonic activation resulting in a rapid desensitization. Therefore, the research focus was shifted to positive allosteric modulators (PAMs). Subsequently several mGluR₅ PAMs have been discovered, e.g. ADX47273 (S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone). In the present study, effects of ADX47273 (1-100 mg/kg) were evaluated in rat models used for detecting antipsychotic-like activity: the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion models. Furthermore, the cataleptogenic potential of ADX47273 was compared to that of haloperidol.ADX47273 (100 mg/kg) and various clinically used neuroleptics (haloperidol, olanzapine, and aripiprazole) attenuated CAR behaviour in rats. However, ADX47273 and aripiprazole failed to reduce the PCP-induced hyperlocomotion, whereas olanzapine and haloperidol diminished it. In contrast to haloperidol, ADX47273 (100 mg/kg) failed to induce consistent catalepsy in rats. In conclusion, ADX47273 shows promising antipsychotic activity in some tests which require future investigation.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) after repeated administration on a conditioned avoidance response (CAR) in the rat

8-OH-DPAT, a selective 5-HT_1A agonist, has variously been found to impair, have no effect on or enhance the conditioned avoidance response (CAR). Procedural differences may account for the difference in results. In the first experiment in the present study rats were trained in the two-way active avoidance procedure to a criterion of 65% avoidance. Separate groups of rats were treated with 0.01, 0.1 or 1.0 mg/kg 8-OH-DPAT SC once per day for 14 days. The rats were tested in the CAR each day 5 min after treatment, using a 10 s light and tone conditioned stimulus and five 0.2 mA/0.5 s electric shocks. On the first day the doses of 0.1 and 1.0 mg/kg impaired avoidance, but by the end of training these two doses increased avoidance. This change in effect was accompanied by a 15-fold increase in the number of trials in which the subject crossed during a 10 s period of the ITI, which in turn led to a significant impairment in the discrimination ratio. The results of this experiment show that with repeated treatment 8-OH-DPAT changes from being antipsychotic like to being stimulant-like. The latter effect produces an improvement in avoidance, probably due to a non-specific increase in activity. In the second experiment, the rats were divided into groups based upon the undrugged performance. The avoidance-enhancing effect of 8-OH-DPAT was greater in magnitude in a group of poor performers, but was qualitatively similar in good performers. In the second stage of the experiment, gradual withdrawal from the drug was compared with sudden withdrawal. In the gradual withdrawal group, a reduction in the dose from 0.085 mg/kg to 0.01 mg/kg resulted in a gradual disappearance of the enhanced activity. There was an almost linear relationship between performance and the log dose of the drug, suggesting that the increase in activity seen after repeated administration of 8-OH-DPAT is directly related to the acute level of drug administered. This effect was evident in both good and poor performers. On the basis of these results it is suggested that many, but not all, antidepressant-like effects of 8-OH-DPAT may result from changes in activity.