Conditioned Avoidance Behavior Research Articles

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.

Plasma concentrations of alpha-melanotropin in the rat during the acquisition and extinction of conditioned avoidance behaviour and during the acquisition of maze learning behaviour.

Concentrations of immunoassayable alpha-melanotropin in plasma were increased above control levels during the acquisition of conditioned avoidance behaviour but not during the extinction of this behaviour. There were no significant variations in levels of alpha-melanotropin in plasma during the acquisition of reward motivated maze learning behaviour. Throughout the latter test hormone concentrations were increased above normal levels. Non-specific stress was thought to be an important factor in the production of increases in concentrations of alpha-melanotropin in plasma. Acute physical stress, such as that caused by the electric foot shock of the avoidance studies, produced the greatest increases, while the smaller increase noted during maze learning was attributed to the stress of the chronic food deprivation schedule used in this test. The data did not support a role for systemic melanotropin in the processes of learning and memory as there were no consistent correlations between levels of alpha-melanotropin in plasma and the parameters of learning in the tests. Although a role for stress-induced alpha-melanotropin release from the pituitary gland in the enhancement of attention was thought possible, actions of exogenous melanotropins on behaviour could be due to effects on melanotropin-containing systems present within the central nervous system.

Effects of acute lithium administration on conditioned avoidance behavior and monoamine synthesis in rats.

The effect of a single injection of various doses of lithium chloride was tested on conditioned avoidance behavior and on the accumulation of DOPA and 5-HTP after inhibition of aromatic amino acid decarboxylase. Lithium specifically suppressed conditioned avoidance behavior and reduced formation of DOPA, but not 5-HTP. The behavioral effect of lithium could be completely antagonized with additional L-DOPA treatment. The results indicate that lithium has a neuroleptlike effect on avoidance behavior, and it is suggested that some of the behavioral effects of lithium may be mediated via interference with central catecholaminergic mechanisms.

Interaction among scopolamine, conditioned stimulus modality, genotype, and either-way avoidance behavior of rats.

Effects of scopolamine were investigated on either-way avoidance in three genetic lines under auditory and visual conditioned stimuli (CS). In the either-way task, the animal has the option to respond in either of the two directions available. In the genetic line selected for high-avoidance the effects of scopolamine were similar with both auditory and visual CS modes. In the genetic line selected for low-avoidance, and in the genetically heterogeneous line, the effects of the drug were different between the auditory and visual CS. It is suggested that scopolamine is more likely to disrupt responsiveness to visual stimuli, which have become less effective in the low-avoidance line during the course of genetic selection.

Disruption of taste aversion learning by pretreatment with diazepam and morphine

Laboratory rats were pretreated with either morphine (9 mg/kg IP), diazepam (4 mg/kg IP) or Ringer's solution 2, 3 1 2 , and 2 hr, respectively, prior to ingestion of a novel tasting saccharin solution followed immediately by a single injection of one of these agents. Animals pretreated with Ringer's solution followed by an injection of either morphine or diazepam showed a conditioned taste aversion (CTA) as determined by a significant reduction in the mean saccharin intake on a subsequent test trial. Although the drug pretreatments alone produced no conditioned avoidance behavior, the diazepam pretreatment completely blocked the developement of both diazepam and morphine-evoked CTAs while the morphine pretreatment prevented a CTA induced by itself but not by diazepam. The results were discussed in terms of the attenuating effects of the pretreatments on the relative saliency of the subsequent conditioning drug injection.

Some aspects of the psychopharmacological activity of maprotiline (Ludiomil): effects of single and repeated treatments.

Three different aspects of the psychopharmacological activity of the antidepressant maprotiline were investigated: its influence on serotoninergic functions the effects produced by chronic treatment its central nervous depressant and anxiolytic properties. Study of the effects of maprotiline on 5-HTP-induced head-twitch in mice pre-treated with pargyline or on hyperpyrexia in rats provided no evidence that the drug interferes with serotonin-mediated functions in the central nervous system even after quite high doses. These findings corroborate the results of extensive neurobiochemical investigations, which failed to demonstrate any influence of maprotiline on the metabolism of serotonin. Chronic studies showed that classical effects of maprotiline such as antagonism against reserpine-induced ptosis or tetrabenazine-induced catalepsy do not change in their intensity after daily administration of the drugs in a dose of 30 mg/kg p.o.for 11 days. A new component of the action of the compound, not detectable after one single dose, seems to appear, however, after repeated treatment (8 days). This effect is manifested in the restoration of conditioned avoidance behaviour after its suppression by pre-treatment with reserpine. The same effect is produced by imipramine. It is suggested that this restorative effect may be due to an additional activation of the dopaminergic nervous system and may have a bearing on the appearance of clinical antidepressant effects. Maprotiline was found to potentiate central nervous depressant effects of drugs like chlorpromazine, phenobarbitone and propranolol. This affords further confirmation that, in addition to its antidepressant qualities, it possesses sedative actions. An anxiolytic component was also demonstrated in rats in which maprotiline suppressed the conditioned, fear-induced rise in body-temperature.

Effects of systemic and intracerebral administration of adrenergic receptor blocking drugs on the conditioned avoidance behavior and maze learning in rats

(1) Effects of α- and β-adrenergic receptor blocking drugs, given systemically or intracerebrally into the brainstem, were studied on the acquisition, retention and extinction of conditioned avoidance behavior. (2) The systemic administration of β-adrenergic receptor blockers, Trasicor and GYKI 41099, led to a marked suppression of the acquisition of a two-way avoidance response but did not modify the retention or the extinction of the avoidance response. (3) Injection of GYKI 41099 into the brainstem reticular formation resulted in a decrease in the acquisition of the conditioned avoidance response. (4) The same treatment with an α-adrenergic receptor blocker, phenoxybenzamine, failed to influence the acquisition of the conditioned avoidance response. (5) These observations led to the conclusion that β-adrenergic receptors are involved in modulating the acquisition of a conditioned response although they do not play a significant role in the retention or the extinction processes.

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.

Neurotoxicity of adriamycin (Doxorubicin) perfused through the cerebrospinal fluid spaces of the rhesus monkey

Adriamycin (Doxorubicin) was perfused through the ventriculo-cisternal (VC) and ventriculo-lumbar (VL) spaces of Rhesus monkeys at inflow concentrations ranging from 1.5 to 100 μg/ml at an average inflow rate of 128 μl/min for 190 min. Animals died or became moribund within 10 days following perfusion of Adriamycin within the range of inflow concentrations of 6.0 to 100 μg/ml. General neurotoxicity consisted of general body weakness, tremors, severe to slight hypokinesia (especially of the hindlimbs), and signs of excitation, nervousness, or depression after a perfusion. Other adverse responses were a significant decrease in water and food intake, mydriasis, and loss of the wink reflex in one or both eyes. With the exception of isolated instances, only trasient minor changes occurred in heart rate and rhythm, respiratory rate, body temperature, cortical EEG, opening ventricular pressure, CSF formation rate, and inulin clearance. Conditioned avoidance behavior was not significantly affected in otherwise normal animals; although, at times, motor deficits of the arms may have interfered with performance. In the brains of three monkeys perfused at 100, 12.5, or 6.0 μg/ml, there was a distinctive necrotizing angiopathy that was noninflammatory and for which it is difficult to find an exact parallel in human pathology. In view of the particular findings shown in this study, it is not recommended that this drug be administered intrathecally in man.

Some behavioral effects of suppressing choline transport by cerebroventricular injection of hemicholinium-3

Evidence supports the proposition that the high affinity Ch uptake system associated with cholinergic nerve terminals can be the rate limiting step in the synthesis of the neurotransmitter, acetylcholine. The present experiment was designed to test the hypothesis that variations of the system would be reflected selectively in changes of conditioned avoidance behavior. HC-3, which primarily affects the high affinity component of Ch transport thus reducing endogenous levels of ACh and the synthetic capacity of cholinergic nerve terminals, was administered cerebroventricularly at 5 doses ranging from 0.0 (saline control) to 10.0 μg. Whole brain ACh levels determined by GCMS analysis following microwave fixation ranged from 25.0 to 5.0 nmol/g −1. Trend analysis demonstrate a precise dose dependent relation between neurochemical and behavioral variables: median trials to condition increased as ACh level decreased. More detailed analyses of the results lead to the interpretation that suppression of high affinity Ch transport in brain is associated with deficiencies in the use of information and not with sensory input and storage nor with motor output.

Disruption of conditioned avoidance behavior by N, N-dimethyltryptamine (DMT) and stereotype by β-phenylethylamine (PEA): Animal models of attentional defects in schizophrenia

Disruption of conditioned avoidance behavior by N, N-dimethyltryptamine (DMT) and stereotype by β-phenylethylamine (PEA): Animal models of attentional defects in schizophrenia

Baclofen-induced modification of conditioned discriminative avoidance behaviour and contraversive turning in the rat

The effects of baclofen, a γ-aminobutyric acid derivative, on conditioned avoidance behaviour and on the turning produced by unilateral 6-OHDA lesions of the s. nigra were investigated in rats. The small impairment of conditioned avoidance behaviour induced by baclofen (1–4 mg/kg i.p.) was potentiated by combination with benztropine, an anticholinergic agent. Moreover, baclofen reversed the suppression of avoidance responses and the inhibition of turning induced by physostigmine, suggesting an interaction of baclofen with cholinergic transmission processes at the nigrostriatal level. After α-methyltyrosine, baclofen like haloperidol, produced a marked increase in avoidance response failures suggesting an additional inhibitory effect of the compound on dopaminergic transmission. The pattern of results indicates that baclofen affects the feedback-loop regulation processes in the nigrostriatal area of the brain.

Antagonism by locally applied dopamine into the nucleus accumbens or the corpus striatum of alpha-methyltyrosine-induced disruption of conditioned avoidance behaviour.

Male Sprague-Dawley rats were trained to avoid an electric shock in a two-way shuttle-box. The local application of dopamine into the nucleus accumbens or the corpus striatum was found to antagonize the suppression of conditioned avoidance behaviour induced by systemically administered alpha-methyltyrosine, emphasizing the importance of these dopamine-rich brain structures in mediating conditioned avoidance behaviour.

Limbic-midbrain lesions and acth-induced excessive grooming

The induction of excessive grooming by intraventricular administration of ACTH 1–24 was studied in rats with lesions in midbrain-limbic structures. Such areas have been reported to be implicated in mediating ACTH-induced effects on avoidance behavior, sexual excitement or stretching and yawning. Electrolytic lesions in the septal complex, the anterior hypothalamic/preoptic area, the mammillary bodies, the amygdala, the posterior thalamus and dorsal or ventral hippocampus did not interfere with ACTH-induced excessive grooming. Lesioning of the hippocampal complex by aspiration led to an inhibition of excessive grooming depending on the degree of hippocampal damage. Amygdala and hippocampal lesions enhanced the display of stretching and yawning activity after treatment with the peptide. The data indicate differences in the neural substrates mediating the effect of ACTH on extinction of conditioned avoidance behavior, excessive grooming, sexual excitement and stretching and yawning.

The effects of behaviorally relevant doses of chlorpromazine and molindone on cardiac adenylate cyclase and on myocardial contractility

Doses of chlorpromazine and of molindone that inhibit conditioned avoidance behavior of rats were tested for their abilities to inhibit cardiac adenylate cyclase. In untreated rats, basal levels of enzyme activity were 201 pinole c-AMP mg −1 5 min −1. Pretreatment of rats either acutely (30–100 min) or chronically (7 days) with either chlorpromazine or molindone (both 10 mg/kg, i.p.) did not alter basal levels of cardiac adenylate cyclase. In vitro, both drugs inhibited the enzyme at concentrations greater than 10 −4M. At concentrations below 10 −4M, neither drug appreciably inhibited basal levels or β-agonist-induced changes in cardiac adenylate cyclase. In related experiments, pithed rats were treated with various doses of chlorpromazine or molindone. Neither drug, at behaviorally relevant doses, depressed cardiac contractility or inhibited β-agonist-induced changes in contractility. At toxic doses, both drugs tended to depress contractility.

Esters of 4-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]-1-piperazieneethanol and related compounds as long-acting antipsychotic agents. Synthesis of the 1-adamantoate, the first crystalline base.

A number of new esters of fluphenazine are described: among these was the 1-adamantoate, 1h, the first highly crystalline ester of that drug. The 1-adamantoate of pipotiazine, 2b, typically, was an oil. Following a single subcutaneous or intramuscular injection of 25 mg/kg of either 1h or 2b, dissolved in sesame oil, each ester was found to be a potent and long-acting inhibitor of conditioned avoidance behavior in the rat.

Effect of brocresine on conditioned avoidance behavior in mice.

Brocresine, an inhibitor of brain histamine biosynthesis, has been found to impair the ability of mice to avoid shock in a shuttle box CAR test; escape performance was unaffected in these studies.

The effect of mepiprazole on central monoamine neurons. Evidence for increased 5-hydroxytryptamine and dopamine receptor activity

In combined biochemical, histochemical and functional studies on central monoamine neurons it has been shown that a pyrozolyl derivative with a phenyl piperazine side-chain (PAP) exerts marked effects on central dopamine (DA) and particularly 5-hydroxytryptamine (5-HT) neurons. The brain 5-HT turnover was reduced with doses down to 0.25 mg/kg, and spontaneous overflow of radioactivity from 3H-5-HT-labelled cortical slices was markedly increased by PAP in a concentration of 10 −6 M. PAP may therefore cause extragranular release of 5-HT stores, since the 5-HT levels were not affected. In agreement with this view, sexual behaviour in the female rat, which is controlled by an inhibitory 5-HT pathway, was inhibited by low doses (0.1–0.5 mg/kg) of PAP. The extensor hindlimb reflex, which is dependent of 5-HT receptor activity, was only increased with higher doses (2.5–10 mg/kg), suggesting that the spinal 5-HT nerve terminals are less sensitive to the releasing action of PAP. A certain direct activation of spinal 5-HT receptors may also be involved, since the actions of PAP in the spinal cord were independent of presynaptic 5-HT stores. The actions of PAP on the DA neurons mainly involve a presynaptic action in the DA nerve terminals leading to increased DA receptor activity. This action may primarily involve a blockade of DA uptake (50% inhibition at 10 −6 M) and/or an extragranular release of DA (two-fold increase in spontaneous overflow at 10 −6 M). The DA turnover was not clearly affected, although a trend to a reduction was observed especially in the nuc. accumbens, probably as a result of a compensatory nervous feedback reducing nervous impulse flow. In agreement with the view mentioned above, PAP mimics amphetamine and not apomorphine in the rotometer model which reveals changes in DA receptor activity. PAP in doses of 0.5–1 mg/kg causes a turning towards the denervated side. The brain noradrenaline (NA) turnover is only significantly increased with somewhat higher doses (5–10 mg/kg) and may be related ot NA receptor blockade, since the L-DOPA-induced increase in flexor activity is blocked by PAP in doses down to 0.5 mg/kg. It is suggested that the extragranular release of 5-HT caused by PAP is partly responsible for the inhibition of conditioned avoidance behaviour and the reduction of threatening behaviour found after PAP in low doses (0.05–0.5 mg/kg). In the clinic, PAP may prove to be a new therapeutic tool in the treatment of depressions due to 5-HT deficiency. Its actions on DA terminals may also prove helpful in this respect. When combined with L-DOPA, PAP may also help to alleviate the motor deficits in parkinsonian patients with a moderate degree of degeneration of the DA system in view of its action on DA uptake and/or release.

Conditioned avoidance behavior in pretrained rats intermittently treated with addictive drugs

Rats pretrained in a conditioned avoidance (CAR) paradigm were put on eight potentially addictive drugs in drinking water at two dose levels each. Fluid intake and body weight, monitored during the drugged (addiction) and nondrugged (withdrawal) states, showed drug/dose-dependent fluctuations in most groups. Extinction and relearning trials were spread over both drug and nondrug phases. CAR-performance generally deteriorated in the early drug phase but improved to near normalcy during the late drug and withdrawal phases in all groups except for alcohol and barbiturate-treated ones. Excluding amphetamine, low-dose morphine and phenobarbital groups, substantial extinction of CAR occurred during the drug phase only; these three groups, as well as the high-dose alcohol, barbiturates and medazepam ones, showed extinction during the nondrug phase also. The rate and extent of a second-order relearning neither differed significantly between the groups nor was truly contingent upon prior extinction. These results are discussed in the light of state-dependent learning, comparing them with those from another series of rats primarily trained under the influence of these addictive drugs.

Modification of avoidance behavior in 6-hydroxydopamine-treated rats by stimulation of central noradrenergic and dopaminergic receptors

Rats showing reliable decrements in conditioned avoidance behavior after the intraventricular administration of 6-hydroxydopamine (6-HD) with pargyline pretreatment were given various dopaminergic and noradrenergic agonists. Intraventricular injections of DA or L-NE or intraperitoneal injections of apomorphine or L-DOPA reversed the avoidance decrements, often restoring performance to pre-6-HD-treatment levels. Furthermore, these agonists all produced behavior characteristic of activity in dopaminergic neurons. Clonidine, a noradrenergic agonist, also reversed avoidance decrements, but did not produce behavior characteristic of stimulation of dopaminergic neurons in the brain. Pretreatment with spiroperidol, a dopaminergic receptor blocker, prevented the recovery induced by all agonists, although clonidine-induced recovery was affected least. The results are discussed in terms of possible separate roles for dopaminergic and noradrenergic neurons in the brain in avoidance behavior.