Behavioral stereotypes

Somatostatin is a 14-amino acid peptide that induces arousal and behavioral stereotypes resembling OCD [Pitman 1989). Somatostatin is synthesized in disparate regions, including the paraventricular nucleus of the hypothalamus, the cerebral cortex, striatum, and hippocampus. When administered centrally, somatostatin delays extinction of avoidant behaviors [Vecsei and Widerlov 1988). Altemus and colleagues [1993) determined CSF somato-... 

Of 55 individuals with cocaine dependence, 53% reported transient cocaine-induced psychotic symptoms (179). Paranoid delusions (related to drug use) and auditory hallucinations were often reported. In addition, almost one-third (all of whom also described psychotic symptoms) reported transient behavioral stereotypes. 

The problem of behavioral stereotypes emphasizs the need for the designer to ensure that systems fit the users or operators mentally. Systems must also fit the users or operators physically. These objectives are the focus of human engineering or ergonomics. 

Give two examples of natural behavioral stereotypes and three examples of learned stereotypes. 

Rule-based behavior Stereotype fixation (cue not defining) Recall ineffective (omission of isolated acts, mistakes among alternatives)... 

It can be seen that the various boxes in the flowchart can be associated with different stages of the stepladder model. For example, the first box on the left corresponds to skill-based behavior and its associated internal failure mechanisms. The second box illustrates the situation (Stereotype Fixation) where the worker erroneously does not change to a rule-based mode when encountering an unusual situation in the skill-based mode (see also the discussion of the GEMS model in Section 2.6.3). 

The most consistent and potent antagonism of amphetamine effects on increased motor activity and stereotyped movements is obtained with antagonists at dopamine receptors of the D2 subtype (Creese et al. 1982). This is not the case with amphetamine s disruptive effects on social and aggressive behavior. So far, no antagonists have been identified that reverse amphetamine s disruption of sexual, play, maternal, or aggressive behavior. 

Randrup, A., and Munkvad, I. Pharmaeologieal studies on the brain mechanisms underlying two forms of behavioral excitation Stereotyped hyperactivity and rage. Ann NY Acad Sci 159 928-938, 1969. 

The motor activation produced by psychomotor stimulants has been long associated with the midbrain dopamine systems. While focused stereotyped behavior produced by high doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the corpus striatum (Creese and Iversen 1975), the locomotor activation produced by low doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the region of the nucleus accumbens (Kelly et al. 1975). This dopaminergic substrate for psychostimulant effects appears selective for the indirect sympathomimetics in that dopamine lesions to the region of the nucleus... 

At the higher doses, several stages of stereotyped behaviors were seen. The transition from amphetamine-induced locomotion to locomotion associated with stereotyped side-to-side head movements was accompanied by a further reduction in firing rate. In those animals in which focused stereotypy was observed following this period of locomotion plus head movements, neurons showed a still further reduction in firing rate (figure 2). 

But there are those in my lab who believe that the excitation is being seen by a bias toward large cells and that they represent a large cell population in the neostriatum. I don t necessarily believe that. I don t know why, in the anesthetized animal, you can flip a nerve cell that is inhibited by amphetamine by increasing the dose. It has been postulated that the excitation is related to the occurrence of both the stereotyped behaviors, and that this may be provoked at doses that produce neurotoxicity. We have also done a number of studies looking at the neurotoxicity of amphetamine administration in animals, most of which replicate Lou Seiden s work. 

We have evaluated the dose-related effects of PCP, ketamine, and selected anticonvulsant drugs on seizure activity in the hippocampal model of kindled seizures. The hippocampal model is particularly well suited for the study of the anticonvulsant effects of drugs because of the slow rate of acquisition of the fully kindled seizure. Electrical stimulation of the dorsal hippocampus initially evokes a stereotyped sequence of behavior, accompanied by a characteristic EEG pattern. Repeated electrical stimulation eventually results in generalized kindled seizures. This allows the testing of drugs on the unkindled hippocampal seizure (afterdischarge) to be compared to effects on the fully kindled seizure in the same rats. 

In rodents, PCP produces not only ataxia, but also stereotyped behavior and hyperactivity. The PCP-induced stereotyped behavior is thought to be due to changes in serotonergic and dopaminergic systems (Nabeshima et al. 1983 Martin et al. 1979 Sturgeon et al. 1981). It is not known whether PCP receptors mediate PCP-induced hyperactivity or stereotyped behavior or even the effect on neurotransmitter systems. It is also possible that mu, kappa, or sigma opioid receptors are involved (Castellani et al. 1982). 

The purpose of these studies was to determine whether stereotyped behavior and ataxia induced by PCP-like drugs and sigma opioids is mediated by PCP receptors. Also, we wanted to investigate whether sigma opioid and PCP receptors are the same receptors using behavioral and radioreceptor assays. 

COMPARISON BETWEEN INDUCTION OF PCP-LIKE STEREOTYPED BEHAVIOR AND ATAXIA TO INTERACTIONS WITH PCP RECEPTORS... 

Using the PCP rating scale for stereotyped behavior and ataxia as described by Sturgeon et al. (1979), the central effects of PCP analogs, dexoxadrol, and its levo-isomer, levoxadrol, were determined. As shown in figure 1, all drugs except the (-) isomers produced dose-dependent stereotyped behavior. In contrast,... 

PCMP was equipotent with (+)PCMP in induction of ataxia (figure 2), Furthermore, TCM, which was one-fifth as potent as PCP in the induction of stereotyped behavior, was as potent as PCP in induction of ataxia. The ability of PCP-like drugs to bind to PCP receptors, as measured by their ability to inhibit the binding of 3H- PC P, was determined as described by Contreras et al. (in preparation). The order of relative potencies of drugs as compared to PCP was TCP > PCE > PCP = NIPCA > dexoxadrol > (+) PCMP > TCM =... 

FIGURE 1. Dose-response curves for induction of stereotyped behavior. Ratings for each animal were determined 5 minutes after ICY administration of each drug. At least 21 rats were used to determine each dose-response curve. 

Thus, stereotyped behavior appears to be mediated by PCP receptors, but ataxia appears to be mediated by more than just an interaction with PCP receptors. 

Only the (+) isomer of SKF-10,047, which very weakly inhibited the binding of 3H- PC P, induced stereotyped behavior. This finding is consistent with the results of the PCP receptor assay showing that (+)SKF-10,047 is one-tenth as potent as PCP, but is fivefold more potent than (-)SKF-10,047 (table 1). However, it was not possible to determine whether SKF-10,047 was a full agonist because of its poor solubility in saline. Also, SKF-10,047 produced weaving and circling behavior that was much less pronounced than that induced by PCP. In contrast to the results of the assays for stereotyped... 

Stereoselectivity was evident in the assays for stereotyped behavior and PCP receptor interaction, but not in the assay for ataxia as the (+) isomers of the PCP-like drugs and SKF-10,047 were more potent than the (-) isomers in induction of stereotyped behavior and inhibition of binding of 3H-PCP. However, one exception to this trend is that the (-) isomer of cyclazocine was more potent than the (+) isomer in industion of stereotyped behavior and inhibition of the binding of 3H-PCP. 

Since large doses of naloxone (10 and 50 m/kg) did not antagonize the ability of PCP or cyclazocine to induce stereotyped behavior... 

Metaphit administered alone at doses up to 1 pmol/rat did not produce any significant behavioral effects. However at doses of 2 pmol/rat and larger, metaphit produced PCP-like stereotyped behavior and ataxia. Thus, metaphit is a very weak PCP agonist. In addition to acute effects, metaphit produced convulsions, which were evident between 5 and 24 hours after ICV administration of 2 pmol/rat. 

Metaphit administered ICV prior to PCP administered ICV antagonized PCP induction of stereotyped behavior and ataxia up to 5 days after metaphit pretreatment. The antagonism of the behavioral effects of PCP by metaphit was dose dependent as is shown in figure 4. Furthermore, this antagonism by metaphit is specific as metaphit pretreatment ICV did not antagonize amphetamine-induced stereotyped behavior and could be prevented by pretreating rats with PCP just prior to metaphit administration. These results indicate that acylation of PCP receptors results in decreased ability of PCP to induce stereotyped behavior. 

Since metaphit appears to specifically acylate PCP receptors, metaphit is a useful tool with which to study the physiological role of PCP receptors. When metaphit was administered ICV prior to IP administration of PCP, metaphit antagonized the ability of PCP to induce stereotyped behavior, but not its ability to induce ataxia. Thus, it appears that ataxia is mediated by both central and peripheral mechanisms. It is unlikely that the peripheral effect of PCP in induction of ataxia is mediated by PCP receptors as 20 mg/kg of metaphit administered IV only antagonized PCP -induced stereotyped behavior when PCP was also administered peripherally. 

Cyclazocine and PCP probably do not induce stereotyped behavior and ataxia through an interaction with the same receptor, as metaphit did not antagonize the behavioral effects of cyclazocine. 

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