Stereotyped behaviors

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. 

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. 

These results clearly demonstrate that PCP-like drugs administered centrally produce stereotyped behavior that is mediated by PCP receptors. A causal relationship between binding to PCP receptors and induction of stereotyped behavior is also supported by the ability of metaphit, which specifically acylates PCP receptors in vivo, to antagonize induction of stereotyped behavior. The order of drug potency of PCP analogs and dexoxadrol to induce stereotyped behavior is similar to that seen in other studies on the binding of 3H-PCP (Hampton et al. 1982 Murray and Leid 1984) and... 

The finding that metaphit did not antagonize (-)cyclazocine induction of stereotyped behavior or ataxia is evidence that PCP receptors and sigma opioid receptors are different receptors. 

Phencyclidine-induced stereotyped behavior and serotonergic syndrome in rat. I ife Sci 24 1699 - 1704, 1979. 

Nabeshima, T, Yamaguchi, K. Yamada, K. Hiramatsu, M. Furukawa, H, and Kameyama, T. Phencyclidine-induced stereotyped behavior in rats following specific neurotoxin lesions of the striatum. LiiL 1 Pharmacol 93 229-234, 1983. 

Sturgeon, R.D. Fessler, R.G. and Meltzer, H.Y. Behavioral rating scales for assessing phencyclidine-induced locomotor activity, stereotyped behavior and ataxia in rats. J. 

Dose-related shifts in predominant EEG frequency for PCP and several phencyclinoids are shown in figure 3. For all 10 compounds tested, there was a shift in predominant EEG frequency into the theta range across the lower doses, associated primarily with increased locomotor activity and stereotyped behaviors. With further increases in dose, PCP and all of its analogues produced shifts to lower predominant frequencies, which typically fell between 2 and 4 Hz. As the dose was incremented geometrically, the lower frequency EEG waves were associated first with ataxia, then with dyskinetic movements, catalepsy, and possibly seizure activity. SKF-10,047 also produced ataxia, but was unique in that it did not cause a shift to a lower predominant frequency and produced only EEG theta activity at all subconvulsant doses. 

Murray, T.F. and Horita, A. Phencyclidine-induced stereotyped behavior in rats Dose response effects and antagonism by neuroleptics. I ife Sci 24 2217-2226, 1979. 

Initially, most prominent effect is elated mood, although depression may occur hypervigilance and anxiety that may progress to panic with high doses or chronic use, may see impairment of judgment, violence to others or self, paranoia or psychosis with delusions and hallucinations (hallucinations are generally tactile or auditory, rarely visual) an increase in motor activity is common compulsive or stereotyped behavior (e.g., skin picking) may be seen severe intoxication may result in a self-limited delirium... 

Asakura W., Matsumoto K, Ohta H., Watanabe H. (1992). REM sleep deprivation decreases apomorphine-induced stimulation of locomotor activity but not stereotyped behavior in mice. Gen. Pharmacol 23, 337-41. 

Reith, M.E.A., Meisler, B.E., Sershen, H., and Lajtha, A., Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior, Biochem. Pharmacol., 35, 1123, 1986. 

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