Attenuation of the behavioral response to quisqualic acid and glutamic acid diethyl ester by chronic haloperidol administration

Wj, Freed; He, Cannon-Spoor; Cr, Rodgers

doi:10.1016/0024-3205(89)90368-8

Cited by 6 publications

(2 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While initial sedation by neuroleptics is associated with acute dopaminergic antagonism, tolerance to neuroleptic sedation which occurs following their chronic administration may be due to the development of dopamine receptor supersensitization which eventually counteracts neuroleptic blockade of dopamine receptors. Interestingly, this 'supersensitivity' of dopamine receptors in the striatum may be associated with a 'subsensitivity' of glutamatergic synapses (Freed 1989;Freed et al 1989). It is proposed that this suppression of glutamatergic transmission in certain synapses is responsible for the antipsychotic effects of neuroleptics.…”

Section: Discussionmentioning

confidence: 95%

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

Cartmell

Monn

Schoepp

2000

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The potent metabotropic glutamate (mGlu) receptor agonist, LY379268, selectively activates mGlu2/3 receptors with EC50 values in the low nanomolar range. We have previously shown in rats that LY379268 reverses phencyclidine (PCP)-induced motor activations (increases in ambulations and fine movements, and decreases in the animals time at rest). Here, we have investigated: (1) the dose-response and time course for this action of LY379268 following oral (p.o.) administration and (2) the therapeutic index in this model following acute versus subchronic (4 days) p.o. dosing. LY379268 (3 mg/kg p.o.) evoked a maximal effect on PCP (5 mg/kg s.c.)-elicited behaviors 4 h post-dosing. At this time point, p.o. LY379268 inhibited the effects on PCP-elicited activities with a similar potency (ED50 values ca 1 mg/kg) to that previously obtained following s.c. administration. Doses up to 3 mg/kg p.o. LY379268 were without effect on the rotorod performance of rats when measured at 1, 2, 4, 8, and 24 h post-administration. In agreement with the peak time-effect on PCP-evoked motor behaviors, 10 mg/kg p.o. LY379268 only significantly impaired rotorod performance at the 4-h time point. Interestingly, acute motor impairment produced by higher doses of LY379268 (10, 30, or 100 mg/kg p.o.) was absent following 4-day repeated administration of LY379268. In contrast, the potency of LY379268 for the inhibition of PCP-evoked motor activities was not affected following multiple dosing over a similar period. These results demonstrate that although the reduction of PCP motor activities by LY379268 is maintained after subchronic dosing, tolerance to the motor impairment evoked by the compound occurs, thus greatly widening the therapeutic index of LY379268.

show abstract

Section: Discussionmentioning

confidence: 95%

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

Cartmell

Monn

Schoepp

2000

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

show abstract

“…To test the current hypothesis more specifically, the effects of chronic haloperidol on behavioral responses to the glutamate agonist quisqualic acid and the antagonist L-glutamic acid diethyl ester HCI (GDEE) were investigated (Freed et al 1988). Mice were chronically given haloperidol or lactic acid vehicle mixed with their drinking water for 4 weeks as described previously (Freed et al 1980).…”

Section: Supporting Evidencementioning

confidence: 99%

The Therapeutic Latency of Neuroleptic Drugs and Nonspecific Postjunctional Supersensitivity

Freed

1988

Schizophrenia Bulletin

View full text Add to dashboard Cite

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.

show abstract

A possible role of AA2 excitatory amino acid receptors in the expression of stimulant drug effects

Freed

Cannon-Spoor

1990

Psychopharmacology

View full text Add to dashboard Cite

GDEE, an antagonist of the AA2 or quisqualic acid category of excitatory amino acid receptor, decreases behavioral activity and locomotor stimulation induced by cocaine and amphetamine when locally injected into the nucleus accumbens. The present experiment was intended to examine the effects of systemic GDEE and other excitatory amino acid antagonists on stimulant-induced locomotor activity. GDEE markedly attenuated the stimulant effect of amphetamine, and partially blocked the effects of phencyclidine (PCP). Apomorphine-induced cage climbing behavior was partially decreased by lower dosages of GDEE, but was almost completely blocked by the highest dosage tested. Amphetamine-induced stimulation of locomotor activity was not decreased by any of the other excitatory amino acid antagonists that were tested, including MK-801, 2-amino-7-phosphonoheptanoic acid (APH), or CNQX. APH decreased stereotypy only at a high dosage (250 mg/kg), which also produces ataxia. Several other compounds, including L-glutamic acid gamma ethyl ester (GMEE), L-glutamic acid, glycine, and L-glutamine did not block amphetamine-induced stimulation in molar dosages equivalent to the highest dosage of GDEE (8 mmol/kg). It is concluded that the AA2 excitatory amino acid receptor is important in the expression of activating effects of stimulant drugs.

show abstract

Attenuation of the behavioral response to quisqualic acid and glutamic acid diethyl ester by chronic haloperidol administration

Cited by 6 publications

References 33 publications

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

The Therapeutic Latency of Neuroleptic Drugs and Nonspecific Postjunctional Supersensitivity

A possible role of AA2 excitatory amino acid receptors in the expression of stimulant drug effects

Contact Info

Product

Resources

About