Evidence that the NH2-terminus of substance P modulates N-methyl-D-aspartate-induced activity by an action involving sigma receptors.
Behaviors induced in mice by intrathecal injections of either N-methyl-D-aspartate (NMDA) or kainic acid are modulated by NH2-terminal fragments of substance P, such as substance P-(1-7). The action of substance P-(1-7) on kainic acid depends on sigma receptor activity. The present study was designed to test the hypothesis that sigma receptor activity is also necessary for modulation of NMDA by substance P-(1-7). Intrathecal injection of mice with NMDA results in a brief burst of biting and scratching behaviors which decrease in intensity when NMDA is injected repeatedly at 2 min intervals. Pretreatment with 1,3-di-O-tolylguanidine (DTG), a ligand at both sigma 1 and sigma 2 sites, converted NMDA-induced desensitization to sensitization, thereby enhancing tonic NMDA receptor activity. Although haloperidol (30 min) alone was without effect, the potentiation of NMDA-induced activity by DTG was abolished by haloperidol but unaffected by an equimolar dose of either spiperone or thiothixine, two dopamine receptor antagonists. When mice received substance P-(1-7), NMDA-induced behaviors were initially inhibited but then potentiated. Pretreatment with haloperidol prevented both inhibitory and potentiative effects of substance P-(1-7) whereas thiothixine did not, suggesting inhibitory as well as potentiative modulation of NMDA by sigma receptor activity. Endogenous sigma 1 receptor activity may enhance NMDA receptor activity as a treatment regimen that down-regulates sigma 1 binding also inhibited responses to NMDA. In contrast, pretreatment with haloperidol just 5 min prior to challenge, which blocks both sigma 1 and sigma 2 receptor activity, increased responses to NMDA suggesting an inhibitory effect of sigma 2 receptor activity. In summary, modulation of NMDA by substance P-(1-7) appears to depend on activity at sigma sites as substance P-(1-7) mimicked the potentiative effects of DTG, while haloperidol inhibited the effects of both DTG and substance P-(1-7).
Hornfeldt
C S
CS
Department of Veterinary PathoBiology, University of Minnesota, St. Paul 55108, USA.
Kitto
K F
KF
Larson
A A
AA
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004359:Drug Therapy, Combination; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017480:Receptors, sigma / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology*
D000927:Anticonvulsants; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D006146:Guanidines; D017480:Receptors, sigma; D013373:Substance P; D016202:N-Methylaspartate; D006220:Haloperidol; C050232:1,3-ditolylguanidine