The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity.

Phencyclidine (PCP), a non-competitive antagonist of ionotropic N-methyl-D-aspartate (NMDA) receptors, produces psychotomimetic effects, such as a disruption in prepulse inhibition (PPI) of the startle response. NMDA antagonists also induce locomotor hyperactivity in rodents. We hypothesized that, like NMDA receptors, metabotropic glutamate receptors (mGluRs) modulate PPI and locomotor activity either alone or, in the case of mGluR5, via interaction with NMDA receptors. Rats treated with the mGluR5 antagonist MPEP (2-methyl-6-phenylethynylpyridine) or the mGluR2/3 agonist LY314582, either alone or in combination with PCP, were tested in PPI and locomotor activity paradigms. Neither MPEP nor LY314582 altered PPI. MPEP, but not LY314582, potentiated the PPI-disruptive effects of PCP. MPEP alone did not alter locomotor or exploratory behavior, but augmented the complex, time-dependent locomotor-stimulating effects of PCP. LY314582 dose-dependently decreased locomotor activity and exploratory holepokes. LY314582 did not alter the PCP-induced increases in locomotor activity, but further decreased the number of holepokes. The effects of MPEP on the response to PCP may reflect the cooperation and co-localization of NMDA and mGlu5 receptors.

Effects of LU-111995 in three models of disrupted prepulse inhibition in rats.

LU-111995 is a novel antipsychotic drug in clinical development. It has a clozapine-like receptor profile and affinities for dopamine D(4) and 5-hydroxytryptamine(2A) receptors. The effects of LU-111995 were examined in three models of disrupted prepulse inhibition (PPI) in rats. The first model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the dopamine agonist apomorphine. LU-111995 significantly reduced the effect of apomorphine on PPI but also slightly increased PPI by itself. Thus, the increases in PPI were not specific to the animals treated with apomorphine but reflected an effect of LU-111995 on PPI. LU-111995 also attenuated the apomorphine-induced increase in startle reactivity. The second model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the psychotomimetic phencyclidine (PCP). LU-111995 significantly blocked the PCP-induced increase in startle reactivity but did not alter the PPI-disruptive effects of PCP. The third model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by isolation-reared rats tested as adults. Isolation rearing of rats produced deficits in PPI. LU-111995 reversed the isolation rearing-induced deficit in PPI without having any significant effect on PPI in socially reared rats. In summary, LU-111995 exhibits potential antipsychotic-like activity in two models of disrupted PPI. It remains to be elucidated whether its effects on PPI can be attributed to a blockade of single dopamine and 5-hydroxytryptamine receptor subtypes, especially D(4) and 5-hydroxytryptamine(2A), or a combination of both.

Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-D-aspartate receptor antagonists in rats.

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine are psychotomimetics and disrupt prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia. Systemically administered competitive NMDA receptor antagonists do not disrupt PPI in rats, leading to speculation that these compounds might have use as neuroprotective agents without the risk of psychotomimetic side effects. The effects on sensorimotor gating and locomotor activity of competitive NMDA receptor antagonists that either penetrate (SDZ 220-581 and SDZ EAB-515) or poorly penetrate [SDZ EAA-494 (D-CPPene)] the blood-brain barrier were compared. Rats were treated with either SDZ 220-581 (0, 2.5, or 5.0 mg/kg) or SDZ EAB-515 (0, 3.0, 10.0, or 30.0 mg/kg) and tested for PPI and locomotor activity. Different rats were tested for PPI after either systemic (0, 0.5, 1.0, or 5.0 mg/kg) or intra-amygdala (0 or 1.0 microg/microl) administration of D-CPPene. Finally, rats were pretreated with clozapine (0 or 5.0 mg/kg) or haloperidol (0 or 0.1 mg/kg), together with SDZ 220-581 (0 or 2.5 mg/kg), and tested. SDZ 220-581 and SDZ EAB-515 decreased PPI without affecting startle magnitude. Reduced PPI was noted after central but not systemic administration of D-CPPene. The gating deficits produced by SDZ 220-581 were blocked by clozapine or haloperidol. Movement pattern analysis indicated that locomotor activity was increased by SDZ 220-581 and SDZ EAB-515 in a phencyclidine-like manner. These results indicate that competitive NMDA receptor antagonists, if they gain sufficient access to the brain, produce a behavioral profile that resembles that of the psychotomimetic noncompetitive antagonists.

Modulation of phencyclidine-induced changes in locomotor activity and patterns in rats by serotonin.

To test the hypothesis that serotonergic modulation of the effects of phencyclidine (PCP) are due to circuit- rather than receptor-based interactions between glutamatergic and serotonergic systems, multivariate profiles of rat behavior were assessed after treatments with the 5-hydroxytryptamine (5-HT) 5-HT2 receptor antagonist ketanserin (1.0 mg/kg), the 5-HT2 receptor agonist (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (DOI; 0.27 mg/kg), various doses of PCP (0.75 to 10.125 mg/kg), or combinations thereof. Ketanserin blocked all effects of DOI, but reduced the effects of PCP only on locomotion. Depending on the dose, PCP was observed to increase or decrease locomotion and the roughness of the rats' patterns of locomotion. In any case, DOI always increased the activity and decreased the roughness of locomotor paths in PCP-treated rats. Thus, co-administration of DOI and PCP did not yield a shift in the dose-effect curve for either drug, but instead resulted in a new behavioral profile consistent with a circuit-based dynamic interaction.

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats.

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.