Effects of the PCP analog dizocilpine on sensory gating: potential relevance to clinical subtypes of schizophrenia.

Prepulse inhibition (PPI) of the acoustic startle reflex, a measure of sensory gating, is reduced in schizophrenic patients. Dopamine agonists and NMDA receptor antagonists such as phencyclidine (PCP) can disrupt PPI in animals, consistent with both the dopamine and glutamate hypotheses of schizophrenia. In this study, we sought to further characterize the effects of the NMDA antagonist dizocilpine on acoustic startle modulation. Fischer 344 rats were tested after one of three doses of dizocilpine (0.05, 0.2, and 0.5 mg/kg) and assessed for PPI as well as for alterations in baseline startle and prepulse facilitation (PPF). Results showed complete disruption of PPI for each inhibitory trial type after 0.2 and 0.5 mg/kg of dizocilpine. Baseline startle and PPF were enhanced by the low dose but decreased with the moderate and high doses of dizocilpine. Although dizocilpine caused alterations in prepulse modulation of startle similar to dopamine agonists, some effects differ. Unique effects of dizocilpine on sensory gating are discussed in terms of their potential for discriminating subtypes of schizophrenic illness with different underlying pathophysiology.

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.

Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage.

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.

Selective inhibition of nociceptive flexion reflex discharge by the kappa agonist bremazocine.

In unanaesthetized decerebrate spinal cats, bremazocine (0.012-0.2 mg/kg, i.v.) selectively inhibited the late C-fibre reflex discharge, recorded in sectioned lumbo-sacral ventral root filaments, after supramaximal electrical stimulation of the ipsilateral sural or common peroneal nerve. This action was naloxone-reversible. The results suggest that activation of kappa opioid receptors in the spinal cord inhibits the integration of nociceptive, but not locomotor, flexion reflexes.

Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.

Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDA

Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus.

Neonatal lesions of the ventral hippocampus in rats produce changes in spontaneous and pharmacologically induced dopamine-dependent behaviors that emerge in early adulthood. Neural mechanisms underlying these changes may have implications for understanding the neurobiology of schizophrenia, putatively a neurodevelopmental disorder. In this study, we evaluated the effects of MK-801 (dizocilpine), on automated measures of distance traveled and stereotypies in adult rats with neonatal (postnatal day 7) lesions, and tested the effects of haloperidol, clozapine and an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) antagonist LY293558 on the MK-801-induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and O.1 mg/kg of MK-801 than did controls. Both haloperidol (0.1 and 0.4 mg/kg) and clozapine (4 and 10 mg/kg) reduced hyperlocomotion elicited by 0.2 mg/kg MK-801 in the ventral hippocampus (VH)-lesioned and sham rats. Haloperidol was more potent than clozapine in decreasing MK-801-induced stereotypy, especially in the lesioned rats. Moreover, an AMPA antagonist normalized exaggerated MK-801-induced hyperolocomotion in the lesioned rats at doses that had no effect in controls. These results demonstrate that the lesioned rats are more sensitive to MK-801 during adulthood than control rats, and that antidopaminergic drugs as well as AMPA antagonists antagonize the MK-801-induced behaviors. The neonatal lesion rat model may be useful to further our understanding of the interactions between dopamine and glutamate and their role in the pathophysiology of schizophrenia.