Hassen Al-Amin

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.

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 AMPA antagonist LY293558 on the MK‐801‐induced behaviors. The lesioned rats showed significantly greater increases in motor activity after 0.05 and 0.1 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.

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.

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.

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<lesion<electrolytic lesion<kainic acid lesion<lidocaine injection. The observed effects were transient despite the permanence of the lesions while lesion of the somatosensorimotor cortices produced sustained reduction of the neuropathic manifestations. Our results correlate well with the established connections of the ventrolateral orbital area with the thalamic nucleus subnucleus involved in the procession of thermal nociception. The transient effects reported following permanent lesions in the orbital areas may reflect its flexible role in pain modulation. This observation provides further evidence on the plasticity of the neural networks involved in the regulation of nociceptive behavior.

Chronic dizocilpine or apomorphine and development of neuropathy in two animal models II: Effects on brain cytokines and neurotrophins

Dopaminergic and glutamatergic mechanisms are involved in the development and modulation of neuropathy. Cytokines and neurotrophins can be also involved in the supraspinal maintenance of neuropathic pain. We assessed the effects of chronic intraperitoneal (ip) injection of dizocilpine (MK-801), a N-methyl-d-Aspartate (NMDA) noncompetitive receptor antagonist, or apomorphine (APO), a dopamine (DA) D1 and D2 receptor agonist, on neuropathic manifestations in the chronic constriction injury (CCI) and the spared nerve injury (SNI) models of neuropathy in rats. Six groups of rats were subjected to SNI or CCI (3 groups each) neuropathy and 5-7 days later received daily ip injections of saline, MK-801, or APO for two weeks. An additional control group was subjected to sham surgery without nerve lesion or injections. Rats were then sacrificed, and levels of IL-1β, IL-6, NGF, BDNF and GDNF were determined in the cingulum, striatum, and hippocampus. In both models, the neuropathy seen in the saline group was associated with decreased BDNF and an increase in IL-1β, IL-6, NGF and GDNF in most brain regions when compared to sham group. Chronic systemic MK-801 or APO injections decreased the neuropathic manifestations in both models, increased the BDNF level and modulated the other cytokines and neurotrophins. This modulation depended on the neuropathy model and the region/side of the brain studied. Our results showed that the changes in surpraspinal cytokines and neurotrophins could parallel neuropathic manifestations. These changes and the observed hyperalgesia can be modulated by chronic systemic injections of NMDA antagonists or DA agonists.

Validation of the Arabic version of the short Geriatric Depression Scale (GDS-15)

BACKGROUND This study aimed to examine the validity and reliability of an Arabic version of the 15-item Geriatric Depression Scale (GDS-15). METHODS 121 community-dwelling older adults and primary care patients aged 60 and above participated in this study. Older adults with dementia, those with thyroid dysfunction, and hearing or speech impairments were excluded. Test-retest reliability was examined by re-administering the translated GDS-15 to a subset of 38 participants at least seven days after the initial interview. RESULTS The Arabic GDS-15 had good psychometric properties, but the best properties were reported for the 7/8 cutoff. Cronbachs alpha as a measure of internal consistency reliability was high (0.88) and kappa ranged from 0.57 to 0.75. The performance of the GDS-15 was equally good for both community-dwelling older adults and those in primary care settings, and for both forms of the GDS (examiner administered vs. self-administered). CONCLUSION The Arabic GDS is a useful measure to assess depression among community-dwelling older adults and primary care patients who do not have dementia. Because of the use of formal Arabic, GDS-15 can be widely used with all Arabic-speaking people.

Validation of the Arabic version of the 5‐item WHO well being index in elderly population

Bonsignore M, 2001, EUR ARCH PSYCHIAT S2, V251, pII27; Chaaya M, 2008, INT PSYCHOGERIATR, V20, P571, DOI 10.1017-S1041610208006741; Chaaya M, 2007, AGING MENT HEALTH, V11, P37, DOI 10.1080-13607860600735812; Heun R, 1999, ACTA PSYCHIAT SCAND, V99, P171, DOI 10.1111-j.1600-0447.1999.tb00973.x; Karam EG, 2006, LANCET, V367, P1000, DOI 10.1016-S0140-6736(06)68427-4

Developmental changes in the mRNA expression of neuropeptides and dopamine and glutamate receptors in neonates and adult rats after ventral hippocampal lesion.

BACKGROUND The neurodevelopment of hippocampus and prefrontal cortex are known to influence different functions in normal and pathological conditions including cognition and sensorimotor functions. The neonatal lesion of the ventral hippocampus (VH) in rats has been established as an animal model of schizophrenia and is used to study postpubertal changes in behavior and neurobiology. In order to investigate whether early VH lesion in rats alters the expression of genes implicated in schizophrenia pre- and post-puberty, we studied the mRNA expression of neuropeptides (substance P, dynorphin and enkephalin), dopamine D1, dopamine D2, and NMDA (subunits NR1 and NR2A) receptors in this animal model. METHODS Rat pups were lesioned at postnatal day 7 by injecting ibotenic acid into the VH bilaterally, and then sacrificed at age 35 (pre-puberty) and 65 (post-puberty) days. Another group of adult rats had the same lesion in the VH, to independently assess the effects of the lesion on the expression of genes, and then sacrificed at week 4 and 8 post lesion. Sham groups were injected with cerebrospinal fluid using the same procedure. Brains were removed and sectioned to study the mRNA expression using in situ hybridization (ISH). RESULTS The main results are the postpubertal onset of increased NR1 mRNA expression in all cortical regions and decreased dopamine D2 receptor, substance P and enkephalin mRNA expression in the striatum only in rats lesioned as neonates. These changes were not observed in the adult group with VH lesion. CONCLUSIONS Our results demonstrate that the postpubertal behavioral changes in this animal model (and possibly schizophrenia) are related to postpubertal onset of changes in the development of functions and interactions of the dopamine and glutamate receptors in the mesocortical system.

Effects of chronic dizocilpine on acute pain and on mRNA expression of neuropeptides and the dopamine and glutamate receptors.

The mesocorticolimbic circuitry has been implicated in the pathophysiology of several neuropsychiatric syndromes like chronic pain and addiction. The aim of this study was to evaluate the effects of dizocilpine (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on sensorimotor behaviors and the consequent changes in the dopamine, glutamate, and opiate systems in rats. Five groups of rats were subjected to acute tests for nociception (hot plate and paw pressure) before and after MK-801 (0.05, 0.1, 0.2 and 0.4 mg/kg, i.p.) or saline. Another two groups received daily i.p. saline or MK-801 (0.4 mg/kg) for 15 days. The nociceptive tests were performed on days 1, 7, and 14. On day 15 the rats received the last injection and were immediately sacrificed. We measured the mRNA expression, by in situ hybridization (ISH), of various dopamine and glutamate receptors, and enkephalin (Enk), dynorphin (Dyn), and substance P (SP) in the striatum, nucleus accumbens (NAC), piriform and cingulate cortex. Acute MK-801, dose-dependently, resulted in hyperalgesia. The chronic effects of 0.4 mg/kg MK-801 showed an extinction of the acute hyperalgesic effects especially with the hot plate test. The ISH studies revealed a decrease in mRNA expression of Enk and SP in the striatum and NAC. Our results indicate that the reversal of acute MK-801-induced hyperalgesia, with repeated exposure to systemic MK-801, is not directly related to changes in dopamine and glutamate receptors and might involve alteration of the striatal neuropeptide system.