Behavioral response to buspirone in cocaine and phencyclidine withdrawal

The effects of buspirone in treating cocaine and phencyclidine (PCP) withdrawal were studied. Withdrawal symptoms of these two street-drugs are thought to be due to norepinephrine, dopamine and possibly serotonin depletion. Buspirone acts by enhancing dopaminergic and noradrenergic firing as well by suppressing serotonergic activity. Thirty-two cocaine abusers and 24 PCP abusers were withdrawn over a 30-day period. Half of each group received buspirone 10 mg t.i.d. and the other half 10 mg placebo t.i.d. In the cocaine group, buspirone was significantly more effective from the fifth day onward. In the PCP group, significant improvement was seen on the thirtieth day. Delayed effectiveness in PCP is thought due to its actions at other neurotransmitter sites.     

Syntheses and pharmacological evaluations of novel N-substituted bicyclo-heptane-2-amines at N-methyl-D-aspartate receptors

Several novel norcamphor (bicycloheptane)-based compounds were designed and synthesized as non-competitive N-methyl-D-aspartate receptor antagonists at the phencyclidine binding sites. The heterocyclic ring was also varied to examine piperidine, pyrrolidine, and morpholine groups. We examined pharmacological activities of these compounds in vitro (binding studies) and in vivo (maximal electroshock test). Pharmacological evaluations revealed one of the compounds, 5a, to be a good lead, exhibiting moderate binding at N-methyl-D-aspartate receptors (IC(50) =7.86 μm; K(i) =5.28 μm), maximal electroshock neuroprotection activity at 100 mg/kg and acceptable toxicity profile.     

Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice

Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson''s and Huntington''s diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre-frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg⁻¹ daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs-treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder.     

Possible association of different G72/G30 SNPs with mood episodes and persecutory delusions in bipolar I Romanian patients

The G72/G30 gene is one of the common loci shared both by schizophrenia and bipolar disorder. Studies accumulating since the discovery of this gene complex produced controversial results in both disorders in different populations.     

Phencyclidine affects firing activity of basolateral amygdala neurons related to social behavior in rats

Negative symptoms of schizophrenia, such as social withdrawal and blunted affect, usually persist for a long period, making rehabilitation difficult. Many studies have demonstrated a close relationship between function of the amygdala and social behavior. Normal social behavior is disturbed in animals administered phencyclidine (PCP), which is now considered a reliable pharmacological model of schizophrenia. Recent studies have reported that disruption of social behavior in PCP-treated rats involved dysfunction of the amygdala. Disturbance of function of the amygdala has also been reported in schizophrenic patients. However, no study has yet examined the effects of PCP on the firing activity of amygdala neurons. In the present study, we recorded the unit activity of basolateral amygdala neurons while rats engaged in socially interactive behavior. After identifying the response properties of recorded neurons, we then recorded the same neurons with systemic PCP administration. Approximately half of the neurons recorded from exhibited an increase in spontaneous discharge rate during social interaction. Only a few neurons exhibited suppression of discharge rate during social interaction. Systemic administration of PCP induced long-lasting activation in half of the neurons that exhibited an increase in firing rate during social interaction. PCP activated half of basolateral amygdala neurons related to socially interactive behavior, and might in this fashion produce dysfunction of social behavior.     

Effect of dopaminergic agents on levels of dynorphin1–8 in rat striatum

1. In this study, the possibility that striatal dynorphin_1–8 levels would be altered by either acute or chronic treatment with dopaminergic agonists or antagonists is examined.

2. Animals were treated chronically (3 weeks) with daily injections of d-amphetamine, phencyclidine or haloperidol. For the acute studies, animals were given a single dose of either d-amphetamine or haloperidol.

3. Dynorphin_1–8 levels were estimated using a radioimmunoassay. Only chronic treatment with d-amphetamine has any effect on dynorphin levels. Following 3 weeks of chronic d-amphetamine, the level of dynorphin_1–8 increased in 2 separate experiments.

4. Acute d-amphetamine or haloperidol treatment or chronic haloperidol or phencyclidine treatment had no effect on striatal dynorphin_1–8 levels. However, chronic (but not acute) d-amphetamine administration does produce a small increase in striatal dynorphin_1–8 levels.     

Altered metabolic activity in the cerebral cortex of rats exposed to ketamine

Uptake of the metabolic marker, [³H]2-deoxy-D-glucose(2DG) was compared in rats given subanesthetic (50–100 mg/kg, i.p.) or anesthetic (200 mg/kg, i.v.) doses of ketamine with that in normal, unanesthetized rats. All doses of ketamine caused a relative increase of 2DG labeling in limbic regions, including the hippocampus, dentate gyrus, and cingulate, piriform, and entorhinal cortices. Striking 2DG-dense zones were confined to the molecular layer in the hippocampus, dentate gyrus, and entorhinal cortex. Sub-anesthetic doses of ketamine produced a relative reduction of 2DG uptake in layers 1-1V of granular somalosensory cortex while sparing up take in layer Va; therefore, the peak of dense uptake shifted from layer IV to layer Va. In regions of the somatosensory cortex which display a dysgranular layer IV, vertical columns of relatively dense 2DG uptake extended through all cortical layers. Columns of 2I) G label also occurred outside of S1, in visual and auditory areas. In the primary visual cortex, this dose of ketamine decreased 2DG uptake relative to secondary visual cortex. Alteration of 2DG uptake in various cortical regions might be the consequence of a ketamine-induced activation of specific neuronal pathways with special neurochemical features. During subanesthetic ketamine administration, peak 2DG uptake shifts from cortical layer IV, which receives specific thalamocortical input to layer Va which receives projections via intrinsic cortical circuits. The ketamine-induced shift in the laminar focus of sensory cortical metabolism may reflect a functional disconnection from peripheral sensory input and/or enhanced internal (corticocortical) processing. These changes are more apparent during ketamine administration at doses too low to induce anesthesia and may, therefore, reflect the metabolic events that occur when ketamine and its analogues are taken as drugs of abuse.     

Synthesis of [11C] N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐methoxyphenyl)‐N′‐methylguanidine ([11C]GMOM): a candidate PET tracer for imaging the PCP site of the NMDA ion channel

The N‐methyl‐D ‐aspartate (NMDA) ion channel plays an important role in a number of neurodegenerative disorders including stroke, Parkinson's disease, Huntington's Chorea, Alzheimer's disease, schizophrenia and epilepsy. To provide effective radioligands for imaging the PCP binding site of the NMDA ion channel, we synthesized and characterized in vitro the candidate PCP site ligand N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐methoxyphenyl)‐N′‐methylguanidine (GMOM: K_i = 5.2 ± 0.3 nM, log P = 2.34). The corresponding PET radiotracer [¹¹C]GMOM was synthesized with a radiochemical yield of 8.4 ± 3.2% EOS and with a specific activity of 1.23 ± 0.25 Ci/μmol EOS (n = 5). The average time required for synthesis, purification and formulation was 52 ± 5 min. The final product was prepared in a sterile saline solution suitable for in vivo use. Copyright © 2002 John Wiley & Sons, Ltd.     

Electrophysiological interactions between haloperidol and reduced haloperidol, and dopamine, norepinephrine and phencyclidine in rat brain

Haloperidol and its metabolite, reduced haloperidol, were compared as antagonists of catecholaminergic neurotransmission in central nervous system of the rat. Agonists and antagonists were applied from multibarrelled micropipettes, which were also used to record extracellularly the effects of these substances on neuronal discharge. Haloperidol antagonized dopaminergic inhibition of caudate neurons and inhibition of cerebellar Purkinje neurons induced by noradrenaline, whereas reduced haloperidol was an ineffective antagonist. Phencyclidine, which is an indirect dopaminergic agonist in the caudate, caused inhibition of the discharges of caudate neurons resembling that induced by dopamine itself. These indirect effects of phencyclidine were also antagonized by haloperidol but not by reduced haloperidol. The data suggest that the metabolite, reduced haloperidol, is not an effective neuroleptic drug in the central nervous system.