Gamma band neural synchronization deficits for auditory steady state responses in bipolar disorder patients

Periodic auditory click stimulation has been reported to elicit an auditory steady state response (ASSR). The ASSR has been suggested to reflect the efficiency of γ-amino butyric acid (GABA) inhibitory interneuronal activity. Although a potential role for GABAergic dysfunction has been previously proposed, the role of neural synchronization in the ASSR in people with bipolar disorder (BD) has received little attention. In the current study, we investigated ASSRs to 20 Hz, 30 Hz, 40 Hz and 80 Hz click trains in BD patients. A total of 14 (4 males) BD patients and 25 (10 males) healthy controls participated in this study. ASSRs were obtained using whole-head 306-channel magnetoencephalography to calculate, ASSR power values and phase locking factors (PLF). BD patients exhibited significantly reduced mean ASSR power and PLF values bilaterally at frequencies of 30, 40, and 80 Hz (p<0.05 for these frequencies). At 20 Hz, bipolar patients showed no significant reduction in mean ASSR power and PLF values. There was a significant negative correlation between 80 Hz-ASSR-power values obtained from the right hemisphere and scores on the Hamilton Depression Rating Scale (rho = −0.86, p = 0.0003). The current study showed reduced low and high gamma band ASSR power and PLF bilaterally with no significant beta band ASSR reduction in BD patients. BD patients are characterized by deficits in gamma band oscillations, which may be associated with GABA inhibitory interneuronal activity dysfunction.     

Attentional Modulation of Auditory Steady-State Responses

Auditory selective attention enables task-relevant auditory events to be enhanced and irrelevant ones suppressed. In the present study we used a frequency tagging paradigm to investigate the effects of attention on auditory steady state responses (ASSR). The ASSR was elicited by simultaneously presenting two different streams of white noise, amplitude modulated at either 16 and 23.5 Hz or 32.5 and 40 Hz. The two different frequencies were presented to each ear and participants were instructed to selectively attend to one ear or the other (confirmed by behavioral evidence). The results revealed that modulation of ASSR by selective attention depended on the modulation frequencies used and whether the activation was contralateral or ipsilateral. Attention enhanced the ASSR for contralateral activation from either ear for 16 Hz and suppressed the ASSR for ipsilateral activation for 16 Hz and 23.5 Hz. For modulation frequencies of 32.5 or 40 Hz attention did not affect the ASSR. We propose that the pattern of enhancement and inhibition may be due to binaural suppressive effects on ipsilateral stimulation and the dominance of contralateral hemisphere during dichotic listening. In addition to the influence of cortical processing asymmetries, these results may also reflect a bias towards inhibitory ipsilateral and excitatory contralateral activation present at the level of inferior colliculus. That the effect of attention was clearest for the lower modulation frequencies suggests that such effects are likely mediated by cortical brain structures or by those in close proximity to cortex.     

Differential regulation of the NMDA receptor by acute and sub-chronic phencyclidine administration in the developing rat

Neurodegeneration induced by the NMDA receptor antagonist, phencyclidine (PCP), has been used to model the pathogenesis of schizophrenia in the developing rat. Acute and sub-chronic administration of PCP in perinatal rats results in different patterns of neurodegeneration. The potential role of an alteration in the membrane expression of NMDA receptors in PCP-induced degeneration is unknown. Acute PCP treatment on postnatal day 7 increased membrane levels of both NMDA receptor subunit 1 (NR1) and NMDA receptor subunit 2B (NR2B) proteins in the frontal cortex; conversely, NR1 and NR2B protein levels in the endoplasmic reticulum fraction were decreased. Acute PCP administration also resulted in increased membrane cortical protein levels of post-synaptic density-95, as well as the activation of calpain, which paralleled the observed increase in membrane expression of NR1 and NR2B. Further, administration of the calpain inhibitor, MDL28170, prevented PCP-induced up-regulation of NR1 and NR2B. On the other hand, sub-chronic PCP treatment on postnatal days 7, 9 and 11 caused an increase in NR1 and NR2A expression, which was accompanied by an increase in both NR1 and NR2A in the endoplasmic reticulum fraction. Sub-chronic PCP administration did not alter levels of post-synaptic density-95 and had no effect on activation of calpain. These data suggest that increased trafficking accounts for up-regulation of cortical NR1/NR2B subunits following acute PCP administration, while increased protein synthesis likely accounts for the increased expression of NR1/NR2A following sub-chronic PCP treatment of the developing rat. These results are discussed in the context of the differential neurodegeneration caused by acute and subchronic PCP administration in the developing rat brain.     

Effects of chronic administration of phencyclidine on stereotyped and ataxic behaviors in the rat

After chronic administration of Phencyclidine (PCP) to rats, a high test dose (15 mg/kg) of PCP produced increases in stereotypic and ataxic behaviors, and a lower test dose of PCP (5 mg/kg) produced decreases in these behaviors, compared to behavioral responses of control rats. Rearing behavior in rats chronically administered PCP was increased at all test doses of the drug. Rats treated chronically with 15 mg/kg PCP for 9 days showed marked increases in most of these behaviors, whereas, rats receiving 5 mg/kg PCP for 9 days showed less change in several stereotypic and ataxic behaviors. Rats receiving 10 mg/kg PCP on a once-weekly schedule also exhibited more rearing and ataxic behavioral responses after the 3rd or 4th weekly PCP injection. Chronic PCP rats did not show more stereotypic or ataxic behavior after administration of apomorphine or amphetamine than control rats. These results suggest that chronic administration of PCP augments sensitivity to the stereotypic inducing effects of high doses, and decreases sensitivity to low doses of PCP.     

Different effects of halothane on diaphragm and hindlimb muscle in rats

The effects of halothane administration on diaphragm and tibialis anterior (TA) muscle were investigated in 30 anesthetized mechanically ventilated rats. Diaphragmatic strength was assessed in 17 rats by measuring the abdominal pressure (Pab) generated during supramaximal stimulation of the intramuscular phrenic nerve endings at frequencies of 0.5, 30, and 100 Hz. Halothane was administered during 30 min at a constant minimum alveolar concentration (MAC): 0.5, 1, and 1.5 MAC in three groups of five rats. For each MAC, Pab was significantly reduced for all frequencies of stimulation except at 100 Hz during 0.5 MAC halothane exposure. The effects of halothane (0.5, 1, and 1.5 MAC) on diaphragmatic neuromuscular transmission were assessed in five other rats by measuring the integrated electrical activity of the diaphragm (Edi) during electrical stimulation of the phrenic nerve. No change in Edi was observed during halothane exposure. In five other rats TA contraction was studied by measuring the strength of isometric contraction of the muscle during electrical stimulation of its nerve supply at different frequencies (0.5, 30, and 100 Hz). Muscle function was unchanged during administration of halothane in a cumulative fashion from 0.5 to 1.5 MAC. These results demonstrate that halothane does not affect hindlimb muscle function, whereas it had a direct negative inotropic effect on rat diaphragmatic muscle.     

Ethanol withdrawal tremor potentiates the tremorogenic action of nicotine

The tremorogenic effect of nicotine was studied in control rats and in rats withdrawn for 16-48 h from six to nine days' ethanol administration. The frequency and the intensity of tremor were measured electronically. A single dose of nicotine 5 mg/kg caused shortlasting (2-3 min) convulsions within 1 min after injection in control rats. Tremor occurred first after five repeated injections of nicotine (5 mg/kg) at half-hour intervals. This tremor encompassed peak frequencies of 6, 10 and 15 Hz. Hexamethonium at a dose of 10 mg/kg did not inhibit the tremor but eliminated the highest peak frequency (15 Hz) and tended to increase the intensity. Propranolol 5 mg/kg completely abolished the nicotine-induced tremor in control rats. Rats withdrawn from repeated ethanol administration showed a marked hypersensitivity to the tremorogenic action of nicotine so that a single dose of 1 mg/kg of nicotine caused clear tremor. The frequency spectra of this tremor showed peak frequencies at 6, 10 and 12 Hz. Hexamethonium did not change these frequencies. Furthermore, it tended to increase the intensity of nicotine-induced tremor in ethanol-withdrawn rats. Propranolol did not inhibit the tremor although it eliminated the 12 Hz peak frequency. The results suggest that the hypersensitivity to the tremorogenic action of nicotine in ethanol-withdrawn rats is not mediated by a sympathetic beta-adrenergic mechanism.     

Influence of the cannabinoid agonist HU 210 on cocaine- and CQP 201-403-induced behavioural effects in rat.

Acute injection of the cannabinoid agonist HU 210 (6.25-100 microg/kg, i.p.) dose-dependently inhibited rat locomotor activity and rearing, while subchronic treatment with the drug (once daily for 7 days) at the same doses only diminished locomotion. Acute but not subchronic administration of HU 210 (12.5-50 microg/kg, i.p.) potently counteracted acute and subchronic cocaine (15 mg/kg, i.p.)-induced hyperlocomotion and enhanced rearing. The acute cannabinoid (6.25-100 microg/kg, i.p.) also inhibited locomotor activity, stereotyped behaviour and shaking elicited by the D1/D2 agonist CQP 201-403 (500 microg/kg, i.p.). On the contrary, subchronic treatments with HU 210 enhanced CQP 201-403-induced locomotor activity and potently stimulated escape attempts. Discussion centers on the influence of cannabinoids on experimental models of psychosis.     

Low frequency-dependent mechanism of the M2 receptor function on vagally mediated bronchoconstriction in rabbits in vivo.

The present study was carried out to investigate whether there is the difference between low and high frequencies of vagal stimulation on the functional appearance of M2 receptors in the rabbit. The animals were anesthetized, artificially ventilated and bilaterally vagotomized. Bilateral vagus nerve stimulation (5 to 30 Hz) for 30 sec caused bronchoconstriction (measured as an increase in R(L) and a decrease in Cdyn) in a frequency-dependent manner. The bronchoconstriction evoked by ACh injection (1 and 3 microg/kg) was dose-dependent. Although administration of methoctramine (50 and 300 microg/kg), a selective M2 receptor antagonist, had no significant effect on ACh-induced bronchoconstriction, methoctramine dose-dependently augmented the R(L) and Cdyn responses to vagal stimulation at 5-15 Hz but did not potentiate bronchoconstrictive responses to the stimulation at 30 Hz. Administration of [D-Pro2, D-Try(7,9)]-SP (0.5 mg/kg, a selective tachykinin receptor antagonist) that had no significant effect on the R(L) and Cdyn responses to vagal stimulation (5-15 Hz) attenuated the bronchoconstrictive response to the stimulation at 30 Hz. Conversely, thiorphan (2 mg/kg, a neutral endopeptidase inhibitor) potentiated the bronchoconstriction evoked by vagal stimulation at 30 Hz only. These results suggest that M2 receptors function as the inhibitory receptors in the bronchoconstrictive response to vagal stimulation at the lower frequencies (5-15 Hz), but that the M2 receptor antagonism is diminished when vagal stimulation at a higher frequency (30 Hz) results in the release of SP from the lungs.     

Effects of Subchronic Clozapine and Haloperidol on Striatal Glutamatergic Synapses

Abstract: Subchronic treatment with haloperidol increases the number of asymmetric glutamate synapses associated with a perforated postsynaptic density in the striatum. To characterize these synaptic changes further, the effects of subchronic (28 days) administration of an atypical antipsychotic, clozapine (30 mg/kg, s.c.), or a typical antipsychotic, haloperidol (0.5 mg/kg, s.c.), on the binding of [³H]MK-801 to the NMDA receptor-linked ion channel complex and on the in situ hybridization of riboprobes for NMDAR2A and 2B subunits and splice variants of the NMDAR1 subunit were examined in striatal preparations from rats. The density of striatal glutamate immunogold labeling associated with nerve terminals of all asymmetric synapses and the immunoreactivity of those asymmetric synapses associated with a perforated postsynaptic density were also examined by electron microscopy. Subchronic neuroleptic administration had no effect on [³H]MK-801 binding to striatal membrane preparations. Both drugs increased glutamate immunogold labeling in nerve terminals of all asymmetric synapses, but only haloperidol increased the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated postsynaptic density. Whereas subchronic administration of clozapine, but not haloperidol, resulted in a significant increase in the hybridization of a riboprobe that labels all splice variants of the NMDAR1 subunit, both drugs significantly decreased the abundance of NMDAR1 subunit mRNA containing a 63-base insert. Neither drug altered mRNA for the 2A subunit, but clozapine significantly increased hybridization of a probe for the 2B subunit. The data suggest that some neuroleptic effects may be mediated by glutamatergic systems and that typical and atypical antipsychotics can have varying effects on the density of glutamate in presynaptic terminals and on the expression of specific NMDA receptor splice variant mRNAs. Alternatively, NMDAR1 subunit splice variants may differentially respond to interactions with glutamate.     

L-NAME raises systolic blood pressure in the pithed rat by a direct adrenal epinephrine releasing action

It is generally thought that inhibition of nitric oxide synthase leads to blood pressure elevation largely through reduction in vascular levels of the vasodilator nitric oxide. However, there are several reports suggesting that NO synthase inhibitors cause adrenal epinephrine (E) release by both central and peripheral mechanisms. We investigated the role of adrenal E in the pressor effects of the nitric oxide synthase inhibitor L-NAME in the pithed rat to help distinguish central from peripherally mediated actions. L-NAME (10 mg/kg) raised both systolic and diastolic BP by about 30 mm Hg (P < .01) in the absence of exogenous electrical stimulation of sympathetic nerves. During stimulation at 10 V and frequencies of 1 or 2 Hz, systolic BP was about 70 mm Hg higher in L-NAME treated rats than in drug free stimulated rats. This enhancement of systolic BP by L-NAME was less pronounced at 5 or 10 Hz stimulation frequencies. Following these types of electrical stimulations of pithed rats, both plasma norepinephrine (NE) and E levels were dramatically elevated above resting plasma levels. L-NAME pretreatment of these electrically stimulated rats increased plasma E levels by an additional 60% and decreased NE by 18%. Acute adrenalectomy dramatically reduced plasma E levels and abolished the ability of L-NAME to enhance the pressor effect of sympathetic stimulation. In contrast, acute adrenalectomy of unstimulated pithed rats did not significantly reduce the pressor response to L-NAME. We conclude that adrenal E release may mediate much of the systolic pressor response of L-NAME in the stimulated pithed rat, but the magnitude of this effect varies with stimulation frequency. Since pithing disrupts central pathways, this induction of adrenal E release by L-NAME is a peripheral effect.     

Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors

Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.     

Prepuberal Stimulation of 5-HT7-R by LP-211 in a Rat Model of Hyper-Activity and Attention-Deficit: Permanent Effects on Attention,Brain Amino Acids and Synaptic Markers in the Fronto-Striatal Interface

The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates.     

Naloxone does not antagonize PCP-induced stimulation of the pituitary-adrenal axis in the rat

Phencyclidine (PCP) has been shown to stimulate the pituitary-adrenal axis in the rat. The purpose of the present study was to determine whether opiate receptors are involved in this effect by testing whether pretreatment with the opiate antagonist naloxone can antagonize PCP-induced ACTH and corticosterone release. PCP (10.0 mg/kg) produced increases in plasma ACTH and corticosterone 60 min after s.c. administration. Pretreatment with naloxone (2.0 mg/kg s.c.) did not reduce the rise in plasma levels of ACTH or corticosterone produced by PCP. These results indicate that naloxone-sensitive opiate receptors are not involved in the PCP-induced stimulation of the pituitary-adrenal axis in rats.     

The release of catecholamines from the adrenal medulla and its modulation by alpha 2-adrenoceptors in the anaesthetized dog

The adrenal nerve of anaesthetized and vagotomized dogs was electrically stimulated (10 V pulses of 2 ms duration for 10 min) at frequencies of 1, 3, 10, and 25 Hz. There was a correlation between the frequency of stimulation and the plasma concentrations of epinephrine, norepinephrine, and dopamine in the adrenal vein, mainly after the 1st min of stimulation and the maximal concentration was reached sooner with higher frequencies of stimulation. Moreover, the relative percentage of catecholamines released in response to the electrical stimulation was not changed by the frequency of stimulation. To test the hypothesis that a local negative feedback mechanism mediated by alpha 2-adrenoceptors exists in the adrenal medulla, the effects of the systemic administration of clonidine (alpha 2-antagonist) on the concentrations of catecholamines in the adrenal vein were evaluated during the electrical stimulation of the adrenal nerve (5 V pulses of 2 ms duration for 3 min) at 3 Hz. Moreover, the effects of the systemic injections of more specific alpha 2-agonist and antagonist (oxymetazoline and idazoxan) were tested on the release of catecholamines in the adrenal vein in response to electrical stimulation of the splanchnic nerve at 1 and 3 Hz frequencies. The injection of 0.5 mg/kg of yohimbine caused a significant increase in the concentrations of epinephrine and norepinephrine in the adrenal vein induced by the electrical stimulation of the adrenal nerve and the injection of 15 micrograms/kg of clonidine had no effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

(C-A) and (G-A) anchored simple sequence repeats (ASSRs) generated polymorphism in soybean, Glycine max (L.) Merr.

 We used thirty simple sequence repeats (SSRs) with a variable 2–4 base ‘anchor’ at their 5′ ends (ASSRs) independently or with arbitrary primers in analysis of soybean germplasm and the intercross of ‘Essex’ and PI 437654. (AG)₆, (GA)₆ or (CT)₆ and (GT)₆, (TG)₆ or (CA)₆ were efficient in the detection of (G-A) and (C-A) ASSR-generated polymorphisms, respectively. DNA sequence analysis of the ASSR-amplified fragments confirmed the presence of SSR sequences. (A-T) ASSRs failed to give amplification or generated fewer number of fragments. Only one of the four tested decamer primers altered ASSR banding patterns in the soybean. All the six long primers (18–20 mer) tested changed ASSR banding profiles. On average, seven polymorphic fragments per ASSR primer were produced in soybean germplasm and four in the intraspecific cross of ‘Essex’ and PI 437654. The grouping of 48 genotypes in UPGMA analysis using four (C-A) and four (G-A) ASSR primers was consistent with the classification obtained with RFLP markers. Seventy-seven (91%) ASSR markers were dominant, while the remaining 8 (9%) showed codominant segregation. Fifty-eight ASSR markers were mapped onto 18 RAPD/RFLP linkage groups, which covered approximately 50% of the soybean genome. Of the (G-A) ASSR-derived markers 49% remained unlinked compared with 17% of (C-A) ASSR markers at LOD 3.0. Map linkage information showed that the assigned (C-A) polymorphisms had a biased distribution, whereas (G-A) polymorphisms were randomly dispersed. Received: 24 July 1997 / Accepted: 17 November 1997     

Dose dependent alteration in lipid and carbohydrate metabolites in streptozotocin induced diabetic rats

1. A relationship is established between different doses of intraperitoneally injected streptozotocin (SZ) and the degree of hyperglycemia and hyperlipemia. 2. Changes in serum level of glucose, cholesterol, triglycerides and NEFA were determined after intraperitoneal administration of three different doses (55 mg, 85 mg and 125 mg/kg body weight) of SZ. Cholesterol level was significantly (P less than 0.001) elevated after 72 hrs only in the animals which received 85 mg/kg and 125 mg/kg SZ. 3. Dose dependent changes in NEFA and triglycerides could be observed after 24 hrs of SZ administration. 4. Diabetic animals consistently showed triphasic blood sugar response, initial hyperglycemia at 5-7 hrs, profound hypoglycemia in between 8-12 hrs and finally an irreversible hyperglycemic state by 24 hrs and onwards. 5. Liver and muscle glycogen were continuously decreased except a significant rise at 12 hrs coinciding with hypoglycemic phase. During the experimental period SZ treated rats continuously lost weight, while control animals progressively gained weight. In summary these changes indicated that diabetogenicity is dose dependent and the severity can be judged by elevated lipid metabolites.     

Developmental changes in neuromuscular transmission in the rat diaphragm.

Neuromuscular transmission was studied in diaphragms from rats of three ages, 4-7 days old, 11-12 days old, and adults with the use of an in vitro phrenic nerve-hemidiaphragm preparation. Each hemidiaphragm was stimulated via either muscle or nerve with 1-s stimulus trains at frequencies from 10 to 100 Hz. The patterns of force development obtained in response to the two routes of stimulation were compared for each group. Diaphragms from adults developed maximum force in response to stimulation of approximately 40 Hz with no significant decrease in force at higher frequencies. Within each stimulus train, once peak force was achieved, it was maintained for the remainder of the stimulus and responses to nerve and muscle stimulation were almost identical. In contrast, diaphragms from 4- to 7-day-old rats developed maximum force at approximately 20 Hz; stimulation at greater than or equal to 60 Hz induced significantly less peak force. This decrease in peak force at higher frequencies was significantly larger for nerve than for muscle stimulation. In addition, during each nerve stimulus train diaphragms from 4- to 7-day-old rats were unable to maintain peak force, which decreased at frequencies greater than 20 Hz. The decrease in force reached approximately 50% of peak at stimulation frequencies greater than or equal to 60 Hz. Diaphragms from 11- to 12-day-old rats showed intermediate responses. Based on the responses to phrenic nerve stimulation, we conclude that the neonatal rat diaphragm shows marked neuromuscular transmission failure that is not seen in the adult.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of phencyclidine on rat prolactin dopamine receptor and locomotor activity

Plasma prolactin (PRL) was decreased in naive rats sacrificed 30 min after phencyclidine (PCP) administration (10 mg/kg, s.c.). There was, however, no decrease in plasma PRL 30 min after s.c. injection of PCP (10 mg/kg) on the 29th day following 28 days of chronic PCP administration. These data suggest the development of tolerance to the PRL-suppressive effect of PCP as result of long-term administration of the drug. The B_max of [³H]-spiperone binding to rat striatal membranes was decreased 24 hrs after 28 days of PCP treatment without change in affinity (Kd). No indication of the development of tolerance in these rats was found with regard to the locomotor-stimulating effect of PCP. The plasma PRL-suppressive effect of the PCP analog PCMP was found to be stereo-specific; (-) PCMP was much less potent than (+)-PCMP.     

Electroacupuncture analgesia could be mediated by at least two pain-relieving mechanisms; endorphin and non-endorphin systems.

This present paper shows different levels of electroacupuncture analgesia (antinociceptive effect) induced by three different frequencies of stimulation (i.e. 0.2, 4 and 200 Hz); highest analgesia is induced at 200 Hz and lowest at 0.2 Hz. Naloxone (1 mg/kg) completely reverses the electroacupuncture effects at low frequency stimulation (4 Hz) but produces no inhibition at high frequency stimulation (200 Hz). Conversely, parachlorophenylalanine (320 mg/kg) partially blocks the high-frequency (200 Hz) analgesia but produces no effect on the low-frequency (4 Hz) electroacupuncture analgesia. This suggests that electroacupuncture analgesia induced by low frequency stimulation may be mediated by endorphins while high frequency stimulation is not endorphinergic but may be partly due to serotonin.     

The cyclooxygenase inhibitors indomethacin and Rofecoxib reduce regional cerebral blood flow evoked by somatosensory stimulation in rats

The present study was designed to investigate whether administration of indomethacin (IMC), a non-selective cyclooxygenase (COX-1 and COX-2) inhibitor, and Rofecoxib, a highly selective COX-2 inhibitor, affect the regulation of regional cerebral blood flow response evoked by somatosensory activation (evoked rCBF). IMC and Rofecoxib were applied intravenously (6.25 and 3 mg/kg/hr, respectively). Somatosensory activation was induced by electrical hind paw stimuli of 0.2, 1, and 5 Hz (5-sec duration, 1.5 mA). The evoked rCBF was measured in alpha-chloralose anesthetized rats using laser-Doppler flowmetry. Before and after drug application, the evoked rCBF showed a frequency-dependent increase in the range of 0.2-5 Hz stimulation. IMC reduced significantly (about 50%-60%) evoked rCBF in response to all frequencies of hind paw stimulation (P< 0.05). Rofecoxib reduced significantly (about 50%) evoked rCBF in response to 1 and 5 Hz stimulation (P< 0.05), but did not affect evoked rCBF at 0.2 Hz. After IMC or Rofecoxib application, the normalized evoked rCBF curves peaked earlier as compared with that before their application (P< 0.05), although the rise time of 0.5 sec was nearly constant regardless of the stimulus frequency. The termination time of evoked rCBF curves was changed significantly after IMC application at 0.2 Hz stimulation (P< 0.05), but was not affected after Rofecoxib application. Neither COX inhibitor significantly affected the baseline level of CBF. The results suggest a participation of COX products in the regulation of evoked rCBF in response to somatosensory stimulation in the brain.