Immediate and simultaneous sensory reorganization at cortical and subcortical levels of the somatosensory system.

The occurrence of cortical plasticity during adulthood has been demonstrated using many experimental paradigms. Whether this phenomenon is generated exclusively by changes in intrinsic cortical circuitry, or whether it involves concomitant cortical and subcortical reorganization, remains controversial. Here, we addressed this issue by simultaneously recording the extracellular activity of up to 135 neurons in the primary somatosensory cortex, ventral posterior medial nucleus of the thalamus, and trigeminal brainstem complex of adult rats, before and after a reversible sensory deactivation was produced by subcutaneous injections of lidocaine. Following the onset of the deactivation, immediate and simultaneous sensory reorganization was observed at all levels of the somatosensory system. No statistical difference was observed when the overall spatial extent of the cortical (9.1 +/- 1.2 whiskers, mean +/- SE) and the thalamic (6.1 +/- 1.6 whiskers) reorganization was compared. Likewise, no significant difference was found in the percentage of cortical (71.1 +/- 5.2%) and thalamic (66. 4 +/- 10.7%) neurons exhibiting unmasked sensory responses. Although unmasked cortical responses occurred at significantly higher latencies (19.6 +/- 0.3 ms, mean +/- SE) than thalamic responses (13. 1 +/- 0.6 ms), variations in neuronal latency induced by the sensory deafferentation occurred as often in the thalamus as in the cortex. These data clearly demonstrate that peripheral sensory deafferentation triggers a system-wide reorganization, and strongly suggest that the spatiotemporal attributes of cortical plasticity are paralleled by subcortical reorganization.

Reconstructing the engram: simultaneous, multisite, many single neuron recordings.

Little is known about the physiological principles that govern large-scale neuronal interactions in the mammalian brain. Here, we describe an electrophysiological paradigm capable of simultaneously recording the extracellular activity of large populations of single neurons, distributed across multiple cortical and subcortical structures in behaving and anesthetized animals. Up to 100 neurons were simultaneously recorded after 48 microwires were implanted in the brain stem, thalamus, and somatosensory cortex of rats. Overall, 86% of the implanted microwires yielded single neurons, and an average of 2.3 neurons were discriminated per microwire. Our population recordings remained stable for weeks, demonstrating that this method can be employed to investigate the dynamic and distributed neuronal ensemble interactions that underlie processes such as sensory perception, motor control, and sensorimotor learning in freely behaving animals.

Estradiol conjugated to BSA releases oxytocin from synaptosome-containing homogenates from the medial preoptic area-hypothalamus.

Estradiol conjugated to bovine serum albumin at position 6(E-6-BSA) released oxytocin (OT) from homogenates of the medial preoptic area and medial hypothalamus (MPOA-MH) within minutes of its superfusion. Using a superfusion system in which synaptosome-containing homogenates were layered onto acrodiscs maintained at 37 degrees C, we have found that E-6-BSA (100 ng/microliters) superfusions significantly elevated OT release within minutes. In contrast, superfusion of the same concentration of BSA or progesterone-3-BSA (P-3-BSA) had no effect on OT release. While superfusing homogenates with augmented levels of K+ had no effect on OT release itself, superfusing E-6-BSA with these concentrations of K+ consistently increased OT release. This is the first demonstration that E-6-BSA increases OT release in a nucleus-free medium.

Analogies between oxytocin systems of the uterus and brain.

In this brief review we have compared OT systems in the brain with those of the uterus and ovary particularly with respect to interactions with steroids. We have presented evidence of heterogeneous OTR and 125I-P-3-BSA binding sites in the MPOA as well as evidence of extensive interactions of steroids and OT in the MPOA, that cannot be adequately explained by genomic effects of steroids. We also discuss a putative analogue between steroid control of OTR stimulation of intracellular calcium levels, phospholipase C activity and prostaglandins in the uterus and steroid effects on OT systems in brain. We have developed a model for steroid control of both OT release and OTR in which we suggest that steroids and OT bind to membrane receptors coupled to G proteins. This model may prove useful in understanding the interactive central actions of steroids and OT systems in regulating the endocrinology and behaviors associated with reproduction.

Characterization of progesterone-3-[125I-BSA] binding sites in the medial preoptic area and anterior hypothalamus.

In this study we utilized radiolabeled progesterone (P) conjugated to bovine serum albumin (BSA) at position 3 (P-3-[125I-BSA]) to examine steroid receptors in membrane fractions from the medial preoptic area-anterior hypothalamus (MPOA-AH) of ovariectomized (OVXed) rats. In the MPOA-AH binding of P-3-[125I-BSA] was linear across a tissue concentration range of 0.005 to 0.02 mg protein/0.1 ml of membrane suspension. Kinetic experiments revealed an association t(1/2) of 51.4 min and a dissociation t(1/2) of 122.5 min for P-3-[125I-BSA] at 0 degrees C. Analysis of data from competition binding experiments using P-3-BSA revealed high- and low-affinity binding sites in the MPOA-AH. Involvement of MPOA-AH binding sites with a G-protein was suggested by a reduction of P-3-[125I-BSA] binding in the presence of the non-hydrolyzable GTP analog GTPgammaS but not ATPgammaS. In addition, if homogenates from the MPOA-AH were preincubated with 10(-5) M of the G-protein antagonist cholera toxin for 30 min at 37 degrees C, competition binding data indicated only high-affinity binding sites. Once daily injections of OVXed rats with 4 mg P for 12 days significantly increased the density of P-3-[125I-BSA] binding sites in the MPOA-AH. This treatment did not affect P-3-[125I-BSA] binding in the dorsal tectum, medial basal hypothalamus, ventral tegmental area or the thymus.

Infusion of an oxytocin antagonist into the medial preoptic area prior to progesterone inhibits sexual receptivity and increases rejection in female rats.

Central administration of an antagonist to the neuropeptide oxytocin (OT) has been shown to block the progesterone-induced facilitation of female sexual receptivity. In this study we examined the effects of infusing an OT antagonist (OTA) into various brain sites before rats were injected with 250 micrograms progesterone (P). Ovariectomized animals were injected daily for three consecutive days with 1 microgram estradiol benzoate and then on the fourth day were infused into the medial preoptic area (MPOA), medial basal hypothalamus (MBH) or ventral tegmental area with either 250 ng/microliter/side OTA or artificial cerebrospinal fluid vehicle. Animals were tested in an arena made of two white polyethylene cages connected by a tunnel that allowed passage of the female but not of the larger male. Several receptive and non-receptive behaviors were recorded for a 15-min period beginning 4 hr after P injection. Animals infused with OTA into the MPOA before P showed an increase in the frequency and total duration of fighting with males and the frequency of audible vocalizations made by females. OTA infusions also increased the frequency of mounts that did not result in a lordosis posture. OTA infusions into the MPOA also reduced the frequency and total duration of lordosis postures in response to mounts. OTA infusions into the MBH and VTA had no effect on measures of sexual behaviors. Blocking OT transmission in the MPOA resulted in increased rejection behaviors and decreased receptivity in females when infused before systemic P injection.

Comparative efficacy, safety and pharmacokinetics of verapamil SR vs verapamil IR in hypertensive patients.

The antihypertensive effects of the regular immediate release formulation of verapamil (verapamil IR) and the newer sustained release formulation of verapamil (verapamil SR) were compared in Hispanic patients with untreated essential hypertension. Verapamil IR was given in 3 divided doses (80 or 160mg 3 times daily) and verapamil SR was given either as a single daily dose of 240mg or as 240mg every 12 hours. With both formulations there was a significant reduction in systolic (SBP) and diastolic blood pressure (DBP); a greater lowering of BP was observed with verapamil 480 mg/day than with 240 mg/day. With verapamil SR 480 mg/day, 91% of patients had reductions in SBP and DBP greater than 20 and 15mm Hg, respectively. In addition, 83% of patients reached normotension. With the lower dose (240mg once daily), 83% of patients had decreases in DBP greater than 10mm Hg and 73% of patients achieved normotension. Comparable effects were achieved with verapamil IR. With verapamil IR there was a more rapid fall in BP which peaked 3 to 4 hours postdose, whereas with verapamil SR a more gradual and sustained BP reduction was observed. Only small changes in heart rate (HR) were observed with verapamil IR and verapamil SR. For verapamil SR, the mean increase in HR was 5 beats/min (to 80 beats/min) and the mean decrease in HR was 13 beats/min (to 62 beats/min). Both verapamil SR and verapamil IR prolonged the PR interval of the ECG. An equal degree of PR prolongation was observed with 240 and 480 mg/day. The incidence of side effects (headache, palpitations, dizziness and flushing) was dose dependent, decreased with continuous treatment and was much higher with verapamil IR than with verapamil SR. Steady-state plasma verapamil concentrations were monitored. Compared with verapamil IR, verapamil SR produced a more gradual rise and a more sustained elevation of plasma verapamil and norverapamil concentrations. Comparable trough verapamil concentrations (Cmin) were observed with verapamil IR (98 micrograms/L) and SR (81 micrograms/L); morning Cmin verapamil concentrations were higher than daytime Cmin values. The normalised area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) were 10 to 20% greater for verapamil IR than SR. The 2-fold increase in oral dose produced a 2.2- and 2.4-fold increase in AUC for verapamil IR and SR, respectively, associated with a 20% reduction in metabolism to norverapamil. Fasting increased the rate and extent of absorption of verapamil.(ABSTRACT TRUNCATED AT 400 WORDS)

Rapid desensitization of dopamine release induced by neurotensin and neurotensin fragments.

Neurotensin (NT), a tridecapeptide, induced a concentration-dependent release of dopamine (DA) from the striatum. In addition, NT8-13 and Nacetyl-NT8-13, the carboxy-terminal-containing hexapeptides, were much more effective as DA releasers than the amino-terminal, NT1-6 peptide. The potency and efficacy of NT in inducing DA release was markedly enhanced by increases in the extracellular concentration of potassium (K+). Similar to electrical stimulation and to elevated extracellular K+, NT-induced DA release was inhibited by 70% in the presence of 0.13 mM calcium. Desensitization to NT was observed after a first exposure to NT for 2.5 to 10 min, despite a 20- to 85-min washout period between exposures, with NT-free medium. The loss of response was not due to degradation or inactivation of the peptide, nor it was due to activation of DA autoreceptors or the DA transporter. NT-induced desensitization was not associated to a loss of responsiveness to DA release elicited by electrical stimulation or by high K+. In addition, desensitization occurred even if NT-induced DA release was markedly enhanced by high extracellular K+ (10 and 15 mM). Inhibition of NT-induced DA release by low calcium (on the first exposure) did not prevent the development of desensitization. Similar to the parent peptide, desensitization was observed with the active carboxy-terminal NT fragments. However, a first exposure to NT1-6 did not induce desensitization to NT8-13. These results are compatible with the view that NT-induced DA release and the development of desensitization are mediated through an action of NT on NT receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotensin-induced dopamine release in vivo and in vitro from substantia nigra and nucleus caudate.

We compared the dopamine (DA) releasing effects of neurotensin (NT) from cell bodies (substantia nigra) and nerve terminals (nucleus caudate). In rats implanted with push-pull cannula, NT induced DA release from substantia nigra and nucleus caudate. NT was more potent in releasing DA from the substantia nigra than from the nucleus caudate (EC50%, 1.1 microM in substantia nigra and 9.8 microM in nucleus caudate). In vitro, in superfused rabbit brain slices, NT enhanced the depolarization-evoked release of DA and exerted a direct releasing effect. The latter was greater in the substantia nigra, and the former in the nucleus caudate. The direct releasing effect of NT was not inhibited, but enhanced by nomifensine (3 microM). Sulpiride, a D2 DA receptor antagonist, failed to modify NT-induced DA release; in addition, NT did not affect the inhibition of DA and acetylcholine release produced by LY-171555, a D2 DA agonist. In both the substantia nigra and the nucleus caudate, desensitization to the releasing effect of NT was observed, either after 2.5, 5, or 10 min of exposure to the peptide. A synergistic interaction on DA release was observed between NT and potassium (K+), and between NT and electrical stimulation. Greater synergism was observed with high extracellular K+. Pretreatment of striatal slices with 15 mM K+ produced a 9-fold enhancement of NT-induced DA release. When K+ (25 mM, 2 min) was given together with NT there was a 2- to 3-fold increase in DA release compared to the release evoked by K+ in the absence of NT.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy, safety, and kinetics of immediate- and slow-release verapamil in hispanic patients with essential hypertension.

We assessed the pharmacokinetics and pharmacodynamics of immediate-release (IR) and slow-release (SR) verapamil in Hispanic patients with mild to moderate essential hypertension. Area under the curve and Cmax increased linearly with the dose of IR and SR. Plasma levels showed a more gradual increase and were maintained elevated for longer periods with SR. Both IR and SR reduced blood pressure (BP) significantly. Peak BP reduction with 240 mg q.i.d. SR (6 h postdose) or 80 mg t.i.d. IR (4 h postdose) averaged 28/18 and 23/20 mm Hg, respectively. Morning predose BP levels were reduced 16/5 mm Hg by SR and 5/6 mm Hg by IR. Peak PR prolongation averaged 43 ms for SR and 56 ms with IR. Heart rate was not modified. With 480 mg/day there was a greater BP reduction with no relevant changes in HR and no further increases in PR intervals. However, incidence of side effects (headaches, dizziness) was enhanced with 480 mg/day IR but not with SR. These results suggest that Hispanic patients have a good response to verapamil. The pharmacokinetic characteristics of SR verapamil account for its more favorable side-effect profile observed with this formulation. SR is considered advantageous to IR for the chronic treatment of hypertensive patients.

Differential alterations in brain sensitivity to amphetamine and pentylenetetrazol in socially deprived mice.

Mice deprived of social interactions for different periods of time (56, 69, 79, 89 or 97 days) were studied. Social isolation increased both general activity observed in an open-field and amphetamine-induced hyperactivity; CNS responsiveness to pentylenetetrazol-induced convulsions, however, decreased. The differences in general activity were detected after 69 and 79 days of social deprivation; the hyperactivity induced by amphetamine was greater after 79 days of isolation and the pentylenetetrazol CD50's were higher after 56, 69 and 79 days of solitude. These data, obtained with mice, show first that isolation time is an important variable to display drug effects and secondly that long-term deprivation of social stimuli does not increase CNS susceptibility to all stimulant drugs. A combination of a higher release of catecholamines onto previously supersensitive receptors was considered to be involved with the differences observed.

Social isolation and tolerance development to sodium barbital in mice.

The effect of the duration of isolation periods on the development of tolerance to sodium barbital was studied in mice. The HD50 values for pentobarbital-induced hypnosis were higher in all mice that were long-term treated with sodium pentobarbital, whether or not they were isolated or in groups. Diazepam HD50s were higher in mice isolated and long-term treated with sodium barbital for 38 days and in grouped animals treated with the barbiturate for 20 and 30 days. Social isolation for 8 weeks plus 23 days increased the pentobarbital hypnotic dose (HD50). These data show that social isolation increased the rate of tolerance acquisition to sodium barbital by mice.

Consideraçöes sobre homeostase: tolerância e abstinência / Homeostasis: tolerance and abstinence

Tecem-se comentários sobre os conceitos de tolerância e dependência a drogas que atuam no Sistema Nervoso Central (SNC), particularmente barbitúricos, considerando-se esses fenômenos como processos adaptativos do organismo que visa manter sua homeostase