Subjective perception of cognition is related to mood and not performance.

OBJECTIVE: Clinicians monitor cognitive effects of drugs primarily by asking patients to describe their side effects. We examined the relationship of subjective perception of cognition to mood and objective cognitive performance in healthy volunteers and neurological patients. METHODS: Three separate experiments used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease. Correlations were calculated for change scores on and off drugs in the first two experiments and for the single assessment in Experiment 3. RESULTS: Across all three experiments, significant correlations were more frequent (chi(2)=259, P < or = 0.000) for mood versus subjective cognitive perception (59%) compared with subjective versus objective cognition (2%) and mood versus objective cognitive performance (2%). CONCLUSIONS: Subjective perception of cognitive effects is related more to mood than objective performance. Clinicians should be aware of this relationship when assessing patients' cognitive complaints.

Tolerability and efficacy of oral loading of levetiracetam.

OBJECTIVE: Nonsedating antiepileptic drugs (AEDs) that can be initiated rapidly are desirable in a variety of clinical situations. Levetiracetam (LEV) is a newer AED, with a recently approved parenteral formulation, that can be initiated at doses effective in controlling seizures. We investigated whether oral loading of levetiracetam is well tolerated and facilitates stabilization and discharge of patients in epilepsy monitoring units (EMU). METHODS: Adult patients in the EMU at two centers were identified who received 1,500 mg of LEV in a single dose. This was an observational study of these patients where LEV was thought to be an appropriate component of the therapeutic regimen. Patients were either LEV naive or had been off all LEV for at least 3 days. LEV maintenance was begun 12 hours later at doses of 500 to 1,000 mg twice a day. RESULTS: A total of 37 adult patients (20 female) were identified. There were no spontaneous complaints of side effects. Upon questioning, 33 patients (89%) denied side effects. The remaining 4 patients (11%) reported transient irritability, imbalance, tiredness, or lightheadedness. Eleven patients (mean weight = 85.0 Kg) had mean LEV serum concentration of 31.5 microg/mL after 1 hour, 23 (mean weight 85.7 Kg) had mean concentration of 30.77 microg/mL after 2 hours, five (mean weight 84.3 Kg) had mean concentration of 12.1 microg/mL after 12 hours, and two (mean weight 94 Kg) had mean concentration of 7.4 microg/mL after 14 hours. No seizures occurred within 24 hours of loading. All patients were able to be discharged 3 to 30 hours after loading. CONCLUSIONS: In the population surveyed, oral loading with levetiracetam was well-tolerated and rapidly yielded serum concentrations thought to decrease seizure frequency. This regimen facilitated discharge from the epilepsy monitoring units.

Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers.

BACKGROUND: The relative cognitive and behavioral effects of lamotrigine (LTG) and topiramate (TPM) are unclear. METHODS: The authors directly compared the cognitive and behavioral effects of LTG and TPM in 47 healthy adults using a double-blind, randomized crossover design with two 12-week treatment periods. During each treatment condition, subjects were titrated to receive either LTG or TPM at a target dose of 300 mg/day for each. Neuropsychological evaluation included 17 measures yielding 41 variables of cognitive function and subjective behavioral effects. Subjects were tested at the end of each antiepileptic drug (AED) treatment period and during two drug-free conditions (pretreatment baseline and 1 month following final AED withdrawal). RESULTS: Direct comparison of the two AEDs revealed significantly better performance on 33 (80%) variables for LTG, but none for TPM. Even after adjustment for blood levels, performance was better on 19 (46%) variables for LTG, but none for TPM. Differences spanned both objective cognitive and subjective behavioral measures. Comparison of TPM to the non-drug average revealed significantly better performance for non-drug average on 36 (88%) variables, but none for TPM. Comparison of LTG to non-drug average revealed better performance on 7 (17%) variables for non-drug average and 4 (10%) variables for LTG. CONCLUSIONS: Lamotrigine produces significantly fewer untoward cognitive and behavioral effects compared to topiramate (TPM) at the dosages, titrations, and timeframes employed in this study. The dosages employed may not have been equivalent in efficacy. Future studies are needed to delineate the cognitive and behavioral effects of TPM at lower dosages.

Phosphorylation enhances inactivation of N-type calcium channel current in bullfrog sympathetic neurons.

We have investigated the effects of phosphatase and protein kinase inhibitors on calcium channel currents of bullfrog sympathetic neurons using the whole cell configuration of the patch clamp technique. Intracellular dialysis with the phosphatase inhibitors okadaic acid and calyculin A markedly enhanced the decline of inward current during a depolarizing voltage step. Tail current analysis demonstrated that this was genuine inactivation of calcium channel current, not activation of an outward current. The rapidly inactivating current is N-type calcium current (blocked by omega-conotoxin and resistant to nifedipine). Staurosporine, a nonselective protein kinase inhibitor, prevented the action of okadaic acid, suggesting that protein phosphorylation is involved. Under control conditions, the time course of inactivation could be described by the sum of two exponentials (tau = 150 ms and 1200 ms), plus a constant (apparently noninactivating) component, during depolarizations lasting 2 s. Okadaic acid induced a rapid inactivation process (tau = 15 ms) that was absent or negligible under control conditions, without obvious effect on the two slower time constants. As in control cells, inactivation in okadaic-acid-treated cells was strongest near -20 mV, with less inactivation at more positive voltages. However, inactivation did not depend on calcium influx. Modulation of calcium channel activity by phosphorylation may underly the spontaneous shift between inactivating and noninactivating modes recently observed for N-type calcium channels. Differences in basal phosphorylation levels could also explain why N-type calcium channels, originally described as rapidly and completely inactivating, inactivate slowly and incompletely in many neurons.

Intracellular ATP and GTP are both required to preserve modulation of N-type calcium channel current by norepinephrine.

Norepinephrine (NE) inhibits voltage-dependent calcium channels of sympathetic neurons. We investigated the role of intracellular nucleotides in this inhibition for clues to receptor-channel coupling mechanisms. Both ATP and GTP are required to preserve NE responsiveness during whole-cell dialysis. The response to NE was gradually lost in bullfrog sympathetic neurons dialyzed with GTP as the only nucleotide, ATP only, or no nucleotides. Replacing ATP with ATP[gamma-S] resulted in spontaneous modulation of calcium channel current, possibly because of production of GTP[gamma-S]. The nonhydrolyzable ATP analog p[NH]ppA could substitute for ATP to preserve NE responsiveness. The protein phosphatase inhibitors okadaic acid and calyculin-A did not affect NE inhibition of calcium channel current, or recovery from that inhibition. These results suggest protein phosphorylation is not involved in the inhibition of calcium channel current, but binding of ATP to some intracellular site is required for the coupling of adrenergic receptors to calcium channels.

Actions of mu, delta and kappa opioid agonists and antagonists on mouse primary afferent neurons in culture.

The effects of selective mu, delta and kappa opioid agonists and antagonists were studied on somatic calcium-dependent action potentials recorded from mouse dorsal root ganglion (DRG) neurons grown in dissociated cell culture. The mu selective agonist, PL 017, and the delta selective agonist, [D-Pen2, L-Pen5] enkephalin (DPLPE), reduced action potential duration of a subpopulation (21/56) of DRG neurons. Leucine-enkephalin reduced action potential duration of all neurons sensitive to PL 017 or DPLPE, whereas 85% of neurons responding to leucine-enkephalin responded to either PL 017 or DPLPE. Only 15% of neurons responded to both PL 017 and DPLPE. There was no significant difference in the response to PL 017 or DPLPE when compared to leucine-enkephalin. In another experiment, the kappa selective agonist dynorphin A (DYN A), PL 017 and DPLPE reduced action potential duration of a subpopulation (15/67) of DRG neurons. There was a heterogeneous response among neurons to PL 017, DPLPE and DYN A inasmuch as 21.4% of neurons responded to all three agonists, 35.7% responded to PL 017 and DYN A, 35.7% responded only to PL 017 and 7.1% responded only to DYN A. Responses to the mu selective agonist PL 017 were antagonized by the reversible opioid antagonist naloxone and the selective mu antagonist SMS 201-995 in a concentration-dependent fashion. Responses to PL 017 were not altered by the selective delta antagonist ICI 174864. Responses to PL 017 were reduced by the irreversible, selective mu antagonists beta-funaltrexamine and naloxonazine in a concentration-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual actions of phorbol esters to decrease calcium and potassium conductances of mouse neurons.

Phorbol esters, which substitute for diacylglycerol to activate protein kinase C, were applied to mouse dorsal root ganglion and cerebral hemisphere neurons in cell culture. The phorbol esters, phorbol 12,13-dibutyrate and 12-O-tetradecanoyl-phorbol-13-acetate, prolonged calcium-dependent action potential duration at resting membrane potential and at more negative membrane potentials but decreased action potential duration following membrane depolarization to less than -45 mV. When calcium and potassium currents were recorded using the single electrode voltage-clamp technique, the phorbol esters were shown to reduce both voltage-dependent calcium and potassium currents. These studies have demonstrated directly that phorbol esters, presumably by activating protein kinase C, can modify more than one membrane conductance in individual neurons.

Phorbol esters: voltage-dependent effects on calcium-dependent action potentials of mouse central and peripheral neurons in cell culture.

The beta-phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol 12,13-dibutyrate (PDBu), which activate protein kinase C, were applied to mouse dorsal root ganglion (DRG) and cerebral hemisphere neurons grown in primary dissociated cell culture. Phorbol esters did not modify the membrane potential or input resistance of either type of neuron. To assess the effects of beta-phorbol esters on voltage-dependent conductances, the effects of PDBu and TPA on action potentials evoked from these neurons were determined. The neurons were bathed in a solution containing 5 mM tetraethylammonium and action potentials that contained sodium and calcium components were evoked. When applied at resting membrane potential and at more negative potentials, PDBu and TPA reversibly increased action potential duration. The alpha-phorbol ester 4-alpha-phorbol, which does not activate protein kinase C, did not modify action potential duration. The effects of the beta-phorbol esters, however, were voltage-dependent. When the neurons were depolarized to membrane potentials less negative than -50 mV, PDBu and TPA reduced action potential duration. The effects of both PDBu (10 nM-1 microM) and TPA (100 pM-100 nM) on action potential duration were dose-dependent. The prolongation of action potentials produced at large negative potentials may be due to a reduction in voltage-and/or calcium-dependent potassium conductance, since the prolongation was associated with a reduction in the potassium-dependent afterhyperpolarization; following membrane depolarization in control solution, action potential duration was increased for several minutes, while the afterhyperpolarization was reduced and, following this prolongation, phorbol esters no longer prolonged the action potentials.(ABSTRACT TRUNCATED AT 250 WORDS)

Forskolin and phorbol esters reduce the same potassium conductance of mouse neurons in culture.

Second messenger systems may modulate neuronal activity through protein phosphorylation. However, interactions between two major second messenger pathways, the cyclic AMP and phosphatidylinositol systems, are not well understood. The effects of activators of cyclic AMP-dependent protein kinase and protein kinase C on resting membrane properties, action potentials, and currents recorded from mouse dorsal root ganglion neurons and cerebral hemisphere neurons grown in primary dissociated cell culture were investigated. Neither forskolin (FOR) nor phorbol 12,13-dibutyrate (PDBu) altered resting membrane properties but both increased the duration of calcium-dependent action potentials in both central and peripheral neurons. By means of the single-electrode voltage clamp technique, FOR and PDBu were shown to decrease the same voltage-dependent potassium conductance. This suggests that two independent second messenger systems may affect the same potassium conductance.

Dynorphin A decreases voltage-dependent calcium conductance of mouse dorsal root ganglion neurones.

The actions of the opioid peptides dynorphin A and (Leu)enkephalin were assessed on calcium-dependent action potentials and inward calcium currents recorded from somata of mouse dorsal root ganglion (d.r.g.) neurones grown in primary dissociated cell culture. Dynorphin A and (Leu)enkephalin decreased the duration of somatic calcium-dependent action potentials in a portion of d.r.g. neurones impaled with potassium acetate-filled micropipettes. When substantial potassium conductance was blocked by intracellular injection of caesium acetate, d.r.g. neurones continued to respond to dynorphin A but responses to (Leu)enkephalin were abolished. In voltage-clamp experiments, dynorphin A but not (Leu)enkephalin reduced the magnitude of inward calcium currents. Dynorphin A responses were blocked by the opiate antagonist naloxone. The dynorphin A effect was due to reduction of voltage-dependent calcium conductance since dynorphin A reduced depolarization-evoked inward currents but did not alter membrane conductance following blockade of calcium channels by cadmium, and because dynorphin A reduced the instantaneous current-voltage slope (chord conductance) during step commands that produced maximal activation of voltage-dependent calcium conductance. Dynorphin A binds with high affinity to kappa-opioid receptors. (Leu)enkephalin, which has affinity for both mu- and delta-receptors but not for kappa-opioid receptors, was without effect on calcium conductance. Therefore, we suggest that kappa-receptors are coupled to voltage-dependent calcium-channels and that binding of dynorphin A produces a decrease of calcium current.

Adenosine agonists reduce voltage-dependent calcium conductance of mouse sensory neurones in cell culture.

Adenosine and several of its analogues produced a concentration-dependent shortening of calcium-dependent action potential (c.a.p.) duration of mouse dorsal root ganglion (d.r.g.) neurones in dissociated cell culture. The following rank order of potency was obtained: N6-(L-phenylisopropyl)adenosine greater than N6-(D-phenylisopropyl)adenosine greater than N6-cyclohexyladenosine greater than 2-chloroadenosine much greater than 1-methylisoguanosine greater than adenosine. Effects of adenosine agonists on c.a.p. duration were blocked by methylxanthine adenosine antagonists. Adenosine monophosphate (AMP) and cyclic AMP shortened c.a.p.s in d.r.g. neurones, while ATP also depolarized cells. Voltage-clamp analysis revealed that the effect arose from reduction of a voltage-dependent calcium conductance. Adenosine agonists reduced depolarization-evoked inward currents but did not alter membrane conductance following blockade of calcium channels by cadmium. Additionally, adenosine reduced the instantaneous current-voltage slope (chord conductance) during step commands that produced maximal activation of voltage-dependent calcium conductance. If effects of adenosine on neuronal somata and synaptic terminals are similar, adenosine agonists may inhibit neurotransmitter release in the central nervous system by inhibiting a voltage-dependent calcium conductance. Since effects of adenosine agonists did not correspond with their relative potencies as modulators of adenylate cyclase activity or inhibitors of neurotransmitter release in peripheral tissues, a novel adenosine receptor may be involved in regulation of this conductance.

Barbiturates decrease voltage-dependent calcium conductance of mouse neurons in dissociated cell culture.

Barbiturates have been shown to reduce presynaptic release of neurotransmitter. It is likely that barbiturates alter transmitter release by decreasing calcium entry since barbiturates decrease calcium influx into synaptosomes and reduce the maximal rate of rise and duration of calcium-dependent action potentials. The mechanisms of barbiturate action on neuronal calcium entry have been studied using mouse dorsal root ganglion neurons in cell culture. Dorsal root ganglion neuron action potentials have a calcium-dependent component which is decreased by the barbiturates, pentobarbital (50-500 microM) and phenobarbital (500-2000 microM). Calcium-dependent action potential after hyperpolarization was also decreased by barbiturates. Intracellular injection of the potassium channel blocker, cesium, enhanced barbiturate actions. In voltage-clamp studies, barbiturates reduced inward calcium current and calcium chord conductance without altering the leak conductance which is present after all calcium conductance was blocked by application of cadmium ions (100 microM). Calcium current inactivation was accelerated by barbiturates but unaffected by cadmium. We conclude that barbiturates reduce calcium conductance by enhancing calcium channel inactivation or by producing open channel block of calcium channels.

Dynorphin and neoendorphin peptides decrease dorsal root ganglion neuron calcium-dependent action potential duration.

Opioid peptides decrease somatic calcium-dependent action potential duration of a subpopulation of mouse dorsal root ganglion (DRG) neurons grown in dissociated cell culture. Based on rank order of potency and naloxone sensitivity, both mu and delta opioid receptors were demonstrated on the somata of DRG neurons and were shown to have a heterogeneous distribution. The purpose of the present investigation was to determine the actions of dynorphin gene products, dynorphin A, dynorphin B, dynorphin A(1-8), dynorphin A(1-9), alpha-neoendorphin and beta-neoendorphin on DRG neuron somatic calcium-dependent action potentials and to compare the actions of dynorphin and neoendorphin peptides to the action of morphiceptin, a mu receptor-selective ligand, and Leu-enkephalin, a delta receptor-preferring ligand. We report that the dynorphin and neoendorphin peptides decreased DRG neuron somatic calcium-dependent action potential duration in a portion of DRG neurons, an action that was dose-dependent and was antagonized by naloxone. DRG neuron responses to the dynorphins and neoendorphins differed from responses to morphiceptin and Leu-enkephalin. First, many DRG neurons responded to dynorphin A but not to morphiceptin or Leu-enkephalin. Second, dynorphin A responses, unlike responses to morphiceptin or Leu-enkephalin, were present after intracellular injection of cesium, a potassium channel blocker. Dynorphin A effectiveness was decreased after deletions at the carboxy-terminus and Leu-enkephalin [dynorphin A(1-5)] was inactive at 10 microM. Thus, on DRG neurons in cell culture, dynorphins and neoendorphins act at opioid receptors distinct from mu and delta receptors, possibly kappa receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynorphin reduces voltage-dependent calcium conductance of mouse dorsal root ganglion neurons.

Dynorphin A (DYN) (1 microM) decreased somatic calcium-dependent action potential (CAP) duration of a portion of dorsal root ganglion (DRG) neurons in a naloxone reversible manner. Responses to DYN differed from responses to Leu-enkephalin in that only DYN decreases of somatic CAP duration were associated with decreased action potential after hyperpolarization and persisted after intracellular injection of the potassium channel blocker cesium. While Leu-enkephalin at 10 microM did not affect somatic CAP duration of DRG neurons impaled with cesium-filled micropipettes, dynorphin A (1-8), dynorphin B, and beta-neoendorphin were effective at 1 microM. During single electrode voltage clamp, DYN decreased inward current in a portion of DRG neurons under conditions that predominately isolated calcium current. Leak current was unaffected by dynorphin A. Therefore, we suggest that DYN decreases voltage-dependent calcium conductance. The action on calcium conductance appears specific for opioids with affinity for kappa-receptors.

Diazepam and its anomalous p-chloro-derivative Ro 5-4864: comparative effects on mouse neurons in cell culture.

The actions of diazepam and its p-chloro-derivative Ro 5-4864 were compared on mouse spinal cord and dorsal root ganglion neurons in cell culture. Diazepam enhanced but Ro 5-4864 reduced iontophoretic GABA responses in a concentration-dependent manner. Both diazepam and Ro 5-4864 limited sustained, high frequency repetitive firing of spinal cord neurons but diazepam was more potent. Ro 5-4864 was, however, more potent than diazepam in inhibiting spontaneous neuronal activity of spinal cord neurons and reducing the duration of calcium-dependent action potentials of dorsal root ganglion neurons. The differing actions of diazepam and Ro 5-4864 may account for the contrasting pharmacological spectra of the two benzodiazepines.

Dynorphin reduces calcium-dependent action potential duration by decreasing voltage-dependent calcium conductance.

The opioid peptide dynorphin decreased somatic calcium-dependent action potential duration in a portion of mouse dorsal root ganglion (DRG) neurons without altering resting membrane potential or conductance. Dynorphin action was antagonized by naloxone. Responses of DRG neurons to dynorphin differed from responses to the opioid peptides leucine-enkephalin, which binds preferentially to delta-opiate receptors, and morphiceptin, which binds preferentially to mu-opiate receptors. Firstly, many DRG neurons responded to dynorphin but not to leucine-enkephalin or morphiceptin. Secondly, dynorphin responses, unlike leucine-enkephalin or morphiceptin responses, persisted following intracellular injection of cesium, a potassium channel blocker. We suggest that dynorphin acts at an opiate receptor distinct from mu- and delta-receptors and that this receptor is coupled to a voltage-dependent calcium channel.

Opioid peptides selective for mu- and delta-opiate receptors reduce calcium-dependent action potential duration by increasing potassium conductance.

We suggest that both mu- and delta-opiate receptors on dorsal root ganglion neuron somata are coupled to voltage- and/or calcium-dependent potassium channels since opioid peptide decreases of calcium-dependent action potential duration were: (1) not associated with a change of resting membrane potential or conductance; (2) accompanied by an increase in action potential after-hyperpolarization, and (3) blocked by intracellular injection of the potassium channel blocker cesium [18]. In contrast, norepinephrine [4] and cadmium [9], which have been reported to act on voltage-dependent calcium rather than potassium channels, shortened action potential duration and decreased after-hyperpolarization amplitude, an action not blocked by intracellular iontophoresis of cesium.

Opioid peptides with differential affinity for mu and delta receptors decrease sensory neuron calcium-dependent action potentials.

Previously, it has been reported that opioid peptides decrease the calcium component of action potentials in a dose-dependent and naloxone-reversible manner consistent with mediation by opiate receptors. To clarify the relation of mu and delta opiate receptors to decreases of somatic calcium-dependent action potential duration, we investigated the potency of two opioid peptides which have different affinities for mu and delta opiate receptors, Leu-enkephalin and morphiceptin. We predicted that Leu-enkephalin would be about 1000-fold more potent than morphiceptin on dorsal root ganglion (DRG) neurons if delta receptors mediated decreases of DRG neuron somatic calcium-dependent action potentials, but that these ligands would be approximately equipotent if mu receptors mediated opiate actions. Additionally, because naloxone has been reported to have a higher affinity for mu receptors in comparison with delta receptors, we investigated agonist sensitivity to naloxone antagonism. When morphiceptin and Leu-enkephalin were tested at equimolar concentrations on individual DRG neurons, a heterogeneous pattern of response to the two opioid peptides was obtained. The response pattern ranged from Leu-enkephalin and morphiceptin producing equal effects to Leu-enkephalin, but not morphiceptin, decreasing action potential duration. DRG neurons that responded only to Leu-enkephalin were approximately 100-fold less sensitive to naloxone antagonism than DRG neurons that responded equally well to both opioid peptides. DRG neurons that responded to both opioid peptides but better to Leu-enkephalin were intermediate in sensitivity to naloxone antagonism. Our results suggest that both mu and delta opiate receptors mediate decreases in somatic calcium-dependent action potentials of DRG neurons.(ABSTRACT TRUNCATED AT 250 WORDS)