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Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid-induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were observed in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala. Taken together, our data demonstrates that chronic administration of clinically relevant doses of ampakines have the ability to elevate neurotrophin expression in different brain regions, and may have therapeutic benefit in multiple neurodegenerative and/or neuropsychiatric disorders. more...

Ampakines are small molecule positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). One class II ("low impact") ampakine, CX717, has been implicated to have a neurotoxic effect based on findings in nonclinical, long-term toxicity studies. The neurotoxicity concerns, which halted the clinical development of the molecule, arose due to a finding of extensive white matter vacuolation in multiple brain regions of animals that were administered high doses of CX717 in several test species (unpublished data). This work characterized the features and a potential mechanism by which ampakines induce vacuoles in brain tissue. Brain sections from adult rats given CX717 (750 mg/kg BID by oral gavage) exhibited no vacuoles with acute or short-term dosing. However, after 14 or more days of treatment, vacuoles were prominent in cerebellum, globus pallidus, and hippocampus. Vacuole margins were lined by glial fibrillary acidic protein (GFAP), and by transmission electron microscopy were shown to be astrocyte processes. CX717-associated vacuoles occurred in formaldehyde-fixed specimens but not flash-frozen samples. Time-course experiments showed that brain tissue slices from CX717-treated animals exhibit no vacuoles until immersed in formaldehyde fixative, whereupon vacuoles form and expand in a time-dependent manner. Chemical interactions in test tube experiments have demonstrated that the combination of CX717 and formalin in an aqueous solution produces an exothermic reaction. Taken together, the data indicate that CX717 does not induce vacuoles in vivo, but rather is associated with astrocyte vacuolation post mortem, likely as the ampakine reacts with formalin to produce gas pockets in brain parenchyma. more...

Preclinical studies demonstrated that ocinaplon, a positive allosteric modulator of GABA(A) receptors, possesses anxiolytic-like actions at doses devoid of the side effects typically associated with benzodiazepines. The aim of this study was to evaluate the effects of ocinaplon in a multicenter, double-blind proof-of-concept trial of male and female outpatients who met DSM-IV criteria for GAD with no coexisting depression, and had a baseline score of > or =20 on the Hamilton Scale for Anxiety (HAM-A). Patients with more...

Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (approximately 1:2:17). This in vitro profile is supported by microdialysis studies in freely moving rats, where bicifadine (20 mg/kg i.p.) increased extrasynaptic norepinephrine and serotonin levels in the prefrontal cortex, norepinephrine levels in the locus coeruleus, and dopamine levels in the striatum. Orally administered bicifadine is an effective antinociceptive in several models of acute, persistent, and chronic pain. Bicifadine potently suppressed pain responses in both the Randall-Selitto and kaolin models of acute inflammatory pain and in the phenyl-p-quinone-induced and colonic distension models of persistent visceral pain. Unlike many transport inhibitors, bicifadine was potent and completely efficacious in both phases of the formalin test in both rats and mice. Bicifadine also normalized the nociceptive threshold in the complete Freund's adjuvant model of persistent inflammatory pain and suppressed mechanical and thermal hyperalgesia and mechanical allodynia in the spinal nerve ligation model of chronic neuropathic pain. Mechanical hyperalgesia was also reduced by bicifadine in the streptozotocin model of neuropathic pain. Administration of the D(2) receptor antagonist (-)-sulpiride reduced the effects of bicifadine in the mechanical hyperalgesia assessment in rats with spinal nerve ligations. These results indicate that bicifadine is a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models, with activation of dopaminergic pathways contributing to its antihyperalgesic actions. more...

Studies using mice with point mutations of GABA(A) receptor alpha subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA(A) receptors bearing the alpha(1) and alpha(2) subunits. This hypothesis predicts that a compound with high efficacy at GABA(A) receptors containing the alpha(1) subunit would produce sedation, whereas an agonist acting at alpha(2) subunit-containing receptors (with low or null efficacy at alpha(1)-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA(A) receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at alpha(1)beta(2)gamma(2S) constructs of the GABA(A) receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing alpha(2), alpha(3), or alpha(5) subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA(A1a) receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by alpha(1) subunit-containing GABA(A) receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators. more...

This report describes the first evaluation in humans of DOV 216,303, a putative antidepressive that inhibits the reuptake of norepinephrine, serotonin, and dopamine. Subjects received single oral doses of 5 to 150 mg of DOV 216,303 or placebo. At 150 mg, 4 of 7 subjects reported gastrointestinal disturbances. In the multiple-dose phase of the evaluation, subjects received total daily doses of 50, 75, or 100 mg of DOV 216,303 or placebo for 10 days. At a total daily dose of 100 mg, gastrointestinal disturbances were reported in 4 of 6 volunteers. In both the single- and multiple-dose evaluations, no significant changes were noted in vital signs, electrocardiogram, hematology, or clinical chemistry, DOV 216,303 was rapidly absorbed (plasma t m a x of 0.7-1.2 hours and t 1 / 2 of 3.3-4.4 hours), with dose-proportional C m a x and AUC values. Furthermore, no remarkable difference was apparent in either the C m a x or AUC τ of DOV 216,303 following 1 and 10 days of dosing. The present results demonstrate that DOV 216,303 is safe and well tolerated both at single doses of up to 100 mg and multiple doses of up to 100 mg/day for 10 days. Plasma concentrations of DOV 216,303 after doses > 10 mg exceed its reported IC 5 0 values for inhibition of biogenic amine reuptake. more...

The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. “Broad spectrum” antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine. more...

DOV 21,947 [(+)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] inhibits the reuptake of [ 3 H]serotonin, [ 3 H]norepinephrine, and [ 3 H]dopamine in human embryonic kidney (HEK) 293 cells expressing the corresponding human recombinant transporters (IC50 values of 12, 23, and 96 nM, respectively). This compound also inhibits [ 125 I]RTI 55 (3h-(4-iodophenyl)tropane-2h-carboxylic acid methyl ester) binding to the corresponding transporter proteins in membranes prepared from these cells (Ki values of 99, 262, and 213 nM, respectively). DOV 21,947 reduces the duration of immobility in the forced swim test (using rats) with an oral minimum effective dose of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. DOV 21,947 also produces a dose-dependent reduction in immobility in the tail suspension test, with a minimum effective oral dose of 5 mg/kg. The ability of DOV 21,947 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or norepinephrine. D 2003 Elsevier Science B.V. All rights reserved. more...

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated. 3. DOV 102,677 is a novel, “triple” uptake inhibitor that suppresses [3H]dopamine (DA), [3H]norepinephrine (NE) and [3H]serotonin (5-HT) uptake by recombinant human transporters with IC50 values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression. more...

Animal tests of anxiety are used to screen novel compounds for anxiolytic or anxiogenic activity, to investigate the neurobiology of anxiety, and to assess the impact of other occurrences such as exposure to predator odors or early rearing experiences. This unit presents protocols for the most commonly used animal tests of anxiety. The Geller-Seifter conflict test, the social interaction test, light/dark exploration, the elevated plus-maze, defensive burying, and the thirsty rat conflict. The protocols are described in terms of drug screening tests, but can be modified easily for other purposes. more...

A simple, sensitive, and efficient HPLC method for the determination of calmodulin levels in brain tissue extracts is described. The assay is linear with respect to both calmodulin and protein concentrations. The specificity and validity of this assay for calmodulin is demonstrated by parallel radioimmunoassay determinations which give equivalent results. Determination of calmodulin levels in various brain regions revealed a high concentration of this protein in the hypothalamus, by comparison to other areas examined. more...

CL 218,872 is the first non-benzodiazepine to selectively displace brain specific 3H-diazepam binding with a potency comparable to that of the benzodiazepines. Like the benzodiazepines, CL 218,872 increased punished responding in a conflict situation and protected against the convulsions induced by pentylenetetrazole. These three pharmacological properties are highly predictive of anxiolytic activity. Unlike the benzodiazepines, however, CL 218,872 was relatively inactive in tests designed to measure effects on neuronal systems which utilize GABA, glycine and serotonin as transmitters. Furthermore, CL 218,872 was relatively free of the ataxic and depressant side effects commonly associated with the benzodiazepines. Because of this high degree of selectivity, CL 218,872 may represent a new probe for investigating neuronal substrates of anxiety. more...

Brain-specific binding sites have been isolated on synaptosomal membrane fragments which recognize pharmacologically active benzodiazepine (BDZ's) and triazolopyridazines (TPZ's). While early evidence indicated the existence of a single homogeneous class of BDZ binding sites, more recent biological and pharmacological studies support the notion of BDZ receptor multiplicity. We now propose that two biochemically distinct BDZ receptors exist in brain which are responsible for the mediation of different pharmacological activities. Type I BDZ receptors display a high affinity for both BDZ's and TPZ's, are not coupled to GABA receptors or to chloride ionophores, and are the sites which mediate anxiolytic actions. Type II BDZ receptors display a high affinity for BDZ's display a low affinity for TPZ's, are coupled to GABA receptors and/or chloride ionophores, and are the sites which mediate pharmacological effects other than anxiolytic activity. more...

Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed. more...

The effects of neuronal degeneration on benzodiazepine binding parameters were assessed following bilateral electrolytic lesions of rat brain lateral olfactory tracts. [3H]Flunitrazepam binding was measured in olfactory bulb homogenates 1, 7 and 14 days post-lesion. Specific [3H]flunitrazepam binding was significantly decreased two weeks after lesions. Diminution in binding was associated with a decreased population of sites (Bmax) rather than affinity alterations (KD). The time course for the loss of receptors is compatible with retrograde degeneration and suggests that specific benzodiazepine binding sites are in part located on mitral cell bodies. more...

A number of investigators have shown compelling evidence for multiplicity of benzodiazepine (BDZ) receptors. The present study addresses the query of BDZ receptor heterogeneity, in vitro, with respect to temperature. In competition studies involving rat cerebellar tissue, CL 218,872 produced Hill slopes near unity at both 0 degree C and 37 degrees C. In contrast, similar experiments utilizing cortical tissue from rats and mice produced Hill slopes of 0.69 and 0.66 at 0 degree C and 37 degrees C respectively. 3H-Flunitrazepam-photoaffinity labeling of cortical and cerebellar membranes was conducted at 0 degree C and 37 degrees C. SDS-PAGE fluorographic analyses of photolysed 3H-flunitrazepam (3H-Flu) revealed one intensely labeled 51K band in the cerebellum at both temperatures, which was specifically chased by diazepam. Similar experiments conducted in cortical tissue revealed photoaffinity labeling of at least three distinct macromolecules, one intense 51K and two less intense 55K and 59K bands. Labeling of each of these bands was chased specifically by diazepam. These data, taken together, indicate the existence of regional BDZ receptor heterogeneity under physiological conditions. more...

Two twelve-animal groups of rats were trained to press a lever for food reinforcement under either a fixed ratio 20 (FR 20) or a fixed interval 2 min (FI 2 min) schedule. During the FI 2 min schedule a measure of adjunctive behavior (i.e., drinking) was taken. Each group was then administered various doses of chlorpromazine (2.5, 5.0, 10.0 mg/kg, P.O.), clozapine (2.5, 5.0, 10.0 mg/kg, P.O.) or diazepam (5.0, 10.0, 15.0 mg/kg, P.O.) in a random order. All three drugs reliably reduced FR 20 response rates in a dose dependent manner, but chlorpromazine and clozapine were more potent in this regard. Chlorpromazine reduced FI 2 min responses rates especially in the terminal portions of the fixed intervals while diazepam generally elevated rates primarily in the min-portion of the interval. Clozapine produced a less defined effect on overall responding. All three drugs affected index of curvature. Only chlorpromazine was able to reliably reduce occurrence of adjunctive behavior and reinforcements. more...

Tolerance to the anti-strychnine and anti-bicuculline properties of diazepam developed after chronic administration of diazepam. No tolerance developed to the anti-pentylenetetrazole activity of diazepam. These latter results suggest that anti-pentylenetetrazole activity may reflect the anxiolytic potential of benzodiazepines. Since bicuculline and strychnine block GABA and glycine receptors, respectively, the present results suggest that the GABA-ergic and glycine-ergic properties of the benzodiazepines develop tolerance and for this reason are unrelated to the anxiolytic actions of benzodiazepines. more...

The increases in firing rates of hippocampal cells were examined following microiontophoretic application of several muscarinic cholinergic receptor agonists. The agonists studied had been pharmacologically characterized previously and divided into two classes: class A agonists (e.g. acetylcholine, carbamylcholine, and oxotremorine-M) which maximally stimulate PI turnover and reveal mAChR heterogeneity, and class B agonists (e.g. bethanecol and oxotremorine-1) which poorly stimulate PI turnover and do not alter mAChR conformation/orientation in the hippocampus. While comparable stimulatory effects on hippocampal pyramidal cell firing rates were seen with both classes of agonists during short (20 s) ejection periods, longer applications (greater than 25 s) produced class-dependent differential firing patterns. Prolonged ejection of class A agonists selectively desensitized cells to further, continued application in the same ejection period, and the firing rates declined. Class B agonists produced stimulatory responses in hippocampal cells during the entire ejection period, and DE was not observed. This desensitization effect (DE) was observed only for bursts and not for simple spikes. more...

Groups of C57 Bl/6j mice (alcohol preferring) and DBA/2j mice (alcohol avoiding) were fasted for 24 hours and administered glucose. At 30, 120 and 300 minutes after glucose, the C57 Bl/6j mice had significantly higher levels of plasma glucose than the DBA/2j strain. These differences were observed in comparable groups given either forced access or no access to alcohol. In ad lib fed animals never exposed to alcohol, C57 Bl/6j mice had higher levels of plasma insulin than DBA/2j mice. Plasma levels of glucose and corticosterone were not significantly different in ad lib or fasted animals. The injection of insulin zinc protamine to DBA/2j mice produced 100% convulsions within one hour, but produced no convulsions in C57 Bl/6j mice for as long as 4 hours after administration. These data demonstrate that an insulin resistancy exists in C57 Bl/6j mice which is not dependent upon any prior alcohol experience. Evidence supporting a functional relationship between this diabetogenic disturbance and alcohol preference was obtained in C57 Bl/6j mice which were allowed to choose between water or a 10% alcohol solution (v/v). Insulin zinc protamine produced a selective dose-dependent reduction in alcohol intake. Additional support is received from the discovery that Chinese hamsters, a species genetically predisposed to diabetes, display an impressive preference for 10% alcohol. more...

The age-related, regionally-specific loss of 3H-diazepam binding sites in nervous mutant mice paralleled the loss of cerebellar Purkinje cells. These results suggest that benzodiazepine receptors reside on cerebellar Purkinje cells. more...

Both clinical and laboratory studies suggest that age-related memory deficits may be due, at least in part, to disturbances in muscarinic acetylcholine (mAChR) receptors. In order to further evaluate this premise, the present studies examined the electrophysiological responses rates of hippocampal pyramidal cells to iontophoretically applied ACh in young, middle-age and aged animals. The relationship between age and muscarinic agonist and antagonist binding in the hippocampus was also examined. In addition, possible age-related changes in receptor-effector coupling were assessed by determining calmodulin levels and the activities of phospholipid methyl-transferase I and II. Analysis of electrophysiological data showed selective age-related decrements in the ability of ACh to alter burst rate but not simple spike rate. These age-related decreases in the efficacy of ACh to increase burst rate were not paralleled by decreases in mAChR density as assessed by 3H-QNB binding, but they were temporally paralleled by age-related changes in the ability of oxotremorine to inhibit 3H-QNB binding. In the young animals, the resultant Hill coefficients derived from these analyses approached 1, while in the middle and old aged animals, the Hill coefficients deviated significantly from 1, indicating the possible existence of 2 or more receptor states with differential affinity for oxotremorine in the 2 older age groups. When carbamylcholine was used to inhibit 3H-QNB, these complex binding patterns were seen even in the young, since carbamylcholine induces conformational/orientational changes in the mAChR while oxotremorine does not.(ABSTRACT TRUNCATED AT 250 WORDS) more...

The imidazopyridines EMD 35993 and EMD 41717 antagonized the anticonflict actions of diazepam and chlordiazepoxide in rodent models which are predictive for anxiolytic action in man. In contrast to other described benzodiazepine antagonists, these compounds did not antagonize either the anticonvulsant or muscle relaxant properties of either benzodiazepine. Both EMD 39593 and EMD 41717 competitively inhibit the binding of [3H]diazepam to brain membranes, but do not exhibit regional differences in potency. These observations suggest that both EMD 39593 and EMD 41717 display some selectivity in antagonizing the anxiolytic properties of benzodiazepines, and as such may be useful tools in identifying neuronal substrates of anxiety. more...

The in vitro and in vivo ability of benzodiazepines to inhibit specific 3H-diazepam binding correlated with their ability to increase punished responding in a conflict situation. Conflict and foot shock, the punishing stimulus used in most conflict procedures, also altered 3H-diazepam binding. These data implicate 3H-diazepam binding sites in mediating at least some of the anxiolytic properties of benzodiazepines and suggest the existence of some endogenous substance which might be involved in the etiology of anxiety. more...

The effects of trimethyl tin on passive and active avoidance behavior, hippocampal muscarinic receptors and hippocampal cell destruction were examined in male rats. The animals were intubated with 18 μmoles/kg (3.5 mg/kg) of TMT hydrochloride or vehicle. When tested two weeks later treated animals exhibited marked deficits in retention of passive avoidance and extinction of active avoidance tasks. Receptor binding analysis, using 3H-QNB, revealed a significant decrease (21%) in muscarinic receptor density in the hippocampus. Histological examination of the hippocampus revealed a concomitant loss in pyramidal cells in these animals. These results suggest that muscarinic receptors reside on the hippocampal pyramidal cells and that these cells and receptors may be involved in retention of passive avoidance behavior. more...

The effects of chronic prolactin administration on amphetamine or dopamine (DA) induced rotational behavior was examined in mature (6 month) and senescent (24 month) Wistar rats which were unilaterally lesioned in the left substantia nigra with 6-hydroxydopamine. Prolactin (150 ng/hr) was administered for 7 days via subcutaneously implanted Alzet minipumps. Amphetamine (AMPH) (0, 10 micrograms) or DA (0, 25 micrograms) was administered through cannula which had been implanted into the right (intact) striatum. Both DA-active agents were given prior to pump implantation and on day 4 of prolactin administration. The AMPH was dissolved in saline (1 microliter; pH, 5.5-6.0), while DA was dissolved in N2 bubbled distilled H2O (1 microliter; pH, 5.5-6.0) and the animals were pretreated with nialamide (50 mg/kg) intraperitoneally 1 hr before DA or DA-vehicle injection. The order of drug administration was counterbalanced within the age groups. Results showed that both groups of animals exhibited higher rotational behavior scores following prolactin treatment. In fact, there was a trend toward greater enhancement of rotational behavior in the senescent animals following prolactin treatment than that seen in mature animals. These results parallel those reported previously wherein it was found that striatal DA receptor concentrations (as assessed with [3H]spiperone binding) were higher in prolactin treated mature and senescent animals than in their respective controls. The findings suggest that there is a relationship between increases in the density of striatal DA receptors and improvement in motor performance tasks in senescent animals. more...

SQ 65,396, a clinically active anti-anxiety agent, enhanced the binding of 3H-diazepam at 1.5 nM. This effect was due to an increase in the affinity for the ligand, without a change in the number of 3H-diazepam binding sites. This action of SQ 65,396 may mediate its anti-anxiety effects by affecting the action of an endogenous modulator of the "benzodiazepine receptor." Several other substances and treatments increase the affinity of 3H-diazepam for its receptors by mechanisms which may be related to the effect produced by SQ 65,396. more...

Synaptosomes from rat cerebral cortex incubated with 3H-S-adenosyl-L-methionine (3H-SAM) displayed an increase in chloroform- extractable tritium when norepinephrine was added to the reaction mixture. The products of this mixture were maximally generated from intact synaptosomes, only partially inhibited by propranolol, and not enhanced by exogenous phospholipids. Thin layer chromatographic analysis of these chloroform extracts in three solvent systems yielded large norepinephrine- stimulated peaks of radioactivity that did not consistently co-chromatograph with authentic methylated phospholipid standards: phosphatidylmonomethylethanolamine (PME), phosphatidyldimethylethanolamine (PDE), and phosphatidylcholine (PC). Further, attempts to identify these peaks of radio-activity using as standards several putative methylated products of varied chemical classes, failed to elucidate likely candidates. It appears that while norepinephrine markedly stimulates the amount of tritium extracted into the chloroform phase, careful and positive structural elucidation of formed products is required before it can be concluded that these are indeed methylated phospholipids. more...

Two groups of non-deprived male Wistar rats and one group of male Sprague-Dawley rats were offered a choice of water an daily-increasing concentrations of ethanol. Each group's distribution of highest ethanol acceptance concentrations approximated a bimodal distribution with respect to concentration. Further, rats in each group which drank ethanol at high concentrations maintained relatively constant intakes of pure ethanol. These results are discussed in terms of taste and olfaction, central nervous system sensitivity and emotionality. more...

The binding of [ 3 H]diazepam and [ 3 H]flunitrazepam in rat cerebral cortex was not altered by either acute or chronic administration of pentylenetetrazol except in rats made to convulse 30 minsbefore sacrifice. Rats treated for up to 6 months with doses of pentylenetetrazol which are below seizure threshold in naive rats, became increasingly sensitive to the CNS stimulant effect of pentylenetetrazol as demonstrated by the development of myoclonus and convulsions during treatment periods. These effects were not correlated with any changes in benzodiazepine binding in cerebral cortex or cerebellum and [ 3 H]quinuclidinyl benzilate binding in cerebral cortex. Acute convulsant doses of pentylenetetrazol increased benzodiazepine binding in cerebral cortex, but only in those rats which actively convulsed. Benzodiazepine and cholinergic receptors of the cortex, and benzodiazepine receptors of the cerebellum, therefore, do not appear to change with either the acute or chronic subconvulsive administration of pentylenetetrazol. more...

Intraventricular injection of 6-hydroxydopamine resulted in only a temporary decrement of self-stimulation. Treatment with the alpha-adrenergic receptor blocking agent, phentolamine, had virtually no effect on self-stimulation in either 6-hydroxydopamine treated or normal rats; whereas haloperidol, a dopamine receptor blocking agent, markedly reduced self-stimulation in normal rats. Treatment with FLA-63, a potent inhibitor of dopamine-beta-hydroxylase, had no effect on self-stimulation but very significantly reduced eating. These results imply that dopamine may be importantly involved in the mediation of positive reinforcement and/or that the role of norepinephrine may be a minor one. more...