A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder.

OBJECTIVE: While Adderall has been available for the treatment of attention-deficit/hyperactivity disorder (ADHD) for several years, there are few controlled studies comparing it to methylphenidate. METHOD: Fifty-eight children with ADHD (mean age 8.1 +/- 1.4 years) were randomly assigned to receive placebo, methylphenidate, or Adderall in a double-blind, parallel-group design for 3 weeks. Dosage was adjusted at the end of weeks 1 and 2 via an algorithm based on teacher and parent ratings. Final doses were 12.5 +/- 4.1 mg/day for Adderall and 25.2 +/- 13.1 mg/day for methylphenidate. Teacher and parent ratings, as well as the psychiatrist's Clinical Global Impression (CGI), were the final outcome measures at the end of week 3. RESULTS: Both medications were superior to placebo at reducing inattentive and oppositional symptoms in the classroom and on the CGI. Adderall produced significantly more improvements on teacher ratings and the CGI than methylphenidate, although the algorithm may have limited dosing in the methylphenidate group. Seventy percent of children in the Adderall group were given medication once a day, compared with 15% of the subjects receiving methylphenidate. CONCLUSIONS: Adderall compared favorably to methylphenidate, and the behavioral effects of Adderall appear to persist longer than those of methylphenidate after individual doses.

4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.

A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring. Furthermore, many of these 4-amino[1,2,4]triazolo[4,3-a]quinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors. A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine. Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent. Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position. The most selective A1 ligand by a factor of greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-1- (trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 28 nM at the A1 receptor. The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1- phenyl[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor. Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices. Thus certain members of this 4-amino[1,2,4]triazolo[4,3-a]quinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.

Unsulfated CCK-8 not blocked by proglumide or CR 1409 in the mouse abdominal irritant-induced stretching assay: possible central site of action.

Previous studies have shown that unsulfated cholecystokinin octapeptide (CCK-8-U) shares with the sulfated octapeptide (CCK-8-S) and the carboxyl-terminal tetrapeptide (CCK-4) the ability to block abdominal irritant-induced stretching when administered intracerebroventricularly. The effects of CCK-8-U, however, are not naloxone-reversible and do not appear upon systemic administration. To assess the hypothesis that the antistretching effects of CCK-8-U are mediated by central-type (CCK-B), rather than peripheral-type (CCK-A) receptors, the present experiments examined the reversal of these effects by CR 1409, a CCK receptor antagonist with in vitro selectivity for CCK-A receptors, and by proglumide. Both antagonists, when administered ICV, blocked the antistretching effects of CCK-8-S and CCK-4 (ICV), but not those of CCK-8-U. CR 1409 was approximately 40 times more potent against CCK-8-S by the ICV route than subcutaneously, indicating a likely action on CCK-A receptors in the brain. The effects of morphine, bombesin and neurotensin (ICV) were not blocked by CR 1409, indicating specificity for CCK receptor-mediated effects. The antistretching effects of CCK-8-U do not appear to be mediated by CCK-A receptors, and the possibility of a CCK-B receptor site of action must be considered.

Bradykinin antagonism: differentiation between peptide antagonists and antiinflammatory agents.

Three non-steroidal antiinflammatory agents were tested for their ability to antagonize bradykinin in the rabbit jugular vein, the dog carotid artery and the guinea pig trachea. The new agents were compared with indomethacin, as well as with [Thi5,8,D-Phe7] bradykinin and [Thi6,9,D-Phe8] kallidin, two B2 receptor antagonists. The antiinflammatory agents did not alter the effects of bradykinin in the two isolated vessels while they completely blocked (like indomethacin) the relaxation induced by bradykinin in guinea pig tracheae contracted with histamine or neurokinin A. The two bradykinin antagonists significantly reduced the contractions of the rabbit jugular vein and the relaxation of the dog carotid artery (with endothelium) in response to bradykinin: these antagonists were however inactive against bradykinin in the guinea pig trachea. The data now reported suggest that B2 receptors are involved in the opposite (stimulant or inhibitor) effects of the kinins in the two isolated vessels while the relaxation of the guinea pig trachea is a prostaglandin-dependent phenomenon which does not involve the activation of B1 or B2 receptors.

Discriminative stimulus properties of phencyclidine (PCP)-related compounds: correlations with 3H-PCP binding potency measured autoradiographically.

Several PCP analogs, the putative PCP agonist MDP, and the sigma receptor agonists SKF-10,047 and dexoxadrol were tested for their ability to substitute for PCP in animals trained to discriminate PCP from saline. The potencies of these compounds in substituting for PCP in the behavioral task correlated with their abilities to inhibit the specific binding of 3H-PCP to rat hippocampal sections measured autoradiographically, which occurred at a single class of sites with an affinity of 85 nM and a capacity of 2646 fmol/mg protein. In addition to this specific binding, an additional nonspecific but displaceable fraction of total 3H-PCP binding was present. These results suggest that the specific 3H-PCP binding site measured in the hippocampus may be the type of binding site which mediates the behavioral effects of PCP and related compounds. Therefore, measurement of the inhibition of 3H-PCP binding at this site might aid in the search for PCP antagonists.

The effect of chronic in vivo infusion of forskolin on noradrenergic receptor sensitivity.

Forskolin, a diterpene isolated from the plant Coleus forskolii, activates the catalytic subunit of adenylate cyclase, resulting in a hormone receptor-independent increase in the intracellular production of cyclic AMP. This study was undertaken to assess the effect of chronic in vivo infusion of forskolin on noradrenergic neuronal activity. Forskolin was infused into the right lateral ventricle of male Sprague Dawley rats via Alzet osmotic minipumps (model 2001) for 7 days. Chronic infusion of forskolin resulted in a decrease in norepinephrine-stimulated cyclic AMP accumulation in the limbic forebrain. Chronic infusion of forskolin also resulted in a decrease in the Bmax for 3H-dihydroalprenolol (3H-DHA) binding to beta-adrenergic receptors in the cerebral cortex and hippocampus, with no apparent change in the Kd values. These data suggest the possibility of a novel therapeutic approach to modulating receptor sensitivity, and that chronic infusion of forskolin may be a useful model for studying the role of cyclic AMP in the control of neuronal activity.

Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin.

Sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine] was found to be a highly selective and potent competitive inhibitor of synaptosomal serotonin uptake. Sertraline also selectively reduced ex vivo uptake of serotonin and strongly antagonized the serotonin-depleting action of p-chloroamphetamine, indicating potent blockade of serotonin uptake in vivo. Acute and repeated dosing of sertraline decreased serotonin content of whole blood. Sertraline only weakly inhibited rat heart uptake of i.v. [3H]norepinephrine. In substantiation of selective blockade of serotonin uptake, sertraline potentiated various symptoms of 5-hydroxytryptophan but did not reverse reserpine-induced hypothermia. Sertraline was a very weak inhibitor of [3H]quinuclidinyl benzilate binding to rat brain membranes in vitro and did not produce anticholinergic effects in mice in vivo. Sertraline was well tolerated in mice, rats and dogs, with no locomotor stimulant effects in rats or untoward cardiovascular effects in dogs. The major metabolite, N-demethylsertraline, was also a selective serotonin uptake blocker. Sertraline strongly reduced immobility of mice in the Porsolt swim test for antidepressants. After repeated dosing in rats, sertraline diminished the cyclic AMP response of limbic forebrain adenylate cyclase to norepinephrine, as well as the binding of [3H]dihydroalprenolol to cortical membranes. It is proposed that selective blockade of serotonin reuptake can induce activation of norepinephrine neurons and subsequent down-regulation of norepinephrine receptors and that sertraline, a highly selective inhibitor of serotonin uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.

Evidence that a behavioral augmentation following repeated amphetamine administration does not involve peripheral mechanisms.

Repeated administration of amphetamine (AMPH) to rats results in an augmentation of the drug-induced locomotion and stereotypy. The studies reported below were directed at examining the potential role for some dispositional and peripheral sympathomimetic factors in mediating the enhanced stereotypy response. These included three factors associated with repeated AMPH administration: (1) the possible accumulation of AMPH in a peripheral mobilizable pool; (2) repeated sympathetic activation; and (3) AMPH metabolite-induced depletion of peripheral stores of norepinephrine. The approach utilized was to selectively reduce or mimic the peripheral actions of AMPH through the use of non-pharmacological or pharmacological manipulations which are relatively lacking in AMPH-like central stimulant effects. The results indicate that these factors cannot account for the augmentation of the behavioral response to AMPH and suggest that these behavioral alterations reflect changes in the responsiveness of brain mechanisms which mediate the behavioral effects of the drug.

Stereoselective antagonism of phencyclidine's discriminative properties by adenosine receptor agonists.

Rats trained to discriminate between phencyclidine and saline vehicle were used to test various agents for their ability to mimic or block the phencyclidine cue. ketamine, dexoxadrol, tiletamine, and phencyclidine analogs were found to mimic phencyclidine's behavioral effects. Treatment with the adenosime receptor agonists N6-cyclohexyladenosine and L-phenylisopropyladenosine blocked the discriminative properties of phencyclidine. These results suggest that adenosine receptor agonists might be useful in treating phencyclidine-induced psychosis.

Discriminative stimulus properties of delta 9-tetrahydrocannabinol: mechanistic studies.

delta 9-Tetrahydrocannabinol (THC) produces a multiplicity of pharmacologic effects including analgesic, antiinflammatory, anticonvulsant, antidiarrheal, antiglaucoma, antihypertensive, and sedative effects. Efforts to elucidate the neurochemical systems mediating the THC effects have used these and related endpoints. However, animal models useful for evaluating the mechanisms by which THC produces its unique subjective effects have only recently been established. The use of drugs as discriminative stimuli provides a means for studying such mechanisms, since generalization data from this test closely correlate with subjective properties observed in clinical studies. The present study examined the ability of various drugs to mimic or block the cue produced by THC in rats. In animals trained to discriminate 3.2 mg/kg THC from vehicle, generalization occurred consistently with cannabinoids such as 11-OH-THC, HHC, and nabilone. Stereoselective generalization was also obtained with isomers of a potent analgesic, nantradol; potencies were consistent with results from other endpoints. In contrast, THC cueing was not produced by agents acting on adrenergic, cholinergic, serotonergic, GABAergic, or opiate systems. Similarly, a number of drugs previously reported to antagonize various nonunique effects of THC uniformly failed to block its subjective properties. These results indicate that the subjective properties of THC are mediated through as yet unidentified neurochemical systems.

Anxiolytics antagonize yohimbine's discriminative stimulus properties.

Male Sprague-Dawley rats were trained to discriminate 3.2 mg/kg yohimbine HCl from saline in a two-lever operant procedure. Generalization tests indicated that piperoxane, another alpha 2-adrenergic blocker with anxiogenic properties in humans, produces yohimbine-like discriminati-effects.. In contrast to yohimbine and piperoxane, many other agents were discriminated as vehicle, including corynanthine, raubasine, phentolamine, prazosin, WB-4101, mianserin, tolazoline, and mezilamine. Diazepam caused a dose-related antagonism of yohimbine's stimulus properties. A partial antagonism of yohimbine cueing was also obtained with meprobamate, phenobarbital, chlordiazepoxide, and clonazepam. These results suggest that yohimbine discrimination in rats may be a useful model for detecting agents with anxiolytic activity.

Behavioral activating effects of opiates and opioid peptides.

Locomotor activity of rats and mice was monitored following administration of the opiates, morphine, methadone, and etonitazene, or the opioid peptides, beta-endorphin, D-Ala2-Met5-enkephalinamide, and D-Met2-Pro5-enkephalinamide. In rats these agents produced dose-related biphasic patterns of activity consisting of an initial depression in locomotion followed by a period of hyperactivity. Intravenous administration of morphine, methadone, or etonitazene in mice produced dose-related increases in stereotyped locomotor activity. The metabolically resistant enkephalin analog, D-Met2-Pro5-enkephalinamide induced a similar pattern of effects. However, doses of beta-endorphin up to 20 mg/kg, iv, failed to elicit locomotor stimulation in mice. The similarity in the naloxone-reversible responses induced by opiates and certain opioid peptides suggests that the same underlying mechanisms may subserve their behavioral effects.

Effects of antidepressants and anticholinergics in a mouse "behavioral despair" test.

A new "behavioral despair" test previously asserted to be selectively sensitive to antidepressant treatments was examined for specificity. The results of the present study demonstrate that, in addition to antidepressants, agents with anticholinergic properties such as scopolamine, danitracin, benactyzine, benztropin, clozapine and cyproheptadine also reduce immobility in this test. These results indicate that the swim test in mice cannot be considered selectively sensitive to antidepressants.

beta-Endorphin: endogenous opiate or neuroleptic?

The opiatelike neuropeptide beta-endorphin produces a spectrum of effects that contrasts with that induced by the neuroleptic haloperidol. Rats injected intraventricularly or directly into the periaqueductal gray with beta-endorphin (0.5 to 50 micrograms) exhibited rigid immobility accompanied by the loss of righting reflex; the period of rigidity was preceded or followed (depending upon dose) by a state of hyperactivity. In contrast, no dose of haloperidol tested (0.5 to 12 milligrams per kilogram) produced rigidity, loss of righting reflex, or behavioral excitation. Furthermore, whereas animals injected with haloperidol remained stationary on a vertical grid, rats injected with beta-endorphin typically slid off the grid. Moreover, combined beta-endorphin and haloperidol treatment produced flaccidity in most animals. These results do not support the contention that this opiatelike peptide may be a naturally occurring neuroleptic.

Metabolic and experimental factors in the behavioral response to repeated amphetamine.

Previous studies have shown that repeated administration of d-amphetamine results in a progressive augmentation of locomotor activity and stereotypy. The present studies demonstrate that rats also exhibit an enhanced behavioral response following multiple daily injections of l-amphetamine and methylphenidate. Furthermore, behavioral augmentation is shown to persist for at least six days after a single injection of d-amphetamine. These results demonstrate the generality of the reverse tolerance phenomenon and indicate that metabolic factors, such as the formation of false neurotransmitters, do not account for the enhanced behavioral responsiveness observed with multiple injections of these drugs. The role of experiential factors in the behavioral augmentation was studied by (1) varying the amount of continuous exposure to the experimental environment prior to d-amphetamine administration, and (2) examining the effects of repeated injections of saline or d-amphetamine in different environments prior to testing in the experimental chambers. The results, which revealed a behavioral augmentation independent of pretreatment condition, indicate that neither acclimation to the test chamber nor state-dependent conditioning to external stimuli accounts for the enhanced locomotor activity and stereotypy observed with repeated administration of psychomotor stimulants.

Role of serotonin in the discriminative stimulus properties of mescaline.

Rats were trained to discriminate intraperitoneally administered mescaline from saline in a two-lever operant chamber for food reinforcement. Reward was contingent upon responses made greater than 15 sec apart (DRL-15) on the appropriate lever paired with either drug or saline administration. Following the establishment of discriminative response control by mescaline, the animals were tested for stimulus generalization produced by mescaline after: (a) blockade of periphreral and central serotonin (5-HT) receptors with cinanserin, methysergide, or cyproheptadine; (b) blockade of peripheral 5-HT receptors with xylamidine tosylate; and (c) depletion of brain 5-HT with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA). The results show that all three central 5-HT antagonists greatly reduced the discriminability of mescaline while the peripheral antagonist, xylamidine tosylate, was without effect. Furthermore, these agents at the doses employed did not effect the discriminability of saline. Depletion of 5-HT with PCPA potentiated the effects of a sub-threshold dose of mescaline and slightly reduced the discriminability of saline. The results indicate that mescaline produces its discriminative stimulus properties by directly stimulating central serotonergic receptors.

Discriminative stimulus properties of mescaline: mescaline or metabolite?

The purpose of this study was to investigate possible similarities in the interoceptive stimuli produced by mescaline and its metabolites. Rats were trained in a 2 lever operant chamber to discriminate between the drugged state (mescaline 25 mg/kg) and the nondrugged state (saline). Following acquisition of discriminative response control the rats were pretreated with either saline, aldehyde dehydrogenase inhibitors or amine oxidase inhibitors and tested stimulus generalization produced by i.p. injections of 3, 4, 5-trimethoxyphenylethanol (TMPE), 3, 4, 5-trimethoxyphenylacetaldehyde (TMPA), N-acetylmescaline, mescaline or saline. The results indicated that both aldehyde dehydrogenase and amine oxidase inhibitors enhanced the effects of mescaline, while TMPE, TMPA and N-acetylmescaline failed to exhibit generalization to the mescaline state, regardless of pretreatment. These findings do not indicate the role of a metabolite in the interoceptive cue produced by mescaline.