Viral gene delivery selectively restores feeding and prevents lethality of dopamine-deficient mice.
Dopamine-deficient mice (DA-/- ), lacking tyrosine hydroxylase (TH) in dopaminergic neurons, become hypoactive and aphagic and die by 4 weeks of age. They are rescued by daily treatment with L-3,4-dihydroxyphenylalanine (L-DOPA); each dose restores dopamine (DA) and feeding for less than 24 hr. Recombinant adeno-associated viruses expressing human TH or GTP cyclohydrolase 1 (GTPCH1) were injected into the striatum of DA-/- mice. Bilateral coinjection of both viruses restored feeding behavior for several months. However, locomotor activity and coordination were partially improved. A virus expressing only TH was less effective, and one expressing GTPCH1 alone was ineffective. TH immunoreactivity and DA were detected in the ventral striatum and adjacent posterior regions of rescued mice, suggesting that these regions mediate a critical DA-dependent aspect of feeding behavior. (+info)
Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.
Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity. (+info)
On the relation between object manipulation and stereotypic self-injurious behavior.
Results from a number of studies have shown an inverse relationship between stereotypic behavior and object manipulation. The purposes of this study were to determine whether techniques similar to those used previously (prompting and reinforcement) would be effective in increasing object manipulation under both prompted and unprompted conditions, and to ascertain whether increases in object manipulation would result in decreases in stereotypic self-injurious behavior (SIB). Two individuals with developmental disabilities who engaged in SIB maintained by automatic reinforcement participated. Results showed that object manipulation increased from baseline levels when experimenters prompted participants to manipulate leisure items, but that object manipulation was not maintained under unprompted conditions, and rates of SIB stayed within baseline levels. We then attempted to increase object manipulation further by (a) reinforcing object manipulation, (b) blocking SIB while reinforcing manipulation, and (c) preventing SIB by applying protective equipment while reinforcing object manipulation. Reinforcing object manipulation alone did not affect levels of object manipulation. Blocking effectively reduced attempts to engage in SIB for 1 participant but produced no increase in object manipulation. When the 2nd participant was prevented from engaging in SIB through the use of protective equipment, rates of object manipulation increased dramatically but were not maintained when the equipment was removed. These results suggest that stimulation derived from object manipulation, even when supplemented with arbitrary reinforcement, may not compete with stimulation produced by stereotypic SIB; therefore, direct interventions to reduce SIB are required. (+info)
SR146131: a new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. II. In vivo pharmacological characterization.
SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans. (+info)
Susceptibility to amphetamine-induced locomotor sensitization is modulated by environmental stimuli.
We have previously reported that intravenous (i.v.) administrations of 0.5-1.0 mg/kg of amphetamine in the absence of any environmental stimuli predictive of drug administration failed to induce psychomotor sensitization whereas the same drug did produce robust sensitization when given in association with environmental novelty. These results were obtained by studying rotational behavior in animals with a unilateral 6-OHDA lesion of the mesostriatal dopamine system. The purpose of this study was to determine if environmental novelty has a similar effect on sensitization to the locomotor activating effects of amphetamine in neurologically intact rats. Rats were implanted with i.v. catheters and divided in four groups. Two groups were housed in locomotor activity cages and given seven consecutive i.v. infusions of either saline (SAL-HOME group) or 0.375 mg/kg of amphetamine (AMPH-HOME group), using a remotely activated delivery system. Simultaneously, the other two groups were transported to the test cages and given the same treatment (SAL-NOVEL and AMPH-NOVEL groups). After one week withdrawal, all groups were given an amphetamine challenge (0.375 mg/kg, i.v.). Amphetamine sensitization developed when the drug was administered under NOVEL conditions, as indicated by a progressive increase in amphetamine-induced locomotor activity over test sessions and by a greater response to the amphetamine challenge in the AMPH-pretreated versus the SAL-pretreated group. In contrast, no sensitization was observed under HOME conditions. Similar results were obtained with the analysis of vertical activity. (+info)
Behavioral effects of psychomotor stimulant infusions into amygdaloid nuclei.
The role of amygdaloid nuclei in locomotion, stereotypy, and conditioned place preference (CPP) produced by psychomotor stimulants was examined. Five 2-day conditioning trials were conducted over 10 consecutive days. Rats received bilateral intracranial infusions of saline, cocaine (25-100 micrograms/side), or amphetamine (0.31-20 micrograms/side) into the ventricles (ICV), basolateral amygdala (BlA), or central amygdala (CeA) and were confined to a compartment. On alternating days, rats received sham infusions and were confined to a different compartment. Locomotion was measured daily, stereotypy was measured on trials 1 and 5, and CPP was measured 24 h after conditioning. ICV infusions of cocaine or amphetamine produced locomotion, rearing, and CPP. Intra-BlA and intra-CeA infusions of the highest dose of cocaine produced locomotion. In contrast, intra-CeA infusions of amphetamine potently produced locomotion and CPP. Intra-BlA infusions of amphetamine, however, did not produce any behavioral changes. These results suggest that the CeA, but not the BlA, is involved in initiating reward and locomotion produced by amphetamine. (+info)
Contributions of tutor and bird's own song experience to neural selectivity in the songbird anterior forebrain.
Auditory neurons of the anterior forebrain (AF) of zebra finches become selective for song during song learning. In adults, these neurons respond more to the bird's own song (BOS) than to the songs of other zebra finches (conspecifics) or BOS played in reverse. In contrast, AF neurons from young birds (30 d) respond equally well to all song stimuli. AF selectivity develops rapidly during song learning, appearing in 60-d-old birds. At this age, many neurons also respond equally well to BOS and tutor song. These similar neural responses to BOS and tutor song might reflect contributions from both song experiences to selectivity, because auditory experiences of both BOS and tutor song are essential for normal song learning. Alternatively, they may simply result from acoustic similarities between BOS and tutor song. Understanding which experience shapes selectivity could elucidate the function of song-selective AF neurons. To minimize acoustic similarity between BOS and tutor song, we induced juvenile birds to produce abnormal song by denervating the syrinx, the avian vocal organ, before song onset. We recorded single neurons extracellularly in the AF at 60 d, after birds had had substantial experience of both the abnormal BOS (tsBOS) and tutor song. Some neurons preferred the unique tsBOS over the tutor song, clearly indicating a role for BOS experience in shaping neural selectivity. In addition, a sizable proportion of neurons responded equally well to tsBOS and tutor song, despite their acoustic dissimilarity. These neurons were not simply immature, because they were selective for tsBOS and tutor song relative to conspecific and reverse song. Furthermore, their similar responses to tsBOS and tutor song could not be attributed to residual acoustic similarities between the two stimuli, as measured by several song analyses. The neural sensitivity to two very different songs suggests that single AF neurons may be shaped by both BOS and tutor song experience. (+info)
OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons.
To study the behavioral role of neurons containing the D1 dopamine receptor (D1+), we have used a genetic neurostimulatory approach. We generated transgenic mice that express an intracellular form of cholera toxin (CT), a neuropotentiating enzyme that chronically activates stimulatory G-protein (Gs) signal transduction and cAMP synthesis, under the control of the D1 promoter. Because the D1 promoter, like other CNS-expressed promoters, confers transgene expression that is regionally restricted to different D1+ CNS subsets in different transgenic lines, we observed distinct but related psychomotor disorders in different D1CT-expressing founders. In a D1CT line in which transgene expression was restricted to the following D1+ CNS regions-the piriform cortex layer II, layers II-III of somatosensory cortical areas, and the intercalated nucleus of the amygdala-D1CT mice showed normal CNS and D1+ neural architecture but increased cAMP content in whole extracts of the piriform and somatosensory cortex. These mice also exhibited a constellation of compulsive behavioral abnormalities that strongly resembled human cortical-limbic-induced compulsive disorders such as obsessive-compulsive disorder (OCD). These compulsive behaviors included episodes of perseverance or repetition of any and all normal behaviors, repetitive nonaggressive biting of siblings during grooming, and repetitive leaping. These results suggest that chronic potentiation of cortical and limbic D1+ neurons thought to induce glutamatergic output to the striatum causes behaviors reminiscent of those in human cortical-limbic-induced compulsive disorders. (+info)