Mark H. Lewis

Markers for biogenic amines in the aged rat brain: Relationship to decline in spatial learning ability

The major goal of the study was to evaluate the relationship of brain aging to individual differences in functional decline in rats. Forebrain choline-acetyltransferase (ChAT) and monoamines, including their metabolites, were examined in young and aged male Long-Evans rats in relation to their spatial learning ability. Aged rats that were unimpaired on a spatial learning task exhibited few changes in neurochemistry relative to the young group: each change in this subgroup was also evident in the remaining aged animals that were behaviorally impaired. Additional changes in neurochemical measures only found in the behaviorally impaired aged animals included decreased ChAT in the basal forebrain, striatum, and frontal cortex. A cluster analysis using the 15 neurochemical measures that were sensitive to aging yielded groupings of aged animals that differed with respect to their spatial learning ability, but not in their cue learning latencies. In this analysis the activity of ChAT in the basal forebrain and striatum appeared to be the best predictors of spatial learning impairment.

Long-term effects of early social isolation in Macaca mulatta: changes in dopamine receptor function following apomorphine challenge

The hypothesis that early social isolation results in long-term alterations in dopamine receptor sensitivity was tested using older adult rhesus monkeys. Isolated and control monkeys were challenged with apomorphine (0.1 and 0.3 mg/kg), and the drug effects on spontaneous blink rate, stereotyped behavior, and self-injurious behavior were quantified using observational measures. Monoamine metabolites were quantified from cisternal CSF by HPLC-EC, prior to pharmacological challenge. Isolated and control monkeys did not differ in CSF concentrations of HVA, 5-HIAA, or MHPG. At the higher dose, apomorphine significantly increased the rate of blinking, the occurrence of whole-body stereotypies, and the intensity of stereotyped behavior (as measured by observer ratings) in isolated monkeys. The frequency of occurrence of self-injurious behavior was too low to allow for meaningful comparisons. These significant differences in response to apomorphine challenge support the hypothesis that long-term or permanent alterations in dopamine receptor sensitivity, as assessed by drug challenge, are a consequence of early social deprivation.

Influence of cholecystokinin on central monoaminergic pathways

Dopamine (DA) and cholecystokinin octapeptide carboxy-terminal (CCK-8) have been found to coexist in some mesolimbic neurons. The present investigation was undertaken in order to study the biochemical and behavioral interactions between CCK-8 and some central monoaminergic pathways. The action of the sulfated form of CCK-8 (10 micrograms/10 microliter intracerebroventricularly) on DA turnover in nucleus accumbens, olfactory tubercles and corpus striatum of the rat was determined after DA synthesis inhibition with alpha-methyl-p-tyrosine (250 mg/kg i.p.). Also, CCK-8 action (1-30 micrograms intracisternally) on DA synthesis was assessed by measuring accumulation of dihydroxyphenylalanine (DOPA) after DOPA-decarboxylase inhibition with NSD-1015 (m-hydroxybenzylhydrazine, 100 mg/kg i.p.). The contents of DA and its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, together with serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in different brain areas after direct injection of CCK-8 into the ventral tegmental area (A10) or nucleus accumbens. Further, the effect of CCK-8 on amphetamine-induced locomotion and apomorphine-induced stereotypies was studied along with changes in spontaneous locomotion and rearing after CCK-8 injection into the ventral tegmental area and nucleus accumbens. No consistent statistically significant effects of CCK-8 on biochemical or behavioral assessments on measures of DA function were observed. However, injection of high doses of CCK-8 into the ventral tegmental area significantly decreased levels of 5-HIAA in the nucleus accumbens, olfactory tubercles and striatum.

Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist

Short communication about the pharmacological activity of dopamine D-1 receptor agonist, dihydrexidine

Stereotyped Mannerisms in Mentally Retarded Persons: Animal Models and Theoretical Analyses

Publisher Summary This chapter provides an overview of various animal models of stereotypy. It examines some neurobiological evidence relevant to theoretical explanations of pathological stereotypies and highlights connections between the pathological stereotypies seen in mentally retarded persons and repetitive movement patterns seen elsewhere in nature. The stereotypies observed in human infants involve rhythmic movement patterns, such as kicking, waving, rocking, head banging, and nonnutritive sucking. Despite evidence for central control, large individual differences in the amount of stereotypy have been observed among normal infants. A fuller understanding requires that stereotypies be conceptualized as biobehavioral processes in which neurochemical and neurophysiological events are in dynamic transaction with environmental and behavioral events. Stereotyped behavior exhibited by mentally retarded people is not discontinuous activities; it represents the logical expression of events along a number of biological continua. The chapter presents specific evidence, which shows that stereotypy is linked to traceable neurochemical events, particularly the activity of the neurotransmitter dopamine.

Dopamine receptor ‘supersensitivity’ occurring without receptor up-regulation

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra have been widely used to study various aspects of dopamine neurobiology, and to screen for antiparkinsonian drugs. This study examined the role of receptor alterations in the pharmacological supersensitivity seen in response to lesioning of central dopamine pathways in rats by intracisternal (IC) administration of 6-OHDA (200 micrograms), as well as by bilateral (BIL) or unilateral (UNI) infusion of 6-OHDA into the substantia nigra (8 micrograms/side). Both IC and BIL lesions resulted in permanent decreases in dopamine concentration in the striatum, the major terminal projection from the substantia nigra. When challenged with apomorphine (0.3 mg/kg), IC-lesioned rats exhibited bursts of rapid locomotion interspersed by rearing, whereas BIL-lesioned rats displayed intense grooming or gnawing and nose poking of the cage floor; these behaviors were not seen in respective sham (i.e. vehicle)-lesioned rats injected with apomorphine. Scatchard analysis of saturation isotherms of both D1 [( 3H]SCH23390 binding sites) and D2 [( 3H]spiperone binding sites) dopamine receptors in the striatum revealed no difference in either the maximum number of binding sites (Bmax), or the dissociation constant (Kd) of either receptor type when BIL and IC lesioned rats were compared to appropriate controls. Conversely, the UNI lesioned rats had, under identical conditions of analysis, the expected increase in the density of D2 receptors on the lesioned side. There was no change in dopamine-sensitive adenylate cyclase activity in the striata of supersensitive IC-lesioned rats, but there was a shift to the left in the dose-response curve in striata from rats bilaterally-lesioned in the substantia nigra, similar to what occurs in UNI lesioned rats. Together, these data clearly demonstrate that although increases in receptor density and changes in cAMP systems are seen in the UNI model, neither mechanism is a requirement for functional supersensitivity in response to 6-OHDA lesions. These data suggest that other cellular events (e.g. alterations in receptor interactions) may play a role in the response to insult, and raise questions about the utility of the unilateral model as a screen for antiparkinsonian drugs.

Triadimefon, a triazole fungicide, induces stereotyped behavior and alters monoamine metabolism in rats.

Triadimefon, a triazole fungicide, has been observed to increase locomotion and induce stereotyped behavior in rodents. The present experiments designed to characterize the stereotyped behavior induced by triadimefon used a computer-supported observational method, and tested the hypothesis that these observed effects involved central dopaminergic systems. Adult male and female Sprague-Dawley rats were injected with triadimefon (0, 50, 100, and 200 mg/kg) in corn oil (2 ml/kg ip) 4 hr prior to behavioral assessment. The two lowest doses of triadimefon increased the frequency of locomotion and rearing, while the highest dose induced highly stereotyped behaviors, including backward locomotion, circling, and head weaving. Immediately after behavioral testing, the rats were sacrificed, and the striata and olfactory tubercles, terminal fields of the nigrostriatal and mesolimbic dopamine systems, respectively, were removed. Steady-state concentrations of the monoamines dopamine and serotonin and their metabolites were determined by HPLC-EC. In independent experiments, the direct effects of triadimefon on dopamine (D1 and D2) receptor binding and dopamine-sensitive adenylate cyclase activity were assessed in vitro using rat striata. Dopamine concentrations were increased in olfactory tubercles, but decreased in striatum. Concentrations of 5-hydroxyindoleacetic acid (the major metabolite of serotonin) were increased only in striatum, and only in animals treated with 200 mg/kg triadimefon. In vitro, triadimefon neither competed with D1 or D2 dopaminergic radioligands nor affected dopamine-stimulated adenylate cyclase activity. Together these behavioral and biochemical data lend support to the hypothesis that triadimefon may have actions similar to those produced by indirect-acting dopamine agonists.

The Multiplicity of the D1 Dopamine Receptor

Dopaminergic neurotransmission is known to modulate a variety of behaviors, including ambulation (Ungerstedt and Arbuthnott, 1970; Pijnenburg et al., 1976), stereotyped behaviors (Creese and Iversen, 1973), self-stimulation (Phillips and Fibiger, 1973), conditioned avoidance responding (Seiden and Carlsson, 1963), stimulus control (Ho and Huang, 1975), and feeding and drinking (Ungerstedt, 1971; Fitzsimons and Setler, 1975). It is not surprising, therefore, that drugs which are believed to act primarily as dopamine receptor agonists or antagonists have important clinical utility. Our work has sought to address two questions of some neuropharmacological importance. First, what is the nature of mechanisms by which dopamine initiates many of these psychopharmacological effects, and second, is it possible to design highly specific drugs targeted only at a selected subpopulation of dopamine receptors?

A computer-supported method for analyzing behavioral observations: studies with stereotypy

The present report describes an observational method for quantifying behavior including drug-induced stereotypy, and employs an electronic data-collecting device with microcomputer hardware and software support. This method generates interval scale data, thus permitting the application of powerful parametric statistics, and also allows examination of discrete response topographies. For example, the method permits parametric comparisons among drug doses, treatment groups, as well as over time. The effects of the atypical antipsychotic drug thioridazine on apomorphine-induced stereotypy were used to illustrate the utility of the method. Thioridazine was found, among other effects, to potentiate apomorphine-induced gnawing and licking, while blocking sniffing.

Serum effects confound the neuroleptic radioreceptor assay

The neuroleptic radioreceptor assay (NRRA) is used widely to monitor total neuroleptic-like activity (NLA) in patients taking one or more antipsychotic drugs. The original report of Creese and Snyder (1) stated that serum alone caused a small effect on binding which was negligible compared to normal daily variations in the assay. Conversely, in studies with striata from rat or cow brain, we found that sera from healthy, drug free volunteers, when used at 50 microL/1 mL assay volume, caused marked inhibition of binding. Although any sample of serum causes reproducible inhibition with a given preparation of bovine or rat striatal membranes, the effects of various serum samples may differ markedly when several striatal membrane preparations are compared. Moreover, samples taken from people at different times may also vary, although less than the interindividual differences. Despite this variance, the slopes of log-logit plots were equal to 1 either in the presence or absence of serum. Because of the differences in the interaction of individual sera with different membrane preparations, it is difficult to compensate accurately for this serum effect by simply including control serum in the standard curve. Thus, the use of the NRRA as a quantitative tool in the clinical pharmacology of neuroleptics may be limited by this non-specific effect of serum, and this finding may offer one explanation for some of the inconsistencies found in comparing the NRRA with direct analytical methods.