FR discrimination training reverses 6-hydroxydopamine-induced striatal dopamine depletion in a rat model of Lesch-Nyhan syndrome

doi:10.1016/0006-8993(96)80777-3

Brain Research

Volume 713, Issues 1–2, 25 March 1996, Pages 246-252

https://doi.org/10.1016/0006-8993(96)80777-3 Get rights and content

Abstract

Five-day-old rats received 6-hydroxydopamine (6-HD; 100 μ,g base) or vehicle intracisternally. Striatal and cortical dopamine (DA) and metabolite levels were then determined when animals were three or 8.5 months of age and the latter rats had been weight-reduced for 5.5 months. In the latter animals these determinations were made I month following 4.5 months of home-cage confinement (untrained animals) or of food-maintained fixed-ratio (FR) discrimination training involving either a single discrimination (performance animals) or incrementally more difficult discriminations. Striatal DA levels in 3-month-old and 8.5-month-old (untrained) 6-HD-treated rats were, respectively, only 3% and I I% of those in untrained vehicle-treated animals (controls). Despite such large depletions, striatal DA levels in 6-HD-treated performance rats were 3-fold higher than those in untrained age-matched 6-HD-treated rats (i.e., were 32% of values in controls) while those in incrementally trained 6-HD-treated animals were even higher (i.e., were 60% of control values). Related changes occurred in levels of most metabolites. However, in incrementally trained rats, striatal 3-methoxytyramine concentrations were 154% of control values. Cortical DA and metabolite levels were little affected by 6-HD treatment. The present results confirm and extend our earlier observations suggesting that reversal of `irreversible' neonatal 6-HD-induced striatal dopamine and metabolite depletion can be accomplished by environmental (training) manipulations in adult rats.

References (34)

G.R. Breese et al.
A dopamine deficiency model of Lesch-Nyhan disease-The neonatal 6-OHDA-lesioned rat
Brain Res. Bull.
(1990)
J.N. Carlson et al.
Selective enhancement of dopamine utilization in the rat prefrontal cortex by food deprivation
Brain Res.
(1987)
A. Cheramy et al.
Presynaptic control of dopamine synthesis and release by excitatory amino acids in rat striatal synaptosomes
Neurochem. Int.
(1994)
J.P. Dausse et al.
Alpha 1- and alpha 2-adrenoceptors in rat cerebral cortex: effects of neonatal treatment with 6-hydroxydopamine
Eur. J. Pharmacol.
(1982)
J. Hudson et al.
Glial cell line-derived, neurotrophic factor augments midbrain dopaminergic circuits in vivo
Brain Res. Bull.
(1995)
K. Inoue et al.
Scheduled feeding cased activation of dopamine metabolism in the striatum of rats
Physiol. Behau.
(1993)
K.A. Keefe et al.
Environmental stress increases extracellular dopamine in the striatum of 6-hydroxydopamine rats: In vivo microdialysis studies
Brain Res.
(1990)
P.S. Loupe et al.
FR discrimination training effects in SHR and microencephalic rats
Pharmacol. Biochem. Behav.
(1995)
A. Nitta et al.
Denervation of dopaminergic neurons with 6-hydroxydopamine increases nerve growth factor content in rat brain
Neurosci. Lett.
(1992)
A. Oke et al.
Dopamine and norepinephrine enhancement in discrete rat brain regions following neonatal 6-hydroxydopamine treatment
Brain Res.
(1978)

A. Oke et al.

Selective attention dysfunction in adult rats neonatally trated with 6-hydroxydopamine

Pharmacol. Biochem. Behav.

(1978)

M.G. Rosales et al.

Activation of subthalamic neurons produces NMDA receptor-mediated dendritic dopamine release in substantia nigra pars reticulata: a microdialysis study in the rat

Brain Res.

(1994)

J.D. Salamone et al.

Behavioral activation in rats increases striatal dopamine metabolism measured by dialysis perfusion

Brain Res.

(1989)

J.E. Springer et al.

Neurotrophic factor mRNA expression in dentate gyrus is increased following in vivo stimulation of the angular bundle

Brain Res. Mol. Brain Res.

(1994)

R.E. Tessel et al.

Reversal of 6-HD-induced neonatal brain catecholamine depletion after operant training

Pharmacol. Biochem., Behav.

(1995)

C.A. Altar et al.

Efficacy of brain-derived neurotrophic factor and neurotrophic-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions

J. Neurochem.

(1994)

T. Archer et al.

Animal models of mental retardation

Neuromethods

(1991)

Cited by (11)

Chapter 6 Animal Models of Self-Injurious Behavior. Induction, Prevention, and Recovery
2008, International Review of Research in Mental Retardation
Citation Excerpt :
Since 6‐OHDA‐induced depletions have generally been regarded up to now as being irreversible (e.g., Oke, Keller, & Adams,1978), these findings were surprising to say the least. We, therefore, performed a replication of this study in another group of neonatal vehicle (control) and 6‐OHDA‐treated animals but added a group of age‐matched, food‐deprived but untrained neonatal 6‐OHDA‐treated rats as additional control groups (Stodgell, Schroeder, & Tessel, 1996). DA concentrations were over 5.5‐fold greater than those in the untrained 6‐OHDA‐treated group in this replication of the preceding study but less than those in trained controls.
The purpose of this review is to organize the literature over the past 50 years on animal models for self‐injurious behavior (SIB). Of the many animal models for SIB, there are four models for inducing it which have been very productive: (1) the isolate‐rearing model in rhesus monkeys; (2) the neonate 6‐hydroxydopamine (6‐OHDA) lesion model in rats; (3) the administration of stimulants, e.g. amphetamine and pemoline to normal rats; and (4) the administration of the l‐type calcium channel blocker BayK8644 to mice. A model of prevention of repetitive behavior in deer mice, some of which is self‐injurious, is based upon environmental enrichment and environmental complexity. The final section of the paper reviews a 10‐year research program by the authors on training‐induced recovery from SIB. In general, the animal literature supports the neurobiological bases for induction, prevention, and recovery from SIB.
Weaver mutant mice exhibit long-term learning deficits under several measures of instrumental behavior
2007, Physiology and Behavior
Citation Excerpt :
An additional feature of the research was to conduct prolonged observations with each subject (60 sessions were conducted in total) to determine the stability of response patterns. Little is known about the permanency of behavioral deficits resulting from dopamine deficiency; under at least some circumstances, sustained practice with the behavioral tasks can lead to partial recovery of functioning [40–43]. Weaver mutant mice may seem unlikely to show recovery because the mutation preferentially destroys dopaminergic cells formed after birth [44].
Homozygous weaver mutant mice (wv/wv) exhibit symptoms that parallel Parkinson's disease, including motor deficits and the destruction of dopaminergic neurons as well as degeneration in the cerebellum and hippocampus. To develop a more complete behavioral profile of these organisms, groups of wv/wv, wv/+ mice and C57BL/6 mice were observed on a within-subjects basis under a fixed-interval schedule of reinforcement, a differential-reinforcement-of-low-rate-of-responding schedule, and a discrimination task in which a saccharin solution and tap water were concurrently available from two food cups. Under both reinforcement schedules, the wv/wv mice responded as frequently as the comparison subjects, but they responded in a manner that was inappropriate to the contingencies. Rather than respond with increasing frequency as the upcoming reinforcer became temporally proximate, wv/wv mice responded with decreasing probability as a function of the time since the previous reinforcer. Under the discrimination task, the wv/wv mice, unlike the controls, obtained saccharin over tap water at the level of chance. The findings suggest that weaver mutant mice express learning deficits similar to those found in other dopamine-deficient organisms.
Chapter 4 Prevention Management and Treatment
2007, Assessment and Treatment of Child Psychopathology and Developmental Disabilities
Citation Excerpt :
The rhythmic proprioceptive and cutaneous input of repetitive training induces long-term potentiation in the sensorimotor cortex, a possible mechanism for motor learning. Richard Tessel and colleagues (Loupe et al., 1995; Stodgell, Schroeder, & Tessel, 1996; Tessel et al., 1995a, 1995b) have also shown dose-effects of operant training-induced recovery of brain neurotransmitters following the lesioning in two rat models of intellectual disability (see also Chapter 2 for a review). In the future, we hope to discover the pathways critical for the successful intervention with infants and toddlers with self-injurious behavior and developmental disabilities.
A large number of people, representing a variety of diagnostic categories exhibit self injurious behavior, including autism, childhood schizophrenia, intellectual disability, visual impairment, emotional disturbance, and learning disabilities. This chapter describes the analyses of different intervention methods for preventing self-injurious behavior and its devastating effects, such as primary, secondary, and tertiary prevention. Both prevalence studies and stimulus control studies of self-injurious behavior suggest that there are risk factors, which, if averted, would decrease the probability of onset of self-injurious behavior. The preventive techniques for averting self-injurious behavior or preventing its development would avoid much human suffering, and be much more cost-effective than current methods; however, the area of early identification and intervention with self-injurious behavior is in its infancy. With the help of the new genetics and advances in the neurobiology of self-injurious behavior, drugs can be prescribed much more effectively, with more specificity and fewer serious side effects than ever before. But, much work remains to be done to have better diagnostic instruments to guide the selection of psychotropic drugs for the appropriate complex disorder related to self-injurious behavior. The chapter also presents a variety of empirically supported, rational treatment procedures for self injurious behavior and also includes noncontingent restraint, sensory integration therapy, and multisensory environments. However, whether changing the context, in which behavior interventions occur, will be sufficient to decrease all self-injurious behavior remains to be seen.
A comparison of intensive behavior analytic and eclectic treatments for young children with autism
2005, Research in Developmental Disabilities
We compared the effects of three treatment approaches on preschool-age children with autism spectrum disorders. Twenty-nine children received intensive behavior analytic intervention (IBT; 1:1 adult:child ratio, 25–40 h per week). A comparison group (n = 16) received intensive “eclectic” intervention (a combination of methods, 1:1 or 1:2 ratio, 30 h per week) in public special education classrooms (designated the AP group). A second comparison group (GP) comprised 16 children in non-intensive public early intervention programs (a combination of methods, small groups, 15 h per week). Independent examiners administered standardized tests of cognitive, language, and adaptive skills to children in all three groups at intake and about 14 months after treatment began. The groups were similar on key variables at intake. At follow-up, the IBT group had higher mean standard scores in all skill domains than the AP and GP groups. The differences were statistically significant for all domains except motor skills. There were no statistically significant differences between the mean scores of the AP and GP groups. Learning rates at follow-up were also substantially higher for children in the IBT group than for either of the other two groups. These findings are consistent with other research showing that IBT is considerably more efficacious than “eclectic” intervention.
Fixed ratio discrimination training increases in vivo striatal dopamine in neonatal 6-OHDA-lesioned rats
2002, Pharmacology Biochemistry and Behavior
Massed training in the conditional discrimination task, the fixed ratio discrimination (FRD) task led to elevated extracellular dopamine (DA) concentrations in the neonatal 6-hydroxydopamine (6-OHDA)-treated rat, a model of Lesch–Nyhan disease (LND). Rats neonatally treated with 6-OHDA or its vehicle were, as adults, implanted with microdialysis probes and assessed for basal pretraining concentrations of DA and its major metabolites. Subsequently, microdialysis samples were collected each day following three separate FRD training periods (trained group) or three separate periods of noncontingent food presentations (untrained group). The present study found that there were significant increases in extracellular DA in the caudate–putamen from basal pretraining concentrations in the repeated sample collections of trained 6-OHDA-lesioned animals but not in the samples of untrained 6-OHDA-lesioned animals. Consistent with previous studies [Brain Res. 508 (1990) 30.], there was an increase in the extracellular concentrations as compared to tissue concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC). Similar to our previous studies with long-term FRD training [Pharmacol. Biochem. Behav. 51 (1995) 861; Brain Res. 713 (1996) 246.], there was also an indication of an increase in cortical and striatal tissue concentration of DA in the trained 6-OHDA-lesioned animals as compared to the untrained 6-OHDA-lesioned animals. The elevations in striatal DA concentrations following operant performance in the present study illustrate how operant procedures of the behavior therapy used with individuals with LND and other mental retardation syndromes may interact with the modulation of dopaminergic function by the pharmaceutical application of DA antagonists to suppress aberrant behaviors.
Behavioural recovery after unilateral lesion of the dopaminergic mesotelencephalic pathway: Effect of repeated testing
1998, Neuroscience
Functional recovery following a complete unilateral lesion of the nigrostriatal pathway in adult rats was studied. We examined the effect of training on the spontaneous or induced postural bias following the lesion. Two tasks measuring lateralization were used to assess the lesion-induced postural bias: spontaneous asymmetry was evaluated in the Y-maze, whereas induced body bias was measured by hanging the rat by its tail. Recovery was assessed at three different times following the lesion. The effects of lesion in adult rats in the short, medium and long term were evaluated and compared with the effects of dopaminergic transplants. In adult lesioned rats, destruction of dopaminergic innervation of the neostriatum induced initially an ipsilateral bias as measured in the “tail hang test” and the Y-maze. Recovery of function was observed in the tail hang test as ipsilateral bias declined on repeated testing. Apart from this effect, there was a post-lesion interval effect, since the postural bias disappeared more rapidly on repeated testing in the long-term lesioned rats. This spontaneous recovery was impaired by intrastriatal dopaminergic grafts. Furthermore, no spontaneous recovery was observed in the Y-maze test.
These observations show that repeated testing can influence the long-term effects of damage to the nigrostriatal dopamine system.

View all citing articles on Scopus

View full text

Research reportFR discrimination training reverses 6-hydroxydopamine-induced striatal dopamine depletion in a rat model of Lesch-Nyhan syndrome

Abstract

Brain Res. Bull.

Brain Res.

Neurochem. Int.

Eur. J. Pharmacol.

Brain Res. Bull.

Physiol. Behau.

Brain Res.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Brain Res.

Brain Res. Mol. Brain Res.

Pharmacol. Biochem., Behav.

Efficacy of brain-derived neurotrophic factor and neurotrophic-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions

J. Neurochem.

Animal models of mental retardation

Neuromethods

Research report
FR discrimination training reverses 6-hydroxydopamine-induced striatal dopamine depletion in a rat model of Lesch-Nyhan syndrome