Pippa S. Loupe

Cross-sensitization between footshock stress and apomorphine on self-injurious behavior and neostriatal catecholamines in a rat model of Lesch-Nyhan syndrome

The effects of footshock sensitization (priming), apomorphine (APO) priming and their combination on behavior and neostriatal and cortical catecholamines were examined in adult rats which had neonatally received bilateral intracerebroventricular injections with 6-hydroxydopamine (6-OHDA; a model of Lesch-Nyhan syndrome (LNS)) or vehicle (unlesioned rats). Lesioned (6-OHDA-treated) rats displayed self-biting (SB; 7/20 rats) and self-injurious behavior (SIB; 1/20 rats) during APO priming, but not during footshock priming. During subsequent acute cumulative APO dosing, 20-30% of lesioned rats primed with APO alone or footshock alone displayed SB and SIB. However, SB and SIB incidence in APO+footshock-primed lesioned rats was nearly tripled. Dopamine (DA) synthesis, metabolism and extracellular concentrations (disposition) in unlesioned rats and in cortices of lesioned animals were unaffected by priming. In lesioned rats primed with APO alone or footshock alone, only neostriatal 3-methoxytyramine (3-MT) was significantly increased. However, neostriatal DA and metabolite concentrations (and norepinephrine (NE)) were all significantly elevated in lesioned rats primed with both APO and footshock. These results confirm that neonatal 6-OHDA-induced neostriatal catecholamine depletion can be antagonized by experiential change, suggest that behavioral and neurochemical cross-sensitization between APO and footshock in such rats is unidirectional and support the view that stress can exacerbate the incidence of SIB in LNS.

FR discrimination training effects in SHR and microencephalic rats

Fixed-ratio (FR) discrimination learning in adult male spontaneously hypertensive rats (SHR), methylazoxymethanol-induced microencephalic Sprague-Dawley (MAM), and Sprague-Dawley control rats was examined. SHR and MAM rats had little problem learning incrementally more difficult FR discriminations (FR1 vs. FR16, FR4 vs. FR16, and FR8 vs. FR16) that resulted in parallel increases in errors in all animals, and displayed only modest learning deficits during a subsequent FR4 vs. FR16 position reversal. When training involved nonincremental changes in difficulty (FR8 vs. FR16, FR4 vs. FR16, FR8 vs. FR16, FR12 vs. FR16, and FR14 vs. FR16), SHR and MAM rats evidenced relatively large learning deficits during the initial FR8 vs. FR16 discrimination but had no difficulty with the last two discriminations. Furthermore, training selectively and significantly elevated hippocampal weight in MAM rats. These findings: a) question prior suggestions that MAM and SHR model separate human developmental disabilities; b) indicate that manifestation of learning deficits in even markedly brain-damaged organisms depends on initial task difficulty and can be overcome by experience; and c) are the first indicating that training-induced antagonism of prenatally induced hippocampal hypoplasia and its consequences is possible.

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

Rats received either vehicle (controls) or 100 micrograms of 6-hydroxydopamine (6HD) base intracisternally on postnatal day 5. At 3 mo of age, striatal and cortical catecholamine and metabolite levels were determined in some animals. Others were subjected to 4.5 mo of training on incrementally more difficult fixed-ratio (FR) discriminations; 2 mo later, their levels were determined. Learning was essentially unaffected by 6HD even though errors in all animals increased with increases in discrimination difficulty and 6HD had markedly depleted levels in the 3-mo-old animals. Moreover, an initial response-rate deficit in 6HD-treated rats disappeared with training. However, after training, levels in 6HD-treated rats were not only not depleted, they were as much as 661% of those in controls. These and others of our findings indicate that FR discrimination training can induce persistent increases in brain catecholamine utilization. They also appear to be the first to suggest that at least some neurochemical effects of neonatal 6HD are not necessarily irreversible, and that such a reversal can be experientially induced and possibly functionally beneficial.

Chapter 6 Animal Models of Self‐Injurious Behavior: Induction, Prevention, and Recovery

Abstract 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.

Fixed ratio discrimination training increases in vivo striatal dopamine in neonatal 6-OHDA-lesioned rats

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.

Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.

Many individuals with mental retardation exhibit chronic aberrant behaviors (CABs) that includes hyperactive, stereotyped, aggressive, and self‐injurious behaviors. Brain imaging studies have found that several of these individuals have abnormalities in their dopaminergic neurotransmitter systems that are thought to be responsible in part, for the development of these behaviors. The present study evaluated the effects of a selective dopamine re‐uptake blocker, GBR‐12909 in three animal models of varying striatal dopamine concentrations. The three animal models included the neonatal 6‐hydroxydopamine (6‐OHDA)‐lesioned rat, a model of dopamine neuronal depletion, the prenatal methylazoxymethanol (MAM)‐exposed rat, a model of hyper‐dopaminergic innervation and control rats, a model of normal dopaminergic function. The animals were given five daily injections of GBR‐12909 and videotaped observations were conducted immediately following the injections and 6 h later. The results of the study indicate that the MAM‐treated rats exhibited more hyperactive behaviors than either the 6‐OHDA or the control animals in response to the GBR‐12909 injections. However, the 6‐OHDA and control rats exhibited more self‐injurious behaviors than the MAM rats. Interestingly, the topography of the self‐injurious behavior exhibited differed from that we have previously observed in 6‐OHDA lesioned rats following dopamine agonists and resembles the mouthing behaviors seen in some individuals with mental retardation, in particular those with Rett syndrome. These findings indicate the models of varying dopaminergic function interact differently with a dopamine re‐uptake blocker than dopamine agonists and that the partially dopamine depleted model may model the behaviors seen in individuals with Rett syndrome.

Using rule induction for prediction of self-injuring behavior in animal models of development disabilities

The data mining system LERS (Learning from Examples using Rough Sets) was used to assess whether animal models of varying basal ganglia dopamine concentrations could be distinguished based on their behavioral responsiveness to a dopamine agonist, GBR12909. GBR12909 causes its agonist effects by increasing synaptic concentrations of dopamine. The three animal models included rats depleted as neonates of striatal dopamine, rats with hyper-innervation of striatal dopamine and control rats with normal striatal dopamine concentrations. The groups received five injections of GBR12909 and were observed for stereotyped and self-injurious behaviors immediately following the injections and six hours after injections. The data mining system LERS induced rules that indicated which of the injections caused several behaviors to be exhibited and which injections caused more focused behaviors. Prediction error rate analysis enable us to determine whether the pattern of behaviors displayed following GBR12909 administration could be distinguished among animal models. Differences in the rule sets formed for each group for each injection enables the prediction of the stereotyped behaviors that may occur prior to occurrence of self-injurious behavior. The ability to predict the occurrence of self-injurious behaviors in the animal models greatly increases our change of suppressing these behaviors through behavioral or pharmacological intervention.

Effects of neuroleptic and anticonvulsant drugs on repeated acquisition learning in microencephalic and normal rats.

Neuroleptic and anticonvulsant drugs are used to reduce the occurrence of aberrant behaviors, seizures, or both in individuals with mental retardation. However, their use may disrupt the learning of desired skills, and the extent to which anatomical (e.g., microencephaly) or biochemical abnormalities or both in such individuals alter the effects of drugs on learning is not known. In this study, the effects of neuroleptics and anticonvulsants on learning and performance in a repeated acquisition task in methylazoxymethanol-induced microencephalic and saline control rats were assessed. Thioridazine was more potent in microencephalic rats than in control rats in increasing errors and decreasing response rates. Clozapine was equally potent in both microencephalic and control rats in increasing errors and decreasing response rates. The effect of carbamazepine was biphasic in both rat groups: Low doses decreased errors and increased response rates, whereas higher doses did the opposite.

Kinetic assessment of the effects of task difficulty, microencephaly, and a response manipulandum alteration on the rate of fixed-ratio discrimination acquisition.

Fixed-ratio discrimination (FRD) training session-accuracy curves were constructed using first-order, nonlinear regression and probit analyses to determine maximal (asymptotic) accuracy and the number of sessions required to reach half-maximal accuracy. Increased FRD difficulty (reductions in the differences between the 2 fixed-ratio values to be discriminated) and a training parameter change each increased the number of sessions required to reach half-maximal accuracy and decreased maximal FRD accuracy (i.e., session-accuracy curves were shifted down and to the right) regardless of analysis procedure. These findings indicate that the above manipulations induced mixed competitive-noncompetitive inhibition of the rate of FRD learning. Microencephalic rats were more sensitive to increases in FRD difficulty, whereas control rats were more sensitive to the training parameter change.