Self-injurious behavior: gene-brain-behavior relationships.

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

To quantitatively assess the orolingual dysfunctions produced by unilateral striatal dopamine depletions, rats first received 6-hydroxydopamine injections into the nigrostriatal bundle and were then trained to lap water from a force-sensing disk in 2-min sessions. Compared with controls and rats with moderate (<75%) dopamine depletions, subjects with substantial (>75%) dopamine depletions showed decreases in number of licks, lick rhythm, and lick peak force. Rats with substantial lesions were also impaired in making initial, within-session adjustments in lick peak force but not in lick rhythm. The results confirm the presence of Parkinson-like deficits in tongue dynamics during consummatory licking behavior in rats. The methods used here should prove useful in providing quantitative measures of the efficacy of experimental therapies in this rodent model of Parkinson's disease.

Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide.

It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.

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.

Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model.

Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some central DA receptors, FR discrimination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-treated rats depend on the age at which 6-OHDA is administered.

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.

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

Five-day-old rats received 6-hydroxydopamine (6-HD; 100 micrograms 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 1 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 11% 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 metabolic depletion can be accomplished by environmental (training) manipulations in adult rats.

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.

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.

Nonpeptide peptidomimetic antagonists of the neuropeptide Y receptor: benextramine analogs with selectivity for the peripheral Y2 receptor.

We synthesized a new series of benextramine analogs as neuropeptide Y (NPY) functional group mimetics and tested them for N-[propionyl-3H]NPY ([3]NPY) displacement activity in rat brain membrane homogenates and for NPY receptor antagonist activity in the rat femoral artery. The tetraamine, carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-1,6-hexanediamine (15) was equipotent with benextramine (based on comparison of the relevant IC50's) in a rat brain [3H]NPY displacement assay, suggesting that the disulfide is not a necessary feature of benextramine's [3H]NPY displacement activity, although this analog maintained selectivity for the benextramine-sensitive binding site population. The bis(N,N-dialkylguanyl) disulfide and carbon analogs 14a-c were 3-4 times more potent than their respective controls in displacing [3H]NPY from rat brain membrane homogenates with IC50's ranging from 15 to 18 microM and maintained selectivity for the benextramine-sensitive, Y1 binding site population. However, the activity of the carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-N,N'-(1,6- hexanediyl)diguanidine tetrahydrochloride (14b) showed a different profile in a femoral artery vasoconstriction assay; at 1.0 nM, this analog shifted the concentration-effect curve of the Y2-selective agonist NPY13-36 to the right (pA2 = 9.2; Kd = 0.63 nM) without a significant change in the maximum effect, while even at 1.0 mM it had no effect on the vasoconstrictive activity of the Y1-selective agonist [Leu31,Pro34]NPY. Thus, the bis(N,N-dialkylguanidine) analogs of benextramine are selective, competitive antagonists of the postsynaptic NPY receptor in the femoral artery.

Characterization of vascular postsynaptic NPY receptor function and regulation and differential sensitivity of Y1 and Y2 receptor function to changes in extracellular calcium availability and prior in vitro peptide exposure.

Effects of calcium-free buffer, nifedipine, or prior cumulative neuropeptide Y (NPY) receptor agonist concentration exposure on vasoconstrictive responsiveness to the agonists were assessed in norepinephrine (NE)-conditioned isolated rat femoral artery rings. Calcium-free buffer and nifedipine partially inhibited responsiveness to initial NPY exposure; residual responsiveness to NPY re-exposure was unaffected. In contrast, these treatments markedly inhibited responsiveness to the Y2 agonist NPY13-36, the calcium channel agonist BAY K 8644 (BAY) and the partial alpha 1 adrenoceptor agonist indanidine but did not alter to the Y1 agonist [Leu31,Pro34]NPY. Responsiveness to NPY and NPY13-36 but not to BAY or indanidine was markedly reduced 120 min following conditioning regardless of prior ring exposure to the same peptide; only prior exposure reduced responsiveness to [Leu31,Pro34]NPY. Responsiveness changes to NPY at various times or after various numbers of NE and/or NPY exposures indicated that pre-exposure and time-related responsiveness reductions were discriminable and temporally unrelated to conditioning. Postsynaptic vascular Y2 receptor activation therefore accounts for the known sensitivity of NPY-induced pressor and vasoconstrictive actions to nifedipine. The 'time-dependent' loss of Y2 receptor function may also explain prior failures to observe postsynaptic arterial Y2 receptors in vitro.

Characterization of vascular postsynaptic neuropeptide Y receptor function and regulation. 1. NPY-induced constriction in isolated rat femoral artery rings is mediated by both Y1 and Y2 receptors: evidence from benextramine protection studies.

Neuropeptide Y (NPY), a potent pressor agent and vasoconstrictor, is thought to contribute to the sympathetically mediated postsynaptic regulation of blood pressure primarily through activation of vascular Y1 rather than Y2 NPY receptors. However, data are available that conflict with this conclusion. In this article, the relative roles of postsynaptic Y1 and Y2 receptors as mediators of direct NPY-induced isolated rat femoral artery ring vasoconstriction were evaluated through use of selective Y1 and Y2 agonists, [Leu31, Pro34]NPY ([Leu, Pro]NPY) and NPY13-36 [NPY(13-36)], respectively, and the NPY receptor antagonist benextramine (BXT). NPY, [Leu, Pro]NPY and NPY(13-36) were equipotent as vasoconstrictors, and constriction induced by each peptide, but not by the calcium channel agonist BAY K 8644 (BAY), was almost completely blocked by 10 microM BXT. Each of the three peptides also induced self- and cross-desensitization and protection from BXT blockade, except that [Leu, Pro]NPY neither desensitized nor protected NPY(13-36)-associated responses. NPY also failed to protect [Leu, Pro]NPY- and NPY(13-36)-elicited constriction, and NPY(13-36) failed to provide self-protection, from BXT blockade. However, in these instances, as opposed to the [Leu, Pro]NPY-NPY(13-36) cross-protection experiments, the occurrence of protection was probably masked by the relatively large magnitude of desensitization concurrently induced by the protecting peptide. Taken together, the present findings suggest that NPY-induced rat femoral artery vasoconstriction is mediated by separate, BXT-sensitive, postsynaptic Y1 ([Leu, Pro]NPY-activated) and Y2 [NPY(13-36)-activated] receptors.

Benextramine-neuropeptide Y (NPY) binding site interactions: characterization of 3H-NPY binding site heterogeneity in rat brain.

Pre-incubation of rat brain membranes with 200 microM benextramine followed by extensive dilution and washing to remove unbound ligand reduced Bmax for N-[propionyl-3H]-NPY (3H-NPY) specific binding by 61% relative to control membranes treated identically but in the absence of benextramine. When rat brain membranes were co-incubated with 3H-NPY and 57 microM benextramine, there was a significant shift to the right; the apparent Kd for 3H-NPY binding increased two-fold relative to control membranes. These data are consistent with the hypothesis that benextramine is a competitive and irreversible ligand for a population (60-65%) of rat brain NPY binding sites. 'Paired tube' assays were then used to determine the selectivity of these benextramine-sensitive and insensitive 3H-NPY binding site populations. PYY, NPY and NPY13-36 each displaced 100% of 3H-NPY from rat brain membrane binding sites both in the absence and presence of 1 mM benextramine. In contrast, [Leu31,Pro34]NPY displayed the same binding site selectivity as benextramine in displacing 65% of 3H-NPY from specific binding sites on untreated rat brain membranes, and it failed to displace 3H-NPY from membranes treated with 1 mM benextramine. Thus the selectivity of the benextramine-insensitive 3H-NPY binding site population--PYY > = NPY > NPY13-36 >> [Leu31,Pro34]NPY--is characteristic of a Y2-like NPY binding site population, while the benextramine-sensitive 3H-NPY binding sites appear to be a Y1-like binding site population.

Age-dependent hyperresponsiveness of spontaneously hypertensive rats to the pressor effects of intravenous neuropeptide Y (NPY): role of mode of peptide administration and plasma NPY-like immunoreactivity.

The effects of various doses of intravenously (i.v.) infused (5-min duration, 0.1-3.2 nmol/kg/min) or bolus-injected (0.1-3.2 nmol/kg) porcine and/or rat/human neuropeptide Y (NPY) on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of porcine NPY-like immunoreactivity (pNPYir) were examined in conscious, unrestrained spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats of various ages. When administered as an infusion to 12- to 17-week-old SHR, WKY, and SD rats, porcine NPY (pNPY) was more potent in increasing MAP in SHR than in either WKY or SD rats. Infusions of rat/human NPY instead of pNPY resulted in similar increases in potency in 12- to 17-week-old SHR as compared with WKY. This potency-associated hyperresponsiveness to infused pNPY was also observed when 36- to 41-week-old and 6-week-old SHR and WKY were examined, but infused NPY induced similar HR reductions in age-matched rats regardless of rat strain. Furthermore, doses of infused pNPY that elicited significantly greater pressor responses in SHR and WKY (0.32 nmol/kg/min in 12- to 17-week-old rats and 1.0 nmol/kg/min in 6-week-old rats) resulted in essentially identical plasma pNPYir concentrations in the two rat strains. In contrast, hyperresponsiveness to the MAP effects of bolus injections of pNPY in 12- to 17-week-old SHR was manifested as an increase in efficacy rather than potency, was associated with significantly smaller reductions in HR in SHR than in WKY and occurred at plasma pNPYir concentrations that were significantly larger than those required for infusion-associated hyperresponsiveness. These results are consistent with the hypothesis that NPY is an important contributor to the development and maintenance of essential hypertension.

Antioxidants prevent the interaction of 3,4-dihydroxyphenylacetic acid at the dopamine D2 receptor.

Antioxidants such as ascorbic acid (AA) and dithiothreitol (DTT), can prevent 3,4-dihydroxyphenylacetic acid (DOPAC) inhibition of [3H]spiperone binding to neuronal dopamine D2 receptors. The DOPAC quinone produced from auto-oxidation is believed to be responsible for the irreversible inhibition noted. Quinone conjugation to proteins occurs readily in vivo, and thus, auto-oxidation of DOPAC and other endogenous catechol containing compounds could be an important component of protein modification during on-going neuronal physiology.

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Mechanisms of phenylalanine-induced pressor effects in conscious rats.

Phenylalanine and tyrosine reportedly decrease blood pressure in conscious restrained rats. However, tyrosine has recently been found to increase blood pressure in anesthetized animals, questioning the generality of findings obtained in restrained animals. The present study therefore evaluated the effects of phenylalanine on mean arterial pressure (MAP) and heart rate (HR) in unrestrained, conscious rats. Phenylalanine (0.32-1.33 mmol/kg i.p.) increased MAP and decreased HR, effects that were antagonized by carbidopa and prazosin but not by desipramine. In addition, both DOPA and tyrosine (1.33 mmol/kg) increased MAP. In contrast, phenylalanine-induced increases in plasma concentrations of its indirectly acting sympathomimetic amine metabolite, phenethylamine, were small and temporally unrelated to the phenylalanine-induced MAP elevation, and desipramine inhibited MAP increases produced by exogenous phenethylamine. These observations indicate that phenylalanine increases MAP in conscious, unrestrained animals by augmenting peripheral catecholamine synthesis and release rather than by affecting phenethylamine bioavailability.

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin.

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1-3.0 mg/kg), cocaine (1.0-3.0 mg/kg) and bupropion (1.0-30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056-0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha 1 antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha 1 receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.

Amphetamine-induced changes in immunoreactive NPY in rat brain, pineal gland and plasma.

Acute injection of d-amphetamine (10 mg/kg), administered to rats 60 minutes prior to sacrifice, induced a doubling of immunoreactive NPY (NPY-IR) in pineal gland. No changes, however, could be detected in levels of NPY-IR in grossly dissected or microdissected regions of rat brain, nor were changes evident in plasma level concentrations of NPY-IR following acute amphetamine pretreatment. When amphetamine was injected twice daily for six days and once more 60 minutes prior to sacrifice, levels of NPY-IR were decreased in caudate putamen and the paraventricular and dorsomedial nuclei of the hypothalamus, while concentrations of NPY-IR were increased in medial preoptic nucleus, pineal gland, and plasma. These data indicate that levels of NPY-IR are susceptible to manipulation by amphetamine, where the extent and direction of change (increase or decrease) depends on both the frequency of drug administration and the nature of the sampled tissue. Based on the effects of amphetamine on central and peripheral norepinephrine and epinephrine disposition observed in other studies, the data also suggest that NPY-IR and catecholamine dispositions are not directly correlated and may be inversely related in some tissue.