For more than 50 years, heavy metal exposure during pre- or post-natal ontogeny has been known to produce long-lived hyperactivity in rodents. Global brain injury produced by neonatal hypoxia also produced hyperactivity, as did (mainly) hippocampal injury produced by ontogenetic exposure to X-rays, and (mainly) cerebellar injury produced by the ontogenetic treatments with the antimitotic agent methylazoxymethanol or with polychlorinated biphenyls (PCBs). More recently, ontogenetic exposure to nicotine has been implicated in childhood hyperactivity. Because attention deficits most often accompany the hyperactivity, all of the above treatments have been used as models of attention deficit hyperactivity disorder (ADHD). However, the causation of childhood hyperactivity remains unknown. Neonatal 6-OHDA-induced dopaminergic denervation of rodent forebrain also produces hyperactivity - and this model, or variations of it, remain the most widely-used animal model of ADHD. In all models, amphetamine (AMPH) and methylphenidate (MPH), standard treatments of childhood ADHD, typically attenuate the hyperactivity and/or attention deficit. On the basis of genetic models and the noted animal models, monoaminergic phenotypes appear to most-closely attend the behavioral dysfunctions, notably dopaminergic, noradrenergic and serotoninergic systems in forebrain (basal ganglia, nucleus accumbens, prefrontal cortex). This paper describes the various pharmacological models of ADHD and attempts to ascribe a neuronal phenotype with specific brain regions that may be associated with ADHD.

In the neonatally 6-hydroxydopamine (6-OHDA)-lesioned rat hyperlocomotor activity, first described in the 1970s, was subsequently found to be increased by an additional lesion with 5,7-dihydroxytryptamine (5,7-DHT) (i.c.v.) in adulthood. The latter animal model (i.e., 134 μg 6-OHDA at 3 d postbirth plus 75 μg 5,7-DHT at 10 weeks; desipramine pretreatments) was used in this study, in an attempt to attribute hyperlocomotor attenuation by D,L-amphet-amine sulfate (AMPH) and m-chlorophenylpi-perazine di HCl (mCPP), to specific changes in extraneuronal (i.e., in vivo microdialysate) levels of dopamine (DA) and/or serotonin (5-HT). Despite the 98-99% reduction in striatal tissue content of DA, the baseline striatal microdialysate level of DA was reduced by 50% or less at 14 weeks, versus the intact control group. When challenged with AMPH (0.5 mg/kg), the microdialysate level of DA went either unchanged or was slightly reduced over the next 180 min (i.e., 20 min sampling), while in the vehicle group and 5,7-DHT (alone) lesioned group, the microdialysate level was maximally elevated by ∼225% and ∼450%, respectively - and over a span of nearly 2 h. Acute challenge with mCPP (1 mg/kg salt form) had little effect on microdialysate levels of DA, DOPAC and 5-HT. Moreover, there was no consistent change in the microdialysate levels of DA, DOPAC, and 5-HT between intact, 5-HT-lesioned rats, and DA-lesioned rats which might reasonably account for an attenuation of hyperlocomotor activity. These findings indicate that there are other important neurochemical changes produced by AMPH-and mCPP-attenuated hyperlocomotor activity, or perhaps a different brain region or multiple brain regional effects are involved in AMPH and mCPP behavioral actions.

5-HT2A/2C receptors are one of the most important in controlling basal ganglia outputs. In rodent models of Parkinson's disease (PD) blockade of these receptors increases locomotion and enhances the actions of dopamine (DA) replacement therapy. Moreover, previously we established that 5-HT 2A/2C antagonist attenuate DA D1 agonist mediated vacuous chewing movements (VCMs) which are considered as an animal representation of human dyskinesia. These findings implicate 5-HT neuronal phenotypes in basal ganglia pathology, and promote 5-HT2 antagonists as a rational treatment approach for dyskinesia that is prominent in most instances of PD replacement therapy. In the current study we determined whether ketanserin (KET) and/or amphetamine (AMPH) affected dopaminergic neurotranssmision in intact and fully DA-denervated rats. Moreover, we looked into extraneuronal content of HO. of the neostriatum after AMPH and/or KET injection, assessed by HPLC analysis of dihydroxybenzoic acids (2,3- and 2, 5-DHBA) - spin trap products of salicylate. Findings from the present study demonstrated that there are no substantial differences in extraneuronal HO. generation in the neostriatum between control and parkinsonian rats. KET did not affect DA release in the fully DA-denervated rat's neostriatum and also did not enhance HO. production. As 5-HT2A/2C receptor-mediated transmission might prove usefulness not only in addressing motor complications of PD patients (dyskinesia) but also in addressing non-motor problems such depression and/or L-DOPA evoked psychosis, the findings from the current study showed that the use of 5-HT2A/2C receptor antagonists in Parkinson's disease does not impend the neostriatal neuropil to be damaged by these drugs. We concluded that 5-HT2A/2C receptor antagonists may provide an attractive non-dopaminergic target for improving therapies for some basal ganglia disorders.

To explore interactive deleterious effects of the teratogens ethanol and cadmium, pregnant rats were given cadmium (CdCl2, 50 ppm) and/or ethanol (10%), or tap water (controls) in the drinking water for the entire 21 days of pregnancy. At 3 months after birth, in vivo microdialysis was used to determine that there was a 4000% evoked release of DA by AMPH (AMPH, 4.0 mg/kg i.p.) in the striatum of rats exposed prenatally to both ethanol and cadmium, vs. a 2000% evoked release by AMPH in rats exposed prenatally to only ethanol or cadmium or tap water. Haloperidol (HAL)-evoked DA release was suppressed in groups exposed prenatally to ethanol, while HAL-evoked DOPAC and HVA release was greatest after co-exposure to prenatal cadmium and ethanol. These in vivo microdialysis results indicate that ontogenetic co-exposure to cadmium, and ethanol produces a long-lived suppressive effect on HAL-evoked DA release and a long-lived enhancing effect on AMPH-evoked DA release in rat striatum. These findings clearly demonstrate that there is marked alteration in dopaminergic regulation after ontogenetic cadmium and ethanol co-exposure, which in this regard resembles the reaction of the striatonigral pathway on AMPH-evoked DA release in rats with behavioral sensitization.

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 μg in 10 μl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.

The intracellular second messenger nitric oxide (NO) is implicated in a variety of physiological functions, including release and uptake of dopamine (DA). In the described study, in vivo microdialysis and differential pulse voltammetric techniques were used to determine the involvement of NO in release of DA and its metabolites (dihydroxyphenylalanine, DOPAC; homovanillic acid, HVA) in neostriatum of freely moving rats. While the NO donor molsidomine (30.0 mg/kg; MOLS) and neuronal NO synthase- (nNOS-) inhbitor 7-nitroindazole (10.0 mg/kg; 7-NI) had no effect on the basal in vivo microdialysate level of DA, 7-NI specifically enhanced D,L-amphetamine- (1.0 mg/kg i.p.; AMPH) evoked release of DA. Basal or AMPH effects on DOPAC and HVA levels were not influenced by MOLS or 7-NI. Findings indicate that nitrergic systems have an important role in mediating effects of AMPH on dopaminergic systems.

Indiana University-Purdue University Indianapolis (IUPUI) / Habit expression is emerging as a theory of addiction: subjects begin to use drugs to attain positive reinforcing effects but continue to use in spite of negative effects because the behavior becomes habitual, and therefore divorced from its outcome. Many studies have shown that a history of drug and alcohol use lead to expedited acquisition of a habit, but the acute effects of these drugs on behavior is still unknown. Behaviors that result from acute intoxication, such as increased aggression, risky sexual behavior, and impaired judgment, could be interpreted as habitual: actions performed without regard for the outcome. Therefore, we studied the transition from goal-directed to habitual behavior, when a response is made regardless of outcome value, and how acute intoxication of ethanol (EtOH), amphetamine (AMP), nicotine (NIC), and yohimbine (YOH) affect the resulting behavior. Through a series of four experiments, selectively bred crossed High Alcohol Preferring (cHAP) mice were trained on an operant task to self-administer 1% banana solution, which was subsequently devalued via LiCl CTA. EtOH (1 & 1.5 g/kg), AMP (2.0 mg/kg), NIC (0.5 mg/kg), YOH (1.0 mg/kg), or SAL were administered prior to baseline and post-devaluation tests. We found that acute EtOH at 1- and 1.5-g/kg doses facilitated the expression of a habit, whereas all other pretreatments resulted in devaluation. These data may indicate a unique role for EtOH in facilitating the retrieval of habitual over outcome-based associations. This could shed light on why intoxicated individuals display impaired judgment and a mechanism by which relapse after a period of abstinence can occur.

No description available.

No description available.

Cocaine- and amphetamine-regulated transcript (CART) was first identified in the rat striatum where levels were upregulated following cocaine or amphetamine administration. A dense plexus of CART-immunoreactive fibers is noted in the nucleus of the solitary tract (NTS). Results from tract-tracing and immunohistochemical studies suggest that the dense network of CARTp-fibers in the NTS may arise from nodose ganglia. The present study was undertaken to evaluate the hypothesis that CARTp may alter baroreceptor function in rats. Rats were intravenously administered phenylephrine every 10 min to elicit a baroreflex. CARTp (0.1- 3 nmol) by intracisternal or bilateral intra-NTS microinjection consistently attenuated the phenylephrineinduced bradycardia. In contrast, CARTp antibody potentiated the bradycardia produced from phenylephrine. Microinjection of saline, normal rabbit serum, or concomitant injection of CARTp and CART antibody into the NTS caused no significant change of phenylephrineinduced baroreflex. The result suggests that CARTp released from primary afferents may modulate baroreflex.