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PubMed1997

Synthesis, dopamine transporter affinity, dopamine uptake inhibition, and locomotor stimulant activity of 2-substituted 3 beta-phenyltropane derivatives.

A series of 2 beta-substituted 3 beta-phenyltropanes were synthesized as analogs of cocaine and tested in vitro for their ability to displace bound [3H]WIN 35,428 (2b) and inhibit dopamine uptake in rat caudate-putamen tissue. The analogs bound with high affinity (Ki = 11-22 nM) to the dopamine transporter. Increased lipophilicity at the beta-C(2)-position was found to lead to increased binding affinity and increased dopamine uptake potency. However, a direct correlation between clogP values and binding affinity and potency of uptake inhibition was not observed. The unsaturated ester 7 was found to possess weak dopamine uptake inhibition relative to the high binding affinity (IC50/Ki = 10.2). In vivo measurement of stimulated locomotor activity and drug discrimination against cocaine (10 mg/kg, ip) with selected analogs (4, 6, and 7) demonstrated that the behavioral effects of these drugs were approximately equipotent with those of cocaine. The structure-activity relationships of this series of cocaine analogs supports a pharmacophore model in which lipophilic interactions between the beta-C(2)-position of 3 beta-phenyltropanes and the cocaine binding site on the dopamine transporter lead to enhanced potency while electrostatic interactions have a nonspecific effect.

Animals↗
PubMed1990

Role of dopamine receptors and the utility of dopamine agonists in heart failure.

The existence of two dopamine receptor subtypes (DA1 and DA2) has been firmly established. Activation of DA1 receptors is associated with vasodilation, primarily in the renal, mesenteric, cerebral, and coronary arterial beds, and a natriuresis. DA2 receptors located on postganglionic sympathetic nerves and sympathetic ganglia mediate a decrease in the release of norepinephrine from sympathetic nerve terminals. The DA receptor activity of dopamine (which activates beta 1- and alpha-adrenoceptors as well as DA receptors) plays a prominent role in determining the beneficial hemodynamic responses to this drug in patients with heart failure. As a result, recent research efforts have been directed toward the development of dopamine analogues, which are orally effective and exhibit more selective agonist activity at DA receptors. Limited clinical experience in heart failure is now available for analogues with different spectra of receptor activity than dopamine, including selective DA1 and DA2 agonists. A review of these data is presented with an attempt to define the clinical relevance of the DA receptor-agonist properties of the compounds. Although the results of early clinical studies with some of these first-generation dopamine congeners are encouraging, analysis of ongoing large-scale placebo-controlled trials will provide valuable insight into their utility as therapeutic agents for patients with heart failure.

Animals↗
PubMed1995

Repeated stimulation of dopamine D2-like receptors: reduced responsiveness of nigrostriatal and mesoaccumbens dopamine neurons to quinpirole.

Extracellular recording techniques were used to study antidromically activated nigrostriatal (NSDA) and mesoaccumbens (MADA) dopamine neurons in chloral hydrate-anesthetized rats. Repeated 14-day i.p. treatment with the dopamine D2-like receptor agonists, quinpirole (2 mg/kg/day) or EMD 23448 (2.6 mg/kg/day), resulted in a significant decrease in the average potency and efficacy of i.v. quinpirole (cumulative doses administered on day 15) to inhibit the spontaneous activity of NSDA neurons relative to vehicle controls. Repeated 14-day quinpirole treatment caused a significantly greater decrease in the sensitivity of MADA neurons to i.v. quinpirole challenges than NSDA neurons. When the effects on NSDA neurons were examined after a shorter treatment period, the decrease in the average potency and efficacy of i.v. quinpirole appeared to occur after only 2 days of i.p. quinpirole treatment (2 mg/kg/day). Iontophoretic studies, however, indicated that the average dopamine sensitivity of somatodendritic dopamine autoreceptors on MADA neurons, but not NSDA neurons, was significantly lower relative to controls after 14-day quinpirole treatment (2 mg/kg/day). These results suggest that this quinpirole treatment regimen can differentially affect the average sensitivity of somatodendritic dopamine autoreceptors on MADA and NSDA neurons. The somatodendritic autoreceptors on MADA neurons appear to be more sensitive to the effects of repeated 14-day quinpirole treatment than those on NSDA neurons.

Animals↗
PubMed1992

Intrastriatal Dopamine-rich Implants Reverse the Increase of Dopamine D2 Receptor mRNA Levels Caused by Lesion of the Nigrostriatal Pathway: A Quantitative In Situ Hybridization Study.

Changes in striatal dopamine D2 receptor mRNA levels provoked by unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway were studied by in situ hybridization. The influence of embryonic dopaminergic neurons implanted into the dopamine-depleted striatum on the lesion-induced changes was also examined. Changes in D2 mRNA levels were compared with changes in D2 receptor densities measured in the same animals by receptor autoradiography using [3H]spiperone or [3H]SDZ 205-501 as ligands. The distribution of D2 mRNA in the striatum of control animals closely paralleled that of the D2 receptor itself, as assessed by autoradiography, and the highest density of D2 mRNA occurred in the lateral part of the striatum. One month after lesion, levels of D2 mRNA were 34% higher in the dorsolateral part of the dopamine-depleted striatum than in the corresponding region of the contralateral control striatum. D2 receptor density in this region was increased by 40% relative to the control level. No significant increases could be measured in the medial part of the striatum. The increases in the lateral part were similar at 7 months post-lesion; however, at this time the increase in both D2 mRNA and receptor levels had spread to the medial part of the striatum as well. In the graft-bearing striatum levels of both D2 mRNA and D2 receptors reverted to control levels. This study shows that the post-lesion increase in striatal dopamine receptor and mRNA level is a biphasic phenomenon with a late-occurring component in the medial striatum. It also shows that once the increase in striatal D2 receptor gene expression is accomplished, it is maintained unchanged for long periods, similar to that of D2 receptor levels themselves. Moreover, grafts of embryonic dopaminergic neurons are able to modulate the expression of the dopamine D2 receptor gene.

Journal Article↗
PubMed1996

D1 dopamine receptor-mediated induction of zif268 and c-fos in the dopamine-depleted striatum: differential regulation and independence from NMDA receptors.

Excitatory amino acid afferents from cerebral cortex and dopamine afferents from the substantia nigra synapse on common projection neurons in the striatum. Activation of D1 dopamine receptors increases immediate early gene expression in the striatum and conductance through the N-methyl-d-aspartate (NMDA) receptor. To examine the contribution of NMDA receptor activation to dopamine receptor-mediated responses, we determined the effects of intrastriatal administration of NMDA antagonists on immediate early gene expression in the striatum and rotational behavior induced by stimulation of the D1 receptor in rats with unilateral dopamine depletions. Systemic administration of SKF 38393 increased c-fos and zif268 mRNAs in the striatum and induced contralateral rotation. Intrastriatal infusion of the competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)-propyl -1-phosphonic acid caused a dose-dependent attenuation of SKF 38393-induced rotation and partially decreased c-fos mRNA expression. However, D1-mediated increases in zif268 mRNA were not affected, except by the highest concentration of antagonist used (10 mM). Another competitive antagonist, 2-amino-5-phosphonovaleric acid, had similar effects. Like the competitive antagonists, intrastriatal infusion of the non-competitive NMDA antagonist MK-801 partially decreased c-fos, but not zif268, mRNA in the area around the microdialysis probe. However, unlike competitive antagonists, local infusion of 1 mM MK-801 potentiated D1-mediated increases in c-fos and zif268 mRNAs in lateral striatum. These data suggest that 1) some D1 dopamine receptor-mediated effects on striatal function are independent of ongoing NMDA receptor activation, whereas other effects are at least partially mediated by NMDA receptor activity in the striatum, and 2) competitive and non-competitive antagonists of the NMDA receptor differently affect D1-mediated immediate early gene expression in the striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Blockade of dopamine storage, but not of dopamine synthesis, prevents activation of a tolbutamide-sensitive K+ channel in the guinea-pig substantia nigra.

The substantia nigra has one of the highest levels of ATP-sensitive K+ channel in the brain. Since this channel is controlled by cell metabolism, the aim of this study was to see how closely it is associated with nigral dopamine systems, which are decreased in Parkinson's disease. In a sub-population of neurons within the rostral substantia nigra pars compacta of the guinea-pig, a brief period of hypoxia resulted in a tolbutamide (100-500 microM) sensitive hyperpolarisation [input resistance (IR) decrease from 144.88 +/- 14.04 M omega pre-hypoxia to 105.91 +/- 13.25 M omega during hypoxia]. Maximal blockade of this decrease was seen in presence of 500 microns tolbutamide [IR decrease only from 161.35 +/- 32.82 M omega to 155.02 +/- 34.29 M omega]. Reserpine (which depletes dopamine stores) but not alpha-methyl-para-tyrosine (which decreases de novo synthesis of dopamine) caused a marked attenuation of this hyperpolarisation [IR decrease only from 163.32 +/- 44.42 M omega pre-hypoxia to 154.42 +/- 50.97 M omega during hypoxia]. This observation suggests that blockade of dopamine storage, but not of de novo synthesis, leads to a loss of responsiveness of certain mid-brain neurons to hypoxia, rendering them potentially more susceptible to subsequent degeneration. The possible link between nigral dopamine systems and ATP-sensitive K+ channels is discussed.

Animals↗
PubMed1999

Inhibition of catechol-O-methyltransferase (COMT) in the brain does not affect the action of dopamine and levodopa: an in vitro electrophysiological evidence from rat mesencephalic dopamine neurons.

In order to study whether the membrane hyperpolarization and firing inhibition caused by dopamine and levodopa on rat midbrain dopamine cells are affected by the inhibition of brain catechol-O-methyl-transferase (COMT), intracellular electrophysiological recordings were made from these neurons maintained in vitro. Here we report that a treatment of the cerebral tissue with tolcapone, a central and peripheral inhibitor of COMT, does not change the membrane responses of midbrain dopamine neurons to dopamine and levodopa. The lack of modification of the dopaminergic effects by tolcapone suggests that the pharmacological inhibition of intracerebral COMT does not have detectable action on dopamine neurotransmission. Therefore, the therapeutic action of tolcapone in Parkinson's disease, might be dependent on the reduction of COMT activity in the extracerebral tissue.

Animals↗
PubMed1985

Dopamine and the action of opiates: a reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia.

It is suggested that the antipsychotic efficacy of opioids in patients suffering from schizophrenia may result from an interaction of opioids with the dopaminergic system. The modulatory effect of opioids on dopaminergic functions has already been demonstrated in basic experiments: Anatomical and biochemical data reveal an interaction between opioid receptors and dopamine (DA) actions on dopaminergic nerve terminals, cell bodies, and afferent nerve endings. Endogenous enkephalin levels correlate well with the endogenous dopamine content in various brain areas. Systemic or iontophoretic administration of morphine alters the spontaneous activity of ventral tegmental dopaminergic neurons. Morphine and enkephalin effectively enhance pituitary prolactin release, whereas dopamine inhibits it. Opioid agonists effectively alter DA release, DA reuptake, and DA metabolism in the striatum and substantia nigra. In reverse, chronic neuroleptic treatment enhances the synthesis and release of pituitary beta-endorphin. Opioids affect contralateral rotation elicited by dopamine agonists in animals with unilateral lesions of the nigrostriatal pathway. Phencyclidine, a psychotropic drug that shares certain pharmacological characteristics with the putative sigma-opioid receptor ligand SKF 10,047, indirectly mimics the effects of dopamine agonists on prolactin release, release of acetylcholine, etc. It is suggested that an imbalance of opiate-DA interaction might be involved in the pathogenesis of schizophrenia. Consequently, clinical studies on the effects of opioids on psychotic symptoms should also examine opioid influence on dopaminergic functions in these patients.

Brain↗
PubMed1984

Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers.

Methamphetamine and amphetamine were continuously administered to rats for 3 days by means of subcutaneously implanted osmotic minipumps. The total daily dose of each drug was approximately 4 mg/day. Dopamine, norepinephrine and serotonin determinations two weeks later indicated that both amphetamines produced a selective striatal dopamine depletion. Anatomical studies indicated that this depletion was associated with striatal nerve fiber degeneration. To determine whether this fiber degeneration induced by amphetamines was dopaminergic, the long-lasting dopamine depletion produced by methamphetamine was antagonized with alpha-methyl-para-tyrosine. This prevented the appearance of nerve fiber degeneration after methamphetamine. These findings suggest that amphetamines produce a long-term striatal dopamine depletion by destroying striatal dopamine nerve fibers.

Amphetamine↗
PubMed1993

The role of brain dopamine in response initiation: effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding.

Two experiments were undertaken to investigate dopaminergic involvement in the local rate of responding on a fixed ratio 5 (FR5) instrumental lever pressing schedule. Rats were trained to press a lever for food reinforcement on a FR5 schedule, and a computer program was used to record the interresponse time (IRT) for each response. The IRT is the time between each lever pressing response, which is equal to the reciprocal of the local response rate. After several weeks of training, rats received i.p. injections of the dopamine antagonist haloperidol (HP; 0.1, 0.2 and 0.4 mg/kg). HP produced a dose-related decline in overall response number. In addition, HP dramatically altered the IRT distribution. HP-treated rats showed a dose-related reduction in the proportion of IRTs with low time values (high local rates of responding), and a corresponding increase in the relative number of IRTs with high time values (low local rates of responding). In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial neostriatum or ventrolateral neostriatum in order to determine the effects of DA depletion on lever pressing performance. Dopamine depletion in all regions significantly reduced lever pressing, and dopamine-depleted rats had substantial changes in their IRT distributions. Rats with dopamine depletions showed significant reductions in the proportion of IRTs with low time values, and increases in the relative number of IRTs with high time values. The greatest reductions in response number and the most pronounced alterations of the IRT distribution were shown by rats with ventrolateral neostriatal dopamine depletions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

1-Methyl-4-phenylpyridine (MPP+): regional dopamine neuron uptake, toxicity, and novel rotational behavior following dopamine receptor proliferation.

The regional uptake and subsequent dopaminergic toxicity, receptor proliferation, and rotational behavior pharmacology following intracerebral 1-methyl-4-phenylpyridine (MPP+) administration was determined in the rat. [3H]MPP+ was transported by the high-affinity dopamine uptake system equally in the caudate-putamen (CP), nucleus accumbens (NA) and olfactory tubercle (OT), and to a lesser extent in the substantia nigra. Consistent with the equivalent uptake of [3H]MPP+ by mesostriatal and mesolimbic dopamine neurons, dopamine concentrations of the ipsilateral CP and NA were decreased equally (83-98%) following a 10, 17.5 or 25 microgram injection of MPP+ along the left medial forebrain bundle (MFB). At four weeks after a 25 microgram injection of MPP+ into the MFB, the concentration (Bmax) of D2 receptors in the left CP was increased by 42% compared with the intact hemisphere. D2 receptors did not proliferate in the denervated nucleus accumbens. The affinity (Kd) of D2 receptors was not affected in either the CP or NA. The MPP+ injection, which was restricted to the region of striatonigral efferent fibers, also produced a 60% decrease in the GABA content of the substantia nigra. Ipsiversive rotational behavior was induced in MPP+-treated rats by systemic injections of d-amphetamine. Systemic injections of neither the dopamine agonist apomorphine nor agonist prodrug formulation of 1-DOPA and carbidopa induced contraversive rotation. These behavioral and neurochemical results are identical to those observed following concomitant destruction of striatonigral GABA and mesostriatal dopamine projections, and indicate that MPP+ may be toxic to GABAergic as well as to A10 and A9 dopaminergic neurons.

1-Methyl-4-phenylpyridinium↗
PubMed1986

ACTH-(1-24) and alpha-MSH antagonize dopamine receptor-mediated inhibition of striatal dopamine and acetylcholine release.

The effects of ACTH-(1-24), alpha-MSH and ACTH-(4-10) were studied on the electrically evoked release of 3H-dopamine and 14C-acetylcholine from striatal slices in the absence and presence of the dopamine receptor agonist TL-99. None of the peptides affected transmitter release when TL-99 was not present. ACTH-(1-24) and alpha-MSH concentration-dependently antagonized the inhibition of striatal transmitter release induced by dopamine receptor stimulation due to the presence of TL-99. ACTH-(1-24), 10(-7)M, reduced the TL-99-induced inhibition of the release of both dopamine and acetylcholine by approximately 50%, and 5 X 10(-6) M ACTH-(1-24) restored the release fully to control values. alpha-MSH was less effective by a factor 20-30 in counteracting the release-inhibiting effect of TL-99. ACTH-(4-10) had no effect at any of the concentrations tested. These results show that ACTH/MSH-like neuropeptides may act by modulating dopamine receptor functions in rat striatum.

Acetylcholine↗
PubMedDate not supplied

Comparison of the acute actions of amine-depleting drugs and dopamine receptor antagonists on dopamine function in the brain in rats.

The effects of the monoamine depleting drugs oxypertine, tetrabenazine and reserpine were compared with those of the dopamine receptor antagonists, chlorpromazine and trifluoperazine, on behavioural and biochemical indices of dopamine function in the brain. Oxypertine (0.625-20 mg/kg, i.p.), chlorpromazine (0.625-20 mg/kg i.p.) and trifluoperazine (0.0625-2.0 mg/kg i.p.), administered to rats 1 hr previously, inhibited stereotyped behaviour induced by both amphetamine (5.0 mg/kg i.p.) and apomorphine (1.0 mg/kg, s.c.) in a dose-dependent manner. Tetrabenazine (0.625-20 mg/kg i.p., 1 hr previously) inhibited stereotypy induced by amphetamine but not that induced by apomorphine. Reserpine (0.1 10 mg/kg i.p., 6 hr previously) did not inhibit, but in larger doses, tended to enhance the stereotyped responses to both amphetamine and apomorphine. Oxypertine (10 mg/kg, i.p., 1 hr previously), tetrabenazine (5 mg/kg i.p., 1 hr previously) and reserpine (2.5 mg/kg i.p., 6 hr previously) reduced the content of dopamine in the striatum but increased the concentrations of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Chlorpromazine (5 mg/kg i.p.) and trifluoperazine (0.5 mg/kg i.p.), given 1 hr previously, did not alter concentrations of dopamine in the striatum but increased those of HVA and DOPAC. Oxypertine, chlorpromazine and trifluoperazine weakly inhibited dopamine-stimulated adenylate cyclase in homogenates of the striatum in the rat. Tetrabenazine and reserpine had no effect. Similarly, trifluoperazine and chlorpromazine displaced the specific binding of [3H]piflutixol to membranes from the striatum. Oxypertine also was weakly effective, but tetrabenazine and reserpine were without effect. Trifluoperazine, chlorpromazine and oxypertine displaced specific binding of [3H]spiperone and [3H]N,n-propylnorapomorphine (NPA) to preparations of the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Binding sites for [3H]dopamine and dopamine-antagonists on cultured astrocytes of rat striatum and spinal cord: an autoradiographic study.

The cellular localization of binding sites for [3H]dopamine, and dopamine-antagonists (D1 and D2) was studied in organotypic cultures of rat striatum and spinal cord by means of autoradiography. In both types of cultures, many astrocytes were labelled by [3H]dopamine, the D1-antagonist [3H]cis-flupenthixol and the D2-antagonists [3H]domperidone and [3H]spiperone (10(-9) to 10(-8) M). Addition of unlabelled dopamine and antagonists at high concentrations (10(-6) to 10(-4) M) inhibited or markedly reduced binding of the radioligands indicating 'specific' binding of the compounds. Our autoradiographic studies are consistent with biochemical investigations by other authors, suggesting that astrocytes possess receptors for dopamine.

Animals↗
PubMed1990

Effects of dopamine autoreceptor stimulation on the release of colocalized transmitters: in vivo release of dopamine and neurotensin from rat prefrontal cortex.

The in vivo release of dopamine and neurotensin from the rat medial prefrontal cortex was studied using perfusion microdialysis coupled with sensitive radioimmunoassay and HPLC techniques. Following stimulation of dopamine autoreceptors with either apomorphine (30 micrograms/kg, s.c.) or EMD-23448 (10 microM in the perfusion buffer) a decrease in dopamine and an increase in neurotensin release was observed. The release of both substances was measured in the same dialysis sample. These data suggest that activation of dopamine autoreceptors in the prefrontal cortex produces opposing effects on the release of dopamine and neurotensin.

Animals↗
PubMed1983

The electrophysiology of dopamine (D2) receptors: a study of the actions of dopamine on corticostriatal transmission.

Electrophysiological recordings from the cells of the neostriatum in rats anaesthetised with halothane revealed only inhibitory actions of dopamine applied iontophoretically close to the cells. Inhibition of cortical driving seemed to have a slightly higher threshold in most cells but dopamine inhibited spontaneous action potentials, glutamate-induced responses, and cortical driving in the cells studied. Fluphenazine applied iontophoretically blocked the actions of dopamine but was itself without effect on the neuronal responses. Sulpiride, in contrast, was without effect on the spontaneous activity of the cells and was ineffective in blocking the action of applied dopamine. Sulpiride, nevertheless, increased the response to cortical stimulation though it had no action on the response to applied glutamate. These results suggest that the sub-class of dopamine receptors on the terminals of the corticostriatal pathway may be inhibitory on glutamate release and preferentially sensitive to blockade by sulpiride.

Acetylcholine↗
PubMed2004

Abnormalities in the dopamine system in schizophrenia may lie in altered levels of dopamine receptor-interacting proteins.

BACKGROUND: Dopamine receptor-interacting proteins constitute a part of the dopamine system that is involved in regulation of dopamine receptor-associated intracellular signaling. Previously, we demonstrated that two such proteins, the D1 receptor-interacting protein calcyon and the D2 receptor-interacting protein neuronal calcium sensor-1 (NCS-1), were elevated in the prefrontal cortex of schizophrenia cases from the Stanley Foundation Neuropathology Consortium. METHODS: The aim of this study was to confirm and expand these findings. We employed Western blot and real-time reverse transcriptase polymerase chain reaction analyses to compare prefrontal (area 46) and occipital (area 17) cortical levels of calcyon and NCS-1 proteins and mRNAs between schizophrenia (n = 37) and control (n = 30) cohorts from the Brain Collection of the Mount Sinai Medical School/Bronx Veterans Administration Medical Center. RESULTS: The schizophrenia cohort showed significant up-regulation of calcyon protein and message levels in both prefrontal and occipital cortical regions, both of which also displayed schizophrenia-associated up-regulation of NCS-1 message. Protein levels of NCS-1 were elevated only in the prefrontal cortex. All increases in protein levels were correlated with those of corresponding messages. Furthermore, schizophrenia-associated alterations in the levels of calcyon and NCS-1 messages were correlated. CONCLUSIONS: Up-regulation of calcyon and NCS-1 in the second schizophrenia cohort strengthens the proposition that abnormalities of the dopamine system in this disease may lie in altered levels of dopamine receptor-interacting proteins. Also, up-regulation of both calcyon and NCS-1 in the cortex of schizophrenia patients can be attributed largely to an enhanced transcription or reduced degradation of their messages. Finally, our findings suggest that elevations in the expressions of calcyon and NCS-1 in schizophrenia may have the same underlying cause.

Age Factors↗
PubMed2003

Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder--the spontaneously hypertensive rat.

RUSSELL, V.A. Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder-the spontaneously hypertensive rat. NEUROSCI. BIOBEHAV. REV.27(2003). Disturbances in glutamate, dopamine and norepinephrine function in the brain of a genetic animal model for attention-deficit hyperactivity disorder (ADHD), the spontaneously hypertensive rat (SHR), and information obtained from patients with ADHD, suggest a defect in neuronal circuits that are required for reward-guided associative learning and memory formation. Evidence derived from (i). the neuropharmacology of drugs that are effective in treating ADHD symptoms, (ii). molecular genetic and neuroimaging studies of ADHD patients, as well as (iii). the behaviour and biochemistry of animal models, suggests dysfunction of dopamine neurons. SHR have decreased stimulation-evoked release of dopamine as well as disturbances in the regulation of norepinephrine release and impaired second messenger systems, cAMP and calcium. In addition, evidence supports a selective deficit in the nucleus accumbens shell of SHR which could contribute to impaired reinforcement of appropriate behaviour.

Animals↗