Striatal dopamine modulates song spectral but not temporal features through D1 receptors

The activity of midbrain dopaminergic neurons and their projection to the basal ganglia (BG) are thought to play a critical role in the acquisition of motor skills through reinforcement learning, as well as in the expression of learned motor behaviors. The precise role of BG dopamine (DA) in mediating and modulating motor performance and learning, however, remains unclear. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. Previously we found that DA acts on D1 receptors in Area X to modulate the BG output signal and thereby trigger changes in song variability. Here, we investigate the effect of D1 receptor blockade in the BG on song behavior in the zebra finch. We report that this manipulation abolishes social context-dependent changes in variability not only in harmonic stacks, but also in other types of syllables. However, song timing seems not to be modulated by this BG DA signal. Indeed, injections of a D1 antagonist in the BG altered neither song duration nor the change of song duration with social context. Finally, D1 receptor activation in the BG was not necessary for the modulation of other features of song, such as the number of introductory notes or motif repetitions. Together, our results suggest that activation of D1 receptors in the BG is necessary for the modulation of fine acoustic features of song with social context, while it is not involved in the regulation of song timing and structure at a larger time scale.     

Striatal dopamine transporters and cognitive functioning in healthy men and women

OBJECTIVE: There is growing interest in distinguishing the biological bases of sex differences in behavior from environmental influences. Sex hormone levels seem to be related to some cognitive abilities, particularly memory, and the dopaminergic system participates in the mediation of memory. The dopamine transporter is the primary indicator of dopaminergic tone. This study investigated the relationship between cognition and dopamine transporter availability in healthy men and women. METHOD: Dopamine transporter levels were measured with a technetium-99m radiolabeled analog of cocaine, TRODAT-1, in 66 healthy volunteers (30 men and 36 women). A neuropsychological battery designed to target functions associated with dopaminergic activity was administered during the uptake interval between the radiopharmaceutical injection and image acquisition. RESULTS: Women and younger participants had higher dopamine availability in the caudate nucleus, and these groups also performed better on verbal learning tasks. Furthermore, dopamine transporter availability was correlated with learning performance within groups. Relationships between dopamine availability in the caudate and putamen and executive and motor functioning were observed in women, but not in men. CONCLUSIONS: The results provide further evidence for age effects and sex differences in the neuromodulatory influences of dopamine on behavior in humans.     

Neurotensin receptors and dopamine transporters: effects of MPTP lesioning and chronic dopaminergic treatments in monkeys.

The effect of denervation with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of the dopamine (DA) nigrostriatal pathway on neurotensin (NT) receptor and DA transporter (DAT) in basal ganglia of monkeys (Macaca fascicularis) was investigated. The MPTP lesion induced a marked depletion of DA (90% or more vs. control) in the caudate nucleus and putamen. The densities of NT agonist binding sites labeled with [125I]NT and the NT antagonist binding sites labeled with [3H]SR142948A decreased by half in the caudate-putamen of MPTP-monkeys. In addition, the densities of [125I]NT and [3H]SR142948A binding sites markedly decreased (-77 and -63%, respectively) in the substantia nigra of MPTP-monkeys. Levocabastine did not compete with high affinity for [125I]NT binding in the monkey cingulate cortex, suggesting that only one class of NT receptors was labelled in the monkey brain. An extensive decrease of [3H]GBR12935 DAT binding sites (-92% vs. Control) was observed in the striatum of MPTP-monkeys and an important loss of DAT mRNA(-86% vs. Control) was observed in substantia nigra. Treatments for 1 month with either the D1 agonist SKF-82958 (3 mg/kg/day) or the D2 agonist cabergoline (0.25 mg/kg/day) had no effect on the lesion-induced decrease in NT and DAT binding sites or DAT mRNA levels. The decrease of striatal NT binding sites was less than expected from the decrease of DA content in this nucleus, suggesting only partial localization of NT receptors on nigrostriatal DAergic projections. These data also suggest that under severe DA denervation, treatment with D1 or D2 DA agonists does not modulate NT receptors and DAT density.     

Striatal hypermetabolism in limbic encephalitis

Striatal hypermetabolism on 18FDG-PET scan is a neuroradiological finding that has been described in association with autoimmune disorders such as Sydenham chorea, lupus or antiphospholipid syndrome. Here, we report three patients with non-paraneoplastic limbic encephalitis characterized by 18FDG-PET hypermetabolism of both striata, in contrast with diffuse hypometabolism in the rest of the brain. All patients developed subacute dementia, and antibodies to voltage-gated potassium channels were found in all cases. Brain metabolism and neurological status improved within a few months of immunosuppressive therapy. The finding of striatal hypermetabolism on 18FDG-PET images could thus be highly indicative of limbic encephalitis associated with anti-neuropil antibodies. It could be of significant help in the diagnosis of this rare and treatable condition, and may also provide a useful marker of disease outcome.     

Striatal dopamine metabolism in living monkeys examined by positron emission tomography

Positron emission tomography, using the dopa analogue [18F]6-fluoro-L-dopa, has been used to depict the neostriatum in living monkeys. The amount of 18F that accumulated preferentially in the striatum could be augmented by a peripheral decarboxylase inhibitor. Striatal 18F could also be discharged with reserpine. This is the first time that the regional distribution of a neurotransmitter has been demonstrated in monkeys.     

Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat

Earlier studies indicate that striatal dopamine D(2) receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D(2) receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D(2) receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D(2) receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D(2) receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D(2) receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D(2) receptors.     

Cocaine occupancy of sigma1 receptors and dopamine transporters in mice

Activation of sigma₁ (σ₁) receptors contributes to the behavioral and toxic effects of (?)‐cocaine. We studied a key step, the ability of (?)‐cocaine to occupy σ₁ receptors in vivo, using CD‐1^® mice and the novel radioligand [¹²⁵I]E‐N?1‐(3′‐iodoallyl)‐N′‐4‐(3″,4″‐dimethoxyphenethyl)‐piperazine ([¹²⁵I]E‐IA‐DM‐PE‐PIPZE). (?)‐Cocaine displayed an ED₅₀ of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED₅₀ of 26 μmol/kg for (?)‐cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [¹²⁵I]3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid isopropyl ester ([¹²⁵I]RTI‐121) binding. A chief finding is the relatively small potency difference between (?)‐cocaine occupancy of σ₁ receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (?)‐cocaine with σ₁ receptors were assessed further using [¹²⁵I]E‐IA‐DM‐PE‐PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (?)‐Cocaine binding to cerebral σ₁ receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E‐IA‐DM‐PE‐PIPZE gave an ED₅₀ of 0.23 μmol/kg for occupancy of cerebral σ₁ receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (?)‐cocaine‐induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E‐IA‐DM‐PE‐PIPZE is a probable σ₁ receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ₁ and σ₂ receptors expressed in CD‐1^® mouse brain. Synapse 70:98–111, 2016. © 2016 Wiley Periodicals, Inc.     

Reactions to familiar and novel objects in infant monkeys with neonatal temporal lesions

Adult monkeys with late temporal lobe damage are known to touch and mouth objects compulsively, even unknown objects. To determine whether infants with early temporal damage display this symptom as well, 9-month-old rhesus monkeys with neonatal ablations of either the medial temporal lobe or inferior temporal cortex were exposed to four objects, two familiar and two novel. All operated infants were less active/more withdrawn than controls and showed neither exaggerated object manipulation nor hyperorality. Furthermore, like controls, they touched novel objects less than they touched familiar ones. Thus, infants with neonatal medial or inferior temporal ablations did not display the compulsive exploration evidenced after similar lesions in adulthood and retained some ability to detect novelty despite their known memory impairments.     

Striatal dopamine D2 receptors in tardive dyskinesia: PET study.

The dopamine D2 receptors were investigated in vivo in eight neuroleptic-free patients with persistent tardive dyskinesia using positron emission tomography and 76Br-bromospiperone. The striatal receptor density, estimated by the striatum/cerebellum radioligand concentration ratio, was not elevated in patients as compared with age-matched controls but was positively correlated with the severity of orofacial dyskinesia assessed with the Abnormal Involuntary Movement Rating Scale. These results indicate that tardive dyskinesia is associated with normal levels of striatal D2 receptors but the severity of orofacial movements may depend on the relative density of striatal D2 receptors.     

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.     

Striatal dopamine turnover and MIF-I

Because of conflicting reports of the actions of the antiparkinsonian agent L-prolyl-L-leucyl-glycine amide (PLG, MIF-I) on the turnover of Striatal dopamine (DA), this process was reinvestigated. In the present series of studies, it was found that neither our MIF-I (200 ng ICV) nor the MIF-I used by Versteeg et al. [25]was effective in altering the rate of decline of endogenous DA in the caudate nucleus of rats pretreated with α-methyl-p-tyrosine (300 mg/kg IP). In addition, our MIF-I (1 mg/kg IP) did not change endogenous dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA) in rat striatum. These studies indicate that MIF-I does not alter the turnover rate of DA in nigrostriatal neurons. It is possible that MIF-I or some substance released by MIF-I acts at a posfsynaptic receptor site.     

Striatal dopamine D1 receptors in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

A considerable number of human and animal studies have implied the importance of dopamine system and alterations in dopamine receptors in the context of alcoholism. However, it has remained unclear if the alcohol-abuse related dopaminergic deficit is specifically associated with certain receptor subtype. The aim of this study was to compare putative alterations of dopamine D(1) receptors in caudate and putamen of nine type 1 alcoholics, eight type 2 alcoholics and 10 healthy controls by using [(3)H]SCH 23390 as a radioligand in postmortem human whole hemisphere autoradiography. In addition, we compared the present results to our earlier studies on dopamine transporters and dopamine D(2) receptors in these same subjects and evaluated the putative correlations of dopamine D(1) receptor densities between the nucleus accumbens and the above-mentioned structures. Our results show that alcoholics do not have significantly different striatal dopamine D(1) receptor densities compared to controls. Neither were there any significant correlations between the dopamine D(1) receptors and the two other dopamine binding sites. However, the correlations of the dopamine D(1) receptors between nucleus accumbens and dorsal striatal structures were consistently and mostly statistically significantly positive in alcoholics, but not in controls, which may suggest some pathology related to addiction. In addition, considering the facts that dopamine D(1) receptors were more abundant in the mesolimbic nucleus accumbens than in the caudate or putamen and that there was a strong tendency towards lower binding among type 1 alcoholics may suggest the importance of dopamine D(1) receptors in reward and/or alcoholism.     

Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the product of age and CAG repeat length (p < 0.0005). Dopamine D2 receptor availability measured by RAC-BP seems the most sensitive indicator of early neuronal impairment in PMC.     

Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra

Parkinson's disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive individuals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1–D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control. © 2013 International Parkinson and Movement Disorder Society     

Neurochemical individuality: genetic diversity among human dopamine and serotonin receptors and transporters

Behavioral variation in human beings encompasses wide differences in personality and susceptibility to psychiatric illness arising from both genotype and experience. Long-lasting behavioral differences generally have heritabilities of 30% or more, and such inheritance is ultimately attributable to functional variants of genes programming brain development and function. The sequencing of the human genome is revealing a pattern of gene sequence variation. The ability of sequence variants to affect neural function either alone or in concert may reveal effects of behavioral selection on the human genome over evolutionary time frames. Dopamine and serotonin are phylogenetically ancient neurotransmitters intrinsic to brain function and behavior. Dopamine and serotonin receptor and transporter genes have been an early focus for efforts to identify and functionally characterize sequence variation. The purpose of this article is to present a preview of a developing new perspective in human behavior: the genetic variation of the brain or neurochemical individuality. Arch Gen Psychiatry. 2000;57:1105-1114.     

Striatal dopamine and homovanillic acid in Huntington's Disease

Summary Using tissue taken post mortem from patients with neuropathologically confirmed Huntington's disease and a series of appropriate control cases, GABA, dopamine and homovanillic acid were measured in the caudate nucleus and the putamen. The previously reported loss of GABA in Huntington's disease was confirmed, while no change in dopamine concentrations and a loss of homovanillic acid in these striatal regions were observed. This loss could not be explained on the basis of agonal state or previous drug treatment.     

Functional recovery after limbic lesions in monkeys

Ten monkeys received lesions of either the hippocampus, or the amygdala and hippocampus, or the anterior and medial thalamus (each group with two monkeys), or of all these structures together with additional septal lesions (four monkeys). Postoperatively, the monkeys were trained in tasks of visual and spatial reversal, several concurrent object discriminations, delayed nonmatch-to-sample, and in an angle threshold discrimination task. Their performance was compared to that of five healthy or sham-operated control monkeys. The single- or double-lesioned monkeys were impaired in the delayed nonmatch-to-sample task and the angle threshold discrimination, whereas monkeys with five-fold lesions were unimpaired in these tasks. Correlations between brain volume loss and behavioral performance indicated negative coefficients for the delayed nonmatch-to-sample task ("delays": rs = -.59, "lists": rs = -.20) and the angle threshold discrimination (rs = -.60). It is concluded that monkeys with massive limbic lesions display a more effective postlesion reorganization than monkeys with smaller limbic lesions; however, reliability of this effect must be proved by future work with a larger sample. Furthermore, the missing impairments of massively lesioned monkeys especially in the delayed nonmatch-to-sample task also indicate that the limbic targets lesioned here may not be as exclusively involved in mnemonic information processing as suggested earlier.