Nucleus Accumbens-olfactory Tubercle Research Articles

Organization of ventral tegmental area projections to the ventral tegmental area–nigral complex in the rat

The ventral tegmental area (VTA) is a nodal link in reward circuitry. Based on its striatal output, it has been subdivided in a caudomedial part which targets the ventromedial striatum, and a lateral part which targets the ventrolateral striatum [Ikemoto S (2007) Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev 56:27–78]. Whether these two VTA parts are interconnected and to what extent the VTA innervates the substantia nigra compacta (SNc) and retrorubral nucleus (RR) are critical issues for understanding information processing in the basal ganglia. Here, VTA projections to the VTA–nigral complex were examined in rats, using Phaseolus vulgaris leucoagglutinin (PHA-L) as anterograde tracer. The results show that the dorsolateral VTA projects to itself, as well as to the dorsal tier of the SNc and RR, largely avoiding the caudomedial VTA. The ventrolateral VTA innervates mainly the interfascicular nucleus. The components of the caudomedial VTA (the interfascicular, paranigral and caudal linear nuclei) are connected with each other. In addition, the caudomedial VTA (especially the paranigral and caudal linear nuclei) innervates the lateral VTA, and, to a lesser degree, the SNc and RR. The caudal pole of the VTA sends robust, bilateral projections to virtually all the VTA–nigral complex, which terminate in the dorsal and ventral tiers. Modest inputs from the medial supramammillary nucleus to ventromedial parts of the VTA–nigral complex were also identified. In double-immunostained sections, PHA-L-labeled varicosities were sometimes found apposed to tyrosine hydroxylase–positive neurons in the ventral mesencephalon. Overall, the results underscore that VTA projections to the VTA–nigral complex are substantial and topically organized. In general, these projections, like the spiralated striato-nigro-striatal loops, display a medial-to-lateral organization. This anatomical arrangement conceivably permits the ventromedial striatum to influence the activity of the lateral striatum. The caudal pole of the VTA appears to be a critical site for a global recruitment of the mesotelencephalic system.

Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of a selective 5-HT2A antagonist, M100907, following single and multiple oral dosing in healthy volunteers

It has long been speculated that feedback inhibition of endogenous opioid neurons may have a role in opiate tolerance and dependence. However, in studies in which opiates or opioid antagonists have been administered to animals, mixed results have been obtained on the ability of these drugs to regulate endogenous opioids. The present studies were undertaken to determine the effects of chronic administration of opiate drugs on opioid peptides. These studies focused on the regulation of prodynorphin (Prodyn) and proenkephalin (Proenk) peptides in striatal tissue. Morphine, whether administered by chronic infusion or repeated injection, was found to increase the concentration of Prodyn peptides in striatum. Increases were statistically significant in the sensorimotor dorsal striatum (caudate-putamen) but not in the limbic-motor ventral striatum (nucleus accumbens-olfactory tubercle). No changes in Prodyn peptides were found following chronic administration of the opioid antagonist naltrexone. No changes in the Proenk peptide MERGL were found following chronic treatment with morphine or naltrexone. These studies are consistent with the suggestion that Prodyn neurons may have a role in the consequences of long-term opiate administration.

Locomotor Activity and Dopamine Synthesis Following 1 and 15 Days of Withdrawal from Repeated Apomorphine Treatments

In two experiments, the effects of repeated apomorphine treatments on locomotor activity and terminal field dopamine synthesis was assessed after either a 1- or 15-day withdrawal period. In the first experiment, rats ( n = 11/group) were treated with apomorphine (1.0 mg/kg, s.c.) or vehicle and tested for locomotor activity daily for 10 days. Fifteen days after the last repeated treatment, all rats received 1.0 mg/kg apomorphine and were tested for locomotor activity. Locomotor sensitization developed over the 10 day period and was still evident after the 15-day withdrawal period. In the second experiment, rats ( n = 11/group) were treated with apomorphine (1.0 mg/kg, s.c.) or vehicle and tested for locomotor activity daily for 10 days. Dopamine synthesis was assessed following 1 or 15 days of withdrawal by measuring dihydroxyphenylalanine (DOPA) accumulation (after DOPA decarboxylase inhibition with NSD-1015) in striatum and nucleus accumbens-olfactory tubercle. As in the first experiment, rats treated with repeated apomorphine showed locomotor sensitization over the 10 days, relative to controls. Dopamine synthesis was reliably enhanced in the striatum, but not nucleus accumbens-olfactory tubercle, following both 1- and 15-day withdrawal periods. These results indicate that enhanced basal dopamine synthesis following repeated apomorphine treatments, similar to locomotor sensitizaton, is a persistent phenomenom.

Effects of chronic opiate and opioid antagonist treatment on striatal opioid peptides

It has long been speculated that feedback inhibition of endogenous opioid neurons may have a role in opiate tolerance and dependence. However, in studies in which opiates or opioid antagonists have been administered to animals, mixed results have been obtained on the ability of these drugs to regulate endogenous opioids. The present studies were undertaken to determine the effects of chronic administration of opiate drugs on opioid peptides. These studies focused on the regulation of prodynorphin (Prodyn) and proenkephalin (Proenk) peptides in striatal tissue. Morphine, whether administered by chronic infusion or repeated injection, was found to increase the concentration of Prodyn peptides in striatum. Increases were statistically significant in the sensorimotor dorsal striatum (caudate-putamen) but not in the limbic-motor ventral striatum (nucleus accumbens-olfactory tubercle). No changes in Prodyn peptides were found following chronic administration of the opioid antagonist naltrexone. No changes in the Proenk peptide MERGL were found following chronic treatment with morphine or naltrexone. These studies are consistent with the suggestion that Prodyn neurons may have a role in the consequences of long-term opiate administration.

Repeated quinpirole treatment: locomotor activity, dopamine synthesis, and effects of selective dopamine antagonists.

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D2-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D2-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbens-olfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D1 antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or SCH 23390) design. Quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: Assessment of the role of D1 dopamine receptor stimulation

Previous research has revealed a role of repeated D1 dopamine receptor stimulation in the development of behavioral sensitization to the D1/D2 agonist apomorphine. The present experiments assessed the role of repeated D1 receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D1 stimulation on dopamine synthesis, rats were injected with the D1 agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D1 agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]SCH 23390 binding to D1 receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid met 5-enkephalin-arg 6-gly 7-leu 8 immunoreactive peptides: differential effect of haloperidol compared to clozapine

It has long been speculated that feedback inhibition of endogenous opioid neurons may have a role in opiate tolerance and dependence. However, in studies in which opiates or opioid antagonists have been administered to animals, mixed results have been obtained on the ability of these drugs to regulate endogenous opioids. The present studies were undertaken to determine the effects of chronic administration of opiate drugs on opioid peptides. These studies focused on the regulation of prodynorphin (Prodyn) and proenkephalin (Proenk) peptides in striatal tissue. Morphine, whether administered by chronic infusion or repeated injection, was found to increase the concentration of Prodyn peptides in striatum. Increases were statistically significant in the sensorimotor dorsal striatum (caudate-putamen) but not in the limbic-motor ventral striatum (nucleus accumbens-olfactory tubercle). No changes in Prodyn peptides were found following chronic administration of the opioid antagonist naltrexone. No changes in the Proenk peptide MERGL were found following chronic treatment with morphine or naltrexone. These studies are consistent with the suggestion that Prodyn neurons may have a role in the consequences of long-term opiate administration.

Distribution of D1 and D2 dopamine receptors in the basal ganglia of the cat determined by quantitative autoradiography.

The patterns of dopamine D1 and D2 receptors were examined in the corpus striatum and related structures in the cat brain by quantitative autoradiography after in vitro radioligand binding with [3H]SCH23390 (D1 antagonist) and [3H]spiperone (D2 antagonist). Highly specific binding for both radioligands occurs in striatal structures known to receive dopaminergic input: the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle. However, the density of binding varies from one structure to another, and the density distribution within striatal nuclei is heterogeneous. In all but one portion of the striatum, the concentration of bound D1 radioligand ranges from 46 to 230% more than that of the D2 radioligand. The exception to this difference occurs at caudal putamenal levels where the two radioligands bind in equal concentrations (approximately equal to 220 fmol/mg tissue wet-weight). The highest density of both D1 and D2 radioligand binding occurs in irregular zones in the head and body of the caudate nucleus. Such high-density zones of D2 radioligand binding appear mainly in the dorsolateral part of the caudate's head. For the D1 radioligand, the high-density zones are more widespread throughout the caudate nucleus, nucleus accumbens, and putamen. The D2 radioligand binding (but not the D1) also exhibits low-density zones at more caudal levels of the caudate nucleus, and these are often in register with the high-density zones of D1 radioligand binding. In the putamen, inverted concentration gradients exist for the two radioligands: the [3H]SCH23390 gradient runs from higher levels rostrally to lower levels caudally. The lowest levels of bound [3H]spiperone in the striatum occur in the nucleus accumbens-olfactory tubercle area, whereas the lowest binding of [3H]SCH23390 occurs in the caudal putamen. Pallidal and nigral structures show marked disparities in binding of the two different radioligands. The D2 radioligand binding in the globus pallidus (80 +/- 8 fmol/mg tissue wet-weight) is about twice that in the entopedunuclear nucleus and pars reticulata of the substantia nigra, the latter two having equal levels (35 +/- 3 fmol/mg). No specific binding of the D2 radioligand occurs in the ventral pallidum. In contrast, D1 radioligand binding is highest in the entopeduncular nucleus (217 +/- 6 fmol/mg) and in the pars reticulata of the substantia nigra (198 +/- 2 fmol/mg) and moderate in the ventral pallidum (135 +/- 15 fmol/mg). In the globus pallidus, no detectable D1 radioligand binding occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum.

Ungerstedt observed that the dopamine-containing innervation of the forebrain can be divided into two parts: a nigrostriatal system, originating mainly in the pars compacta of the substantia nigra and innervating the caudoputamen; and a mesolimbic system arising mainly in the ventral tegmental area and innervating the nucleus accumbens and olfactory tubercle. This classification has since been modified and extended with the discovery of the mesocortical dopamine system. The original distinction between nigrostriatal and mesolimbic systems nevertheless was pivotal in suggesting that the basal ganglia are related to limbic as well as to sensorimotor functions, and remains of interest because dopaminergic mechanisms may be implicated not only in the aetiology of sensorimotor impairments such as those of Parkinson's disease, but also in neuropsychiatric disorders such as schizophrenia. The striatal targets of the mesolimbic and nigrostriatal systems are now known to be distinct also in terms of forebrain connections, despite some overlap of fibre projections. The nucleus accumbens-olfactory tubercle region and abutting caudoputamen (together called the 'ventral' or 'limbic' striatum) are characteristically related to limbic parts of the forebrain, whereas the large remainder of the caudoputamen (the 'dorsal' or 'non-limbic' striatum) is most closely related to sensorimotor regions. We report here evidence that the mesolimbic and nigrostriatal systems are differentially affected in the mutant mouse weaver, and in particular that dopamine is severely depleted in the dorsal striatum of weaver but relatively spared in the ventral striatum. We conclude that dopamine-containing fibre systems innervating the limbic and non-limbic striatum can be influenced separately in genetic disease and that genetic control, whether direct or indirect, may be exerted at the single-gene level.

Differential effects of limbic versus striatal dopamine loss on motoric function

Bilateral 6-hydroxydopamine injections into either the ventral tegmental area, or the substantia nigra pars compacta in rats, produced severe losses of dopamine in the nucleus accumbens-olfactory tubercle and striatum respectively. After 1 and 3 months postoperation, the depletion of limbic dopamine was associated with reduced spontaneous locomotor activity, which was enhanced by apomorphine (0.125 mg/kg), but not amphetamine (1.0 mg/kg). The severe loss of striatal dopamine had no persistent effect on spontaneous or d-amphetamine-induced locomotor activity, but did produce a persistent augmentation of rigidity. Although there was considerable recovery, both lesions chronically increased catalepsy scores. The results of this study suggested that limbic dopamine deficits may be important in initiation of movement; whereas, striatal dopamine deficits may contribute more to the rigidity aspects of Parkinsonism.

In vivo effects of apomorphine and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20–1724) on cyclic nucleotides in rat brain and pituitary

The effect of apomorphine or of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20–1724), a potent phosphodiesterase inhibitor, on levels of cyclic AMP and cyclic GMP in vivo was examined in the pituitary, cerebellum, corpus striatum and nucleus accumbens-olfactory tubercle. RO 20–1724 was also tested in combination with apomorphine to determine whether this drug could potentiate the effect of apomorphine. Rats were injected with vehicle or RO 20–1724 (30 mg/kg) 30 min prior to an injection of saline or apomorphine hydrochloride (1 or 10 mg/kg). The animals were killed by microwave irradiation 7 min after the second injection. RO 20–1724 increased levels of cyclic AMP in all four regions, especially in the pituitary. RO 20–1724 increased levels of cyclic GMP in the cerebellum, but not in the pituitary. Apomorphine increased cyclic AMP in the pituitary, and cyclic GMP in all four regions. RO 20-1724 did not produce supra-additive effects with apomorphine. The system most responsive to either drug was cyclic AMP in the pituitary, where cyclic AMP increased approximately 10-fold after either apomorphine or RO 20–1724.

Examination of des-tyrosine 1-γ-endorphin activity at 3H-spiroperidol binding sites in rat brain

Des-tyrosine 1-γ-endorphin (DTγE, β-LPH 62–77) was tested for its ability to affect the binding of 3H-spiroperidol in rat corpus striatum, frontal cortex and nucleus accumbens-olfactory tubercle. 3H-Spiroperidol binds with high affinity and specificity to neuroleptic receptors in brain tissue. The inability of DTγE to inhibit specific 3H-spiroperidol binding reported here suggests that DTγE is not acting at the neuroleptic receptor labeled by 3H-spiroperidol in these regions of rat brain.