Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

Spampinato, Umberto; Esposito, Ennio; Romandini, S.; Samanin, R.

doi:10.1016/0006-8993(85)91326-5

Cited by 51 publications

(17 citation statements)

References 30 publications

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“…In contrast, -and ␦-opioids had no effect on 5-HT when infused into the MRN or NAcc. These results are consistent with other reports that systemic administration of morphine elicits selective increases in 5-HT in forebrain sites innervated by the DRN (Spampinato et al, 1985;Tao and Auerbach, 1995). In contrast, -receptor agonists decreased 5-HT during infusion into the DRN, MRN, or NAcc.…”

Section: Discussionsupporting

confidence: 93%

Opioid Receptor Subtypes Differentially Modulate Serotonin Efflux in the Rat Central Nervous System

Tao¹,

Auerbach²

2002

J Pharmacol Exp Ther

110

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Opioid receptor subtypes may have site-specific effects and play different roles in modulating serotonergic neurotransmission in the mammalian central nervous system. To test this hypothesis, we used in vivo microdialysis to measure changes in extracellular serotonin (5-hydroxytryptamine; 5-HT) in response to local infusion of -, ␦-, and -opioid receptor ligands into the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and nucleus accumbens (NAcc) of freely behaving rats ]enkephalin (DPDPE), and deltophin-II into the DRN also increased extracellular 5-HT, an effect that was blocked by selective ␦-receptor antagonists. In contrast to the DRN, local infusion of -and ␦-opioids had no effect on 5-HT in the MRN or NAcc. These data indicate that -and ␦-opioid ligands have a selective influence on serotonergic neurons in the DRN. Finally, the -receptorbenzeneacetamide] produced similar decreases in 5-HT during local infusion into the DRN, MRN, and NAcc. These results provide evidence of differential regulation of 5-HT release by opioid receptor subtypes in the midbrain raphe and forebrain.The largest population of serotonergic cell bodies is located in the dorsal raphe nucleus (DRN) within the ventral portion of periaqueductal gray (PAG), an area richly endowed with opioids and involved in integrating responses to stress (Basbaum and Fields, 1984). Pain and stressful stimuli activate opioidergic neurons in the PAG, which in turn may modulate the activity of serotonergic neurons with projections to sites involved in arousal and emotional state (Ma and Han, 1992;Grahn et al., 1999). Immunocytochemical (Kalyuzhny et al., 1996) and neurochemical (Tao and Auerbach, 1995) studies provide further evidence that opioids modulate serotonergic neuronal activity. However, single unit recording data suggest that the opioid receptor agonist morphine does not directly stimulate serotonergic neurons (Haigler, 1978). Instead, opioids may inhibit both inhibitory and excitatory afferents to the DRN (Jolas and Aghajanian, 1997) and thus could indirectly affect the pattern of serotonergic neuronal discharge.Four types of opioid receptors, , ␦, , and ORL-1, have been identified on the basis of pharmacological and molecular criteria (Knapp et al., 1995;Neal et al., 1999). Endogenous ligands for opioid receptors have been determined, and these have distinct, albeit overlapping, patterns of distribution in the CNS (Mansour et al., 1995;Martin-Schild et al., 1999;Neal et al., 1999). In particular, the ventral PAG, which encompasses the DRN, has moderate to high densities of each of the endogenous opioids and corresponding opioid receptor types (Mansour et al., 1995;Neal et al., 1999). Moreover, there are distinctive and in some instances opposing physiological effects of selective agonists of the four opioid receptor types. For example, selective -opioid receptor agonists are strong analgesics but produce greater physical dependence relative to selective ␦-opioid receptor agonists (Maldonado et al., 1990). In contrast, -and ORL-1...

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Section: Discussionsupporting

confidence: 93%

Opioid Receptor Subtypes Differentially Modulate Serotonin Efflux in the Rat Central Nervous System

Tao¹,

Auerbach²

2002

J Pharmacol Exp Ther

110

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“…Although morphine administration enhances 5-HT and DA levels within the accumbens (Spampinato et al 1985;Tao and Auerbach 1995;Wise et al 1995) (Ettenberg et al 1982;Gerrits and Van Ree 1996;Pettit et al 1984) or morphine place preference in animals (Mackey and van der Kooy 1985; however, also see Bozarth and Wise 1981;Smith et al 1985;Spyraki et al 1983). On the other hand, chemical lesions of 5-HT terminals in the accumbens impair morphine self-administration without affecting responding for food or water (Smith et al 1987), and also block the acquisition of morphine conditioned place preference (CPP) (Spyraki et al 1988).…”

Section: Recent Studies Have Found That Acute Morphine Administrationmentioning

confidence: 99%

“…Acute morphine also enhances the turnover and release of 5-HT and dopamine (DA) in widespread areas of the forebrain (Spampinato et al 1985;Tao and Auerbach 1994). The effect of morphine on 5-HT release appears to be mediated by activation of dorsal raphe neurons (Spampinato et al 1985;Tao and Auerbach 1994) and may reflect disinhibition caused by direct inhibition of GABA transmission. A similar mechanism has also been proposed for the excitatory effects of opiates on DA neurons in the ventral tegmental area (Bloom et al 1972;Bonci and Williams 1997).…”

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confidence: 99%

“…Although morphine administration enhances 5-HT and DA levels within the accumbens (Spampinato et al 1985;Tao and Auerbach 1995;Wise et al 1995), the transmitter systems involved in opiate reward are not decisively known. It has been shown that chemical le-sions of DA systems or blockade with dopamine antagonists do not affect opiate self-administration (Ettenberg et al 1982;Gerrits and Van Ree 1996;Pettit et al 1984) or morphine place preference in animals (Mackey and van der Kooy 1985; however, also see Bozarth and Wise 1981;Smith et al 1985;Spyraki et al 1983).…”

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confidence: 99%

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Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal

Harris

Aston‐Jones

2001

Neuropsychopharmacology

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Recent studies have found that acute morphine administration increases serotonin (5-HT) transmission within the nucleus accumbens and other forebrain regions. In contrast, 5-HT transmission is depressed during withdrawal from chronic morphine. We show that pharmacological agents that increase brain 5-HT levels In addition to gross neurological and somatic signs the abstinence syndrome associated with opiate dependence involves important subjective responses including anxiety, anhedonia, depression and drug craving (Jaffe 1990). The control and elimination of the subjective symptoms, which linger long after the physical symptoms of opiate withdrawal have dissipated, has been a major obstacle to the successful treatment of opiate dependence (Childress et al. 1994). Understanding the alterations in brain chemistry that occur during abstinence from opiate abuse may lead to improved treatments for these symptoms, and greater success in treating opiate addiction.Acute systemic administration of morphine enhances brain 5-HT synthesis (Garcia-Sevilla et al. 1980) and tryptophan hydroxylase activity (Boadle-Biber et al. 1987). Acute morphine also enhances the turnover and release of 5-HT and dopamine (DA) in widespread areas of the forebrain (Spampinato et al. 1985;Tao and Auerbach 1994). The effect of morphine on 5-HT release appears to be mediated by activation of dorsal raphe neurons (Spampinato et al. 1985;Tao and Auerbach 1994) and may reflect disinhibition caused by direct inhibition of GABA transmission. A similar mechanism has also been proposed for the excitatory effects of opiates on DA neurons in the ventral tegmental area (Bloom et al. 1972;Bonci and Williams 1997).Neurons in the nucleus accumbens have been shown to be critically involved in the reinforcing properties of opiates (Dworkin et al. 1988;Pettit et al. 1984;Zito et al. 1985). Although morphine administration enhances 5-HT and DA levels within the accumbens (Spampinato et al. 1985;Tao and Auerbach 1995;Wise et al. 1995) (Ettenberg et al. 1982;Gerrits and Van Ree 1996;Pettit et al. 1984) or morphine place preference in animals (Mackey and van der Kooy 1985; however, also see Bozarth and Wise 1981;Smith et al. 1985;Spyraki et al. 1983). On the other hand, chemical lesions of 5-HT terminals in the accumbens impair morphine self-administration without affecting responding for food or water (Smith et al. 1987), and also block the acquisition of morphine conditioned place preference (CPP) (Spyraki et al. 1988).Withdrawal from opiates decreases both dopamine and 5-HT transmission in the brain. A single dose of morphine induces measurable reductions in both 5-HT and DA levels at 24 hours post-injection (AntkiewiczMichaluk et al. 1995). Withdrawal from longer chronic opiate treatments produces profound decreases in both dopamine (Acquas et al. 1991;Pothos et al. 1991;Rossetti et al. 1992) and 5-HT transmission (Ahtee 1980;Tao et al. 1998). Reduced 5-HT levels have been linked to both depression (Maes and Meltzer 1995) and compulsive behavior (Dolberg et al. ...

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“…We did observe, however, decreased levels of the serotonin metabolite 5-hydroxyindoleacetic acid in striatum and in frontal (Brodmann areas 6, 10, 10 medial, 12), temporal (area 21), and cingulate (area 24) cortices (data not shown) of the heroin users. Animal studies suggest that opiates acutely enhance activity of brain serotonergic neurons innervating the basal forebrain, as indicated by increased levels of 5-hydroxyindoleacetic acid in striatal microdialysates (Wise et al 1995;Enrico et al 1998) and in "whole" tissue (Spampinato et al 1985; Wakabayshi et al. 1995;Desole et al 1996).…”

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confidence: 99%

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

Kish

Kalasinsky

Derkach

et al. 2001

Neuropsychopharmacology

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To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) An important feature of psychostimulant and opiate drugs of abuse is their ability, upon acute administration, to activate brain dopaminergic neurons as evidenced by increased striatal synaptic concentrations of dopamine (DiChiara 1995). Chronic dopaminergic overactivity caused by drugs of abuse leads to a variety of compensatory changes that could influence behavior of the drug user. Synaptic levels of dopamine are decreased in experimental animals withdrawn from chronic psychostimulants (cf. DiChiara 1995) whereas striatal tissue dopamine levels are reduced in human chronic psychostimulant users: moderately for methamphetamine users (Wilson et al. 1996a) or slightly for cocaine users (Wilson et al. 1996b). These changes could explain the dysphoric anhedonic motivational state during withdrawal to psychostimulant drugs. Both experimental animals and humans (cf. Wilson et al. 1996a,b) exposed to psychostimulants also demonstrate altered striatal levels of the dopamine transporter (DAT), a 24 , NO . 5 component of the dopamine nerve terminal critically involved in regulation of synaptic dopamine levels.Relatively less attention has been focused on longterm effects of opiate drugs of abuse on the dopamine system. In fact, it has been assumed that opiates do not produce "enduring changes" in dopaminergic transmission or cellularity (Rogers et al. 1999). Chronic administration of morphine or heroin to rodents, however, causes decreased striatal concentrations of synaptic dopamine (Acquas et al. 1991;Crippens and Robinson 1994), its biosynthetic enzyme tyrosine hydroxylase (Self et al. 1995) and those of DAT (Simantov 1993). Chronic morphine appears to damage dopaminergic neurons as indicated by impaired axonal transport from the dopamine cell body area of the ventral tegmental area (VTA) to nucleus accumbens, decreased size of dopaminergic cell bodies, and by increased expression in VTA of a marker of injury, glial fibrillary acidic protein (Beitner-Johnson et al. 1992;1993;Self et al. 1995; SklairTavron et al. 1996). As these animal data suggest that opiates might impair, reversibly or irreversibly, brain dopaminergic function in humans, we determined whether concentrations of biochemical markers of dopamine nerve terminal function and integrity are decreased in post mortem striatum (caudate, putamen, nucleus accumbens) of human chronic heroin users. The markers included ...

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Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

Cited by 51 publications

References 30 publications

Opioid Receptor Subtypes Differentially Modulate Serotonin Efflux in the Rat Central Nervous System

Opioid Receptor Subtypes Differentially Modulate Serotonin Efflux in the Rat Central Nervous System

Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

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