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1.
Neuroscience ; 169(2): 751-7, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20452406

ABSTRACT

There is evidence that the kappa opioid system plays an important role in cocaine addiction and that chronic cocaine administration and withdrawal from chronic cocaine alter kappa opioid receptor (KOPr) density. The present study employed in situ [(35)S]guanosine 5'-O-[gamma-thio]triphosphate acid (GTPgammaS) binding autoradiography to measure KOPr-stimulated activation of G-protein in the caudate putamen, nucleus accumbens core and shell, lateral hypothalamus, basolateral amygdala, substantia nigra compacta, substantia nigra reticulata and ventral tegmental area (VTA), in response to chronic cocaine administration or acute and chronic withdrawal from chronic cocaine. Male Fischer rats were injected i.p. with saline or cocaine three times daily at 1 h intervals in an escalating-dose paradigm for 14 days (from 3x15 mg/kg/injection on days 1-3 up to 3x30 mg/kg/injection on days 10-14). Identically treated separate groups were withdrawn from cocaine or saline for 24 h or 14 days. No significant change in KOPr agonist U-69593-stimulated [(35)S]GTPgammaS was found in the seven regions studied 30 min or 14 days after chronic 14 days escalating-dose binge cocaine administration. However there was an increase in KOPr -stimulated [(35)S]GTPgammaS binding in the VTA (P<0.01) of rats withdrawn for 24 h from chronic cocaine. Our results show a cocaine withdrawal induced increase of KOPr signaling in the VTA, and suggest that the KOPr may play a role in acute withdrawal from cocaine.


Subject(s)
Cocaine/adverse effects , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Receptors, Opioid, kappa/physiology , Substance Withdrawal Syndrome/metabolism , Ventral Tegmental Area/metabolism , Animals , Autoradiography , Benzeneacetamides/pharmacology , Cocaine/administration & dosage , Male , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Rats, Inbred F344 , Receptors, Opioid, kappa/agonists , Substantia Nigra/metabolism
2.
Neuroscience ; 147(1): 197-206, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17507169

ABSTRACT

[N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (SR 141716A), a selective cannabinoid CB1 receptor antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against CB1 receptors, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that CB1 receptors in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of CB1 receptors decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with [(3)H](-)-CP 55,940 show that chronic treatment with SR 141716A for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of CB1 receptors in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of SR 141716A injected into the PVN as compared with control rats. The present findings confirm that PVN CB1 receptors, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of CB1 receptors by SR 141716A increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of SR 141716A, which is still present 3 days after the end of the chronic treatment.


Subject(s)
Neural Inhibition/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Penile Erection/physiology , Receptor, Cannabinoid, CB1/metabolism , Animals , Glutamic Acid/metabolism , Immunohistochemistry , Male , Microinjections , Neural Inhibition/physiology , Neurotransmitter Agents/administration & dosage , Oxytocin/metabolism , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/physiology , Penile Erection/drug effects , Piperidines/administration & dosage , Pyrazoles/administration & dosage , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Rimonabant , Sexual Behavior, Animal/drug effects , Sexual Behavior, Animal/physiology , Signal Transduction/physiology , Tissue Distribution , gamma-Aminobutyric Acid/metabolism
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