Articles: nucleus-accumbens-drug-effects.
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We have previously reported that at the initiation of cocaine self-administration sessions, neurons in the nucleus accumbens (NA) exhibit a spontaneous transition in firing rate from activity unrelated to the reinforced response, to one of four types of patterned discharges (Carelli RM, King VC, Hampson RE, Deadwyler SA. Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats. Brain Res 1993;626:14-22; Carelli RM, Deadwyler SA. ⋯ Eticlopride increased the number of Session responses (5, 10, and 20 microg/kg), but did not alter the number of Load-up responses at any dose tested. The transition in NA cell firing corresponded with the shift in behavioral responding and was delayed within the session following SCH23390 but not eticlopride pretreatment. These findings support the notion that cocaine self-administration sessions in rats consists of two distinct behavioral phases that are mediated by different neurophysiological mechanisms operating in the NA.
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J. Pharmacol. Exp. Ther. · Apr 1999
Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo.
The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. ⋯ Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavioral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo.
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The administration of psychostimulants increases dopamine (DA) release within the nucleus accumbens (NAC), a terminal projection site of mesolimbic DA neurons, originating in the ventral tegmental area (VTA). Recent evidence demonstrates that two subdivisions of the NAC, the dorsolateral core and the ventromedial shell, can be distinguished by morphological and immunohistochemical differences, as well as by their distinct anatomical connections. It has been suggested that these two subregions subserve different functions that are related to goal-directed behaviors, stimulus-reward associations, and reinforcement induced by addictive drugs. ⋯ The highest dose of AMPH significantly increased dialysate 5-HT levels over baseline only in the caudal shell of the NAC. The basal dialysate 5-HT levels did not significantly differ between the three subterritories of the NAC. These results emphasize the heterogeneity and functional compartmentalization within the NAC, the differential regulation of neurochemical and motor responses across the anteroposterior axis of the NAC, and the preferential effect of AMPH in the rostral shell subterritory of the NAC.
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In vivo microdialysis was used to compare the effects of serotonergic drugs on morphine- and cocaine-induced increases in extracellular dopamine (DA) concentrations in the rat nucleus accumbens (NAc). Systemic administration of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg, s.c. ) prevented the increase in extracellular DA in the NAc produced by morphine (5 mg/kg, i.p.). In contrast, this dose of DOI had no effect on the ability of cocaine (10 mg/kg, i.p.) to increase extracellular DA concentrations in the NAc. ⋯ In order to determine if inhibition of the firing of 5-HT neurons contributes to the serotonin agonist-mediated inhibition of morphine-induced accumbens DA release, rats were pretreated with the 5-HT1A agonist, 8-OHDPAT. At a dose of 100 microg/kg (sc), 8-OHDPAT did not interfere with morphine's ability to increase DA concentrations in the NAc. These results suggest that the activation of 5-HT2C receptors selectively inhibits morphine-induced DA release in the NAc in a manner which is independent of the inhibition of 5-HT neurons.
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Cloning studies have identified a novel seven transmembrane receptor displaying high sequence homology to the three classical opioid receptors (mu, delta and kappa). This receptor is widely distributed throughout the CNS. 1 Recently, an endogenous ligand for this receptor was isolated (termed either "orphanin FQ" or "nociceptin") and identified as a heptadecapeptide showing sequence homology with the endogenous opioids. Surprisingly, in contrast to known opioids, orphanin FQ displays hyperalgesic rather than analgesic properties. ⋯ These preliminary data suggest that orphanin FQ systems may act in an opposing manner to the previously well-described enkephalin and endorphin systems. Since numerous studies have implicated activation of the mesolimbic dopamine pathway to be central to the rewarding actions of opiates such as morphine and heroin, as well as several other abused drugs, and also to mediate the hyperlocomotory action of such drugs, we sought to determine the effect of orphanin FQ on this pathway. In accordance with the inhibitory effect of this peptide on locomotor activity, we now report that orphanin FQ suppresses dopamine release in the nucleus accumbens in a dose-dependent manner, providing the first neurochemical evidence for a modulatory role of this recently described peptide in the CNS.