Effect of medial prefrontal cortex injections of SCH 23390 on intravenous cocaine self-administration under both a fixed and progressive ratio schedule of reinforcement

McGregor, Alison; Roberts, David C. S.

doi:10.1016/0166-4328(94)00106-p

Cited by 81 publications

(62 citation statements)

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“…The results of the present study are consistent with previous pharmacological studies and provide evidence for two major points to be made regarding the dopamine receptor subtypes that underlie cocaine regulation of MC4-R. First, the actions of cocaine on MC4-R expression are dependent on D 1 receptor activation, inasmuch as daily pretreatment with a D 1 receptor antagonist, SCH 23390, completely blocks the up-regulation of MC4-R mRNA. A similar pharmacological profile for D 1 receptors has also been reported for cocaine reward (Maldonado et al, 1993;McGregor and Roberts, 1995) and the acute neurochemical actions of cocaine (Graybiel et al, 1990;Young et al, 1991;Couceyro et al, 1994). Second, chronic D 2 receptor blockade, either with a nonselective dopamine D 1 /D 2 receptor antagonist, haloperidol, or a very selective D 2 receptor antagonist, eticlopride, also increased the expression of MC4-R mRNA in striatum.…”

Section: Discussionsupporting

confidence: 68%

Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine

Alvaro

Taylor²,

Duman³

2003

J Pharmacol Exp Ther

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Behavioral and molecular studies have established a link between drugs of abuse and the central melanocortin system, particularly the melanocortin 4 receptor (MC4-R). The present study expands this line of investigation to characterization of the neurochemical and behavioral interactions between MC4-R and the psychomotor stimulant, cocaine. The results demonstrate that repeated, but not acute, cocaine administration upregulates MC4-R mRNA expression in the striatum and hippocampus, but not cerebral cortex. Pharmacological studies indicate that the up-regulation of MC4-R expression occurs via dopamine D 1 and D 2 receptor-dependent mechanisms. The D 1 /D 2 antagonist haloperidol and the D 2 -selective antagonist eticlopride mimic the effect of cocaine on MC4-R expression. In addition, coadministration of a D 1 -selective antagonist, SCH 23390 [R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], completely blocks the up-regulation of MC4 mRNA by cocaine, demonstrating that D 1 receptor activation is necessary for this response. Moreover, the results demonstrate that cocaine treatment increases behavioral responses (grooming and locomotor activity) to infusions of a melanocortin agonist, indicating that up-regulation of MC4-R expression results in functional consequences. These data further support a role for the melanocortin-MC4-R neuropeptide system in the biochemical and behavioral effects of cocaine.Pro-opiomelanocortin (POMC) serves as a precursor for a number of neuropeptides, including the melanocortins, ␣-, ␤-, and ␥-melanocyte-stimulating hormone (MSH), and adrenocorticotrophic hormone, as well as ␤-endorphin. POMC-expressing neurons are located in the pituitary, the arcuate nucleus of the hypothalamus, and the nucleus of the solitary tract; and the latter two structures send projections to a number of different brain regions, including the mesolimbic dopamine system (Jacobowitz and O 'Donohue, 1978;Eskay et al., 1979). The melanocortin neuropeptides are reported to influence a variety of behavioral and neuroendocrine systems via regulation of central nervous system centers, including grooming, thermoregulation, and learning (Alvaro et al., 1997). The actions of melanocortins are mediated via activation of melanocortin receptors, of which there are five subtypes, all of which belong to the G-protein-coupled receptor superfamily. Two of these, melanocortin-3 and -4 (MC3-R and MC4-R) are expressed in significant levels in the brain and are thereby thought to mediate the central actions of melanocortin neuropeptides.Melanocortins are also reported to play a role in the behavioral and neurochemical actions of opiates, psychostimulants, and alcohol. Early studies indicated that melanocortin treatment could antagonize opiate tolerance and dependence, and even induce opiate withdrawal-like effects in naive animals (Szekaly et al., 1979;Contreras and Takemori, 1984). A preliminary study also found that a selective MC4-R antagonist attenuates the signs of morphine withdrawal tha...

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Section: Discussionsupporting

confidence: 68%

Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine

Alvaro

Taylor²,

Duman³

2003

J Pharmacol Exp Ther

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“…The present data demonstrate the ability of noncontingent nicotine to enhance responding for the VS using two distinct reinforcement schedules (FR and PR), which have been postulated to provide unique but complementary information on the processes that govern reinforcement. While FR schedules are thought to measure the hedonic impact of a drug, PR schedules have been used to index the motivational strength of pharmacological, natural and nonpharmacological reinforcers (Markou et al 1993;Depoortere et al 1993;Donny et al 1999;Risner and Goldberg 1983;Stafford et al 1998;McGregor and Roberts 1995;Barr and Phillips 1999;Donny et al 1999;Nicola and Deadwyler 2000). The present data suggest that regardless of contingency, nicotine can increase motivation to obtain the VS, which may reflect a corresponding increase in the incentive salience of the stimulus induced by nicotine.…”

Section: Discussionmentioning

confidence: 60%

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

et al. 2005

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Although considerable progress has been made we do not yet fully understand the behavioral and neurobiological bases of nicotine reinforcement, and without this knowledge treatment strategies aimed at reducing smoking remain deficient. This dissertation provides an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. The present experiments tested the hypothesis that nicotine reinforcement derives from at least two sources: 1) the primary reinforcing properties of nicotine, an action that requires response-dependent drug administration, and 2) the more prominent ability of nicotine to enhance behavior maintained by salient non-nicotine stimuli, an action that does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing properties of psychostimulant drugs. Empirical support for the application of this hypothesis to nicotine reinforcement will be presented. By investigating the interaction between nicotine and nonpharmacological stimuli within the context of drug selfadministration in rats, the present research has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in selfadministration and in smoking. Hypotheses generated by these data provide important direction for future investigations into the neurobiology of nicotine reinforcement.iii

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“…Catheter patency was verified after testing by brief anesthesia with sodium methohexital (0.1 mg in 0.1 ml). In some experiments, the reinforcement contingency was changed to a progressive-ratio schedule similar to that described by McGregor and Roberts (1995). Under this schedule, response requirements for each successive injection increased by progressive increments of the following series (Richardson and Roberts, 1996): 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, and so on according to response requirement ¼ (5e (injection times Â 0.2) )À5.…”

Section: Sucrose Training and Surgerymentioning

confidence: 99%

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

Wang

et al. 2009

Neuropsychopharmacol

159

156

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The regulation of gene expression in the brain reward regions is known to contribute to the pathogenesis and persistence of drug addiction. Increasing evidence suggests that the regulation of gene transcription is mediated by epigenetic mechanisms that alter the chromatin structure at specific gene promoters. To better understand the involvement of epigenetic regulation in drug reinforcement properties, rats were subjected to cocaine self-administration paradigm. Daily histone deacetylase (HDAC) inhibitor infusions in the shell of the nucleus accumbens (NAc) caused an upward shift in the dose-response curve under fixed-ratio schedule and increased the break point under progressive-ratio schedule, indicating enhanced motivation for self-administered drug. The effect of the HDAC inhibitor is attributed to the increased elevation of histone acetylation induced by chronic, but not acute, cocaine experience. In contrast, neutralizing the chronic cocaine-induced increase in histone modification by the bilateral overexpression of HDAC4 in the NAc shell reduced drug motivation. The association between the motivation for cocaine and the transcriptional activation of addiction-related genes by H3 acetylation in the NAc shell was analyzed. Among the genes activated by chronic cocaine experiences, the expression of CaMKIIa, but not CaMKIIb, correlated positively with motivation for the drug. Lentivirus-mediated shRNA knockdown experiments showed that CaMKIIa, but not CaMKIIb, in the NAc shell is essential for the maintenance of motivation to self-administered cocaine. These findings suggest that chronic drug-use-induced transcriptional activation of genes, such as CaMKIIa, modulated by H3 acetylation in the NAc is a critical regulatory mechanism underlying motivation for drug reinforcement. Neuropsychopharmacology (2010) 35, 913-928; doi:10.1038/npp.2009; published online 9 December 2009 Keywords: histone acetylation; nucleus accumbens; motivation; cocaine self-administration; addiction; CaMKIIa INTRODUCTIONDrug addiction is a debilitating psychiatric disorder characterized by (1) a compulsion to seek and take the drug, (2) a loss of control in limiting intake, and (3) the emergence of a negative emotional state when access to the drug is prevented (Hyman et al, 2006;Kalivas et al, 2005;Koob and Kreek, 2007). The complex behavioral changes leading to drug addiction are thought to result from molecular and cellular adaptation in specific brain regions (Brami-Cherrier et al, 2005). One area of intensive research to clarify neuroadaptation addresses the regulation of gene expression induced by the drug (Nestler, 2001). The drug induces changes in gene expression in key brain reward regions, such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and ventral tegmental area (VTA). For instance, the expression of the immediate early gene c-Fos and several other Fos family proteins is upregulated in the nucleus accumbens, striatum (Courtin et al, 2006) and frontal cortex (Thiriet et al, 2000) after acute cocaine treatment. T...

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Effect of medial prefrontal cortex injections of SCH 23390 on intravenous cocaine self-administration under both a fixed and progressive ratio schedule of reinforcement

Cited by 81 publications

References 39 publications

Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine

Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

Chronic Cocaine-Induced H3 Acetylation and Transcriptional Activation of CaMKIIα in the Nucleus Accumbens Is Critical for Motivation for Drug Reinforcement

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