Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

Increased drug availability can precipitate a rapid transition to compulsive drug use in both vulnerable humans and laboratory animals. Recent studies have shown that despite equivalent levels of psychomotor sensitization, only rats with prolonged, but not limited, access to cocaine self-administration respond to the priming effects of cocaine on drug seeking, as measured in a within-session reinstatement model of drug craving. In this model, drug seeking is first extinguished and then reinstated by non-contingent presentations of the drug alone in the absence of response-contingent stimuli. Here, we assessed the generality of this observation in rats with daily short (1 h, ShA) vs long access (6 h, LgA) to i.v. heroin self-administration. As expected, heroin intake by LgA rats (n ¼ 24) increased over time to become excessive compared to heroin intake by ShA rats (n ¼ 24). After escalation, LgA rats tended to be less sensitive to heroin-induced locomotion (7.5-30 mg, i.v.) than ShA rats. In contrast, only LgA rats, not ShA rats, responded to the priming effects of heroin, as measured by the ability of heroin alone (7.5-30 mg, i.v.) to reinstate extinguished drug-seeking behavior. Finally, during the course of heroin intake escalation, a large proportion of LgA rats developed self-injury (mostly targeting the nails and digit tips of the forepaws), a negative consequence not seen in ShA rats. This study reproduces and extends previous research on compulsive cocaine use by showing that heroin-induced reinstatement is also specific to compulsive drug use and dissociable from heroin-induced reward and psychomotor sensitization. Neuropsychopharmacology (2007) 32, 616-624.

Section: Introductionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 77%

Heroin-Induced Reinstatement is Specific to Compulsive Heroin Use and Dissociable from Heroin Reward and Sensitization

Lenoir¹,

Ahmed²

2006

“…The sensitization of prefrontal corticoaccumbens glutamate transmission is associated with increased sensitivity to cocaine reward and psychomotor activation (eg Pierce et al, 1996;McFarland et al, 2003). Thus, the present data are consistent with the reported effectiveness of selective serotonin reuptake inhibitors to attenuate cocaine self-administration and/or cocaine seeking in animal models of relapse (Baker et al, 2001;Tran-Nguyen et al, 2001;Czoty et al, 2002;Glatz et al, 2002) and pose a critical and selective role for MRN serotonin regulation of prefrontal cortex glutamate transmission in the enduring behavioral consequences of repeated cocaine administration.…”

Section: Serotonin Projections From the Mrn Regulate The Development supporting

confidence: 88%

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

Szumlinski

Frys

Kalivas

2004

A distinct role for serotonin transmission from the dorsal and median raphé nuclei (DRN and MRN, respectively) was identified in regulating the behavioral and neurochemical effects of acute and repeated cocaine administration. Serotonin 1A (5-hydroxytryptophan (5-HT)1A) receptors were stimulated by intraraphé microinjection of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT; 5 or 10 mg) and behavior, as well as extracellular neurotransmitter content in the nucleus accumbens was measured. Pretreatment of the DRN with DPAT caused a sensitization-like potentiation of acute cocaine-induced motor activity and an elevation in extracellular dopamine and glutamate. In contrast, DPAT microinjection into the MRN did not alter acute cocaine-induced motor activity or extracellular levels of dopamine or glutamate. Acutely, DPAT microinjection into either raphé nucleus reduced the basal and acute cocaine-stimulated levels of extracellular serotonin. Pretreatment with DPAT before systemic cocaine administration was continued for 5 days, and 3 weeks after the last injection, all rats were administered a cocaine challenge injection. The sensitized behavioral and neurochemical response produced by repeated cocaine in control subjects was unaffected by the intra-DRN administration of DPAT. However, in animals administered DPAT into the MRN, both the sensitized motor response and the increase in glutamate were augmented, while the sensitized serotonin response was blocked, without altering dopamine sensitization. These data show a differential role for 5-HT1A receptors in the DRN and MRN in the acute and sensitized effects of cocaine. While the DRN is involved in the acute effects of cocaine, neuroadaptations in the MRN may regulate the long-term consequences of repeated cocaine exposure.

“…Treatment with dexfenfluramine reduces responding for a CRf (Fletcher, 1995;Wilson et al, 2000), while whole-brain 5-HT neuron ablation enhances this behavior (Fletcher et al, 1999). In tests of drug-seeking behavior, dexfenfluramine and the SSRI fluoxetine also diminished the ability of a cocaine-paired stimulus to reinstate responding under extinction conditions (Baker et al, 2001;Burmeister et al, 2003). Furthermore, we have recently shown that another SSRI, citalopram, reduced responding for a CRf and a USRf (Browne et al, 2016).…”

Section: Introductionmentioning

confidence: 88%

Decreased Incentive Motivation Following Knockout or Acute Blockade of the Serotonin Transporter: Role of the 5-HT2C Receptor

Browne

Fletcher

2016

Acute pharmacological elevation of serotonin (5-hydroxytryptamine; 5-HT) activity decreases operant responding for primary reinforcers, suggesting that 5-HT reduces incentive motivation. The mechanism by which 5-HT alters incentive motivation is unknown, but parallel evidence that 5-HT 2C receptor agonists also reduce responding for primary reinforcers implicates this receptor as a potential candidate. These experiments examined whether chronic and acute disruptions of serotonin transporter (SERT) activity altered incentive motivation, and whether the 5-HT 2C receptor mediated the effects of elevated 5-HT on behavior. To assess incentive motivation, we measured responding for three different reinforcers: a primary reinforcer (saccharin), a conditioned reinforcer (CRf), and an unconditioned sensory reinforcer (USRf). In the chronic condition, responding was compared between SERT knockout (SERT-KO) mice and their wild-type littermates. In the acute condition, responding was examined in wild-type mice following treatment with 10 or 20 mg/kg citalopram, or its vehicle. The ability of the selective 5-HT 2C antagonist SB 242084 to prevent the effects of SERT-KO and citalopram on responding was subsequently examined. Both SERT-KO and citalopram reduced responding for saccharin, a CRf, and a USRf. Treatment with SB 242084 enhanced responding for a CRf and a USRf in SERT-KO mice and blocked the effects of citalopram on CRf and USRf responding. However, SB 242084 was unable to prevent the effects of SERT-KO or citalopram on responding for saccharin. These results support a powerful inhibitory function for 5-HT in the control of incentive motivation, and indicate that the 5-HT 2C receptor mediates these effects of 5-HT in a reinforcer-dependent manner.