Withdrawal from chronic cocaine up-regulates 5-HT1B receptors in the rat brain

Przegaliński, Edmund; Czepiel, Klaudia; Nowak, Ewa; Dlaboga, Daniel; Filip, Małgorzata

doi:10.1016/j.neulet.2003.08.007

Cited by 30 publications

(19 citation statements)

References 16 publications

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“…2001). Furthermore, 5-HT 1B Rs are upregulated in various regions throughout the mesocorticolimbic pathway following chronic cocaine self-administration (Hoplight, Vincow & Neumaier 2007) and periods of abstinence (Przegalinski et al . 2003), which may produce sensitization to the cocaine prime.…”

Section: Discussionmentioning

confidence: 99%

PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

et al. 2009

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Paradoxically, stimulation of 5-HT 1B receptors (5-HT 1B Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/ reinstatement model. We revisited this issue by examining the effects of a 5-HT 1B R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT 1B Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT 1B Rs may be a novel target for developing medications for cocaine dependence.

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Section: Discussionmentioning

confidence: 99%

PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

et al. 2009

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“…These receptors likely regulate both dopamine and 5-HT since both transmitters are reduced in the striatum of 5-HT 1B R knockout mice (Ase et al, 2000). Repeated cocaine administration followed by brief abstinence (1–5 days) increases 5-HT 1B R mRNA and 5-HT 1B R binding within regions of the mesolimbic and nigrostriatal pathways (Hoplight et al, 2007; Przegalinski et al, 2003). In contrast, following 14 days of abstinence from cocaine SA, 5-HT 1B R mRNA is reduced throughout the striatum compared to controls without a history of abstinence (Neumaier et al, 2009).…”

Section: Dysregulation Of 5-ht1brsmentioning

confidence: 99%

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

2014

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Addiction to psychostimulants, including cocaine and amphetamine, is associated with dysregulation of dopamine and serotonin (5-HT) neurotransmitter systems. Neuroadaptations in these systems vary depending on the stage of the drug taking-abstinence-relapse cycle. Consequently, the effects of potential treatments that target these systems may vary depending on whether they are given during abstinence or relapse. In this review, we discuss evidence that dopamine D3 receptors (D3Rs) and 5-HT1B receptors (5-HT1BRs) are dysregulated in response to both chronic psychostimulant use and subsequent abstinence. We then review findings from preclinical self-administration models which support targeting D3Rs and 5-HT1BRs as potential medications for psychostimulant dependence. Potential side effects of the treatments are discussed and attention is given to studies reporting positive treatment outcomes that depend on: 1) whether testing occurs during abstinence versus relapse, 2) whether escalation of drug self-administration has occurred, 3) whether the treatments are given repeatedly, and 4) whether social factors influence treatment outcomes. We conclude that D3/D2 agonists may decrease psychostimulant intake; however, side effects of D3/D2R full agonists may limit their therapeutic potential, whereas D3/D2R partial agonists likely have fewer undesirable side effects. D3-selective antagonists may not reduce psychostimulant intake during relapse, but nonetheless, may decrease motivation for seeking psychostimulants with relatively few side-effects. 5-HT1BR agonists provide a striking example of treatment outcomes that are dependent on the stage of the addiction cycle. Specifically, these agonists initially increase cocaine’s reinforcing effects during maintenance of self-administration, but after a period of abstinence they reduce psychostimulant seeking and the resumption of self-administration. In conclusion, we suggest that factors contributing to dysregulation of monoamine systems, including drug history, abstinence, and social context, should be considered when evaluating potential treatments to better model treatment effects in humans.

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“…We employed a targeted metabolomic approach for this study. The rationale to study the metabolites of the tryptophan/ tyrosine/purine/and oxidative stress pathways is as follows: Data from animal experiments suggest that modifications in 5-HT activity may contribute to drug reinforcement (Burmeister et al 2003;Hall et al 2004;Przegalinski et al 2003). Neurobiological studies in humans tend to support these findings (Buydens-Branchey et al 1999;Jacobsen et al 2000;Little et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study

et al. 2009

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Withdrawal from chronic cocaine up-regulates 5-HT1B receptors in the rat brain

Cited by 30 publications

References 16 publications

PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study

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Withdrawal from chronic cocaine up-regulates 5-HT1B receptors in the rat brain

Cited by 30 publications

References 16 publications

PRECLINICAL STUDY: Stimulation of 5‐HT1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

PRECLINICAL STUDY: Stimulation of 5‐HT1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study

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PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior