Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats

doi:10.1016/j.bbr.2014.04.013

Behavioural Brain Research

Volume 269, 1 August 2014, Pages 1-5

https://doi.org/10.1016/j.bbr.2014.04.013 Get rights and content

Highlights

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The results extend our previous work with intracranial administrations of TCAP-1.
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Here, repeated IV injections of TCAP-1 attenuated the CRF-induced reinstatement of cocaine seeking in rats.
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The TCAP-1 regimen had a differential effect in rats that self-administered cocaine for 6, relative to 3, hours per day.
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The results point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

Abstract

The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3 h (“short access”; ShA) or 6 h (“long access”; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3000 pmol, IV) in their home cage. Subsequently, they were returned to the self-administration chambers where extinction of cocaine seeking and testing for CRF-induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors.

Section snippets

Conflict of interest

Dr. DA Lovejoy is the Chief Scientific Officer of Protagenic Therapeutics Inc (PTI).

Acknowledgements

This work was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council (NSERC) to SE, and by a MITACS Accelerate Ontario Internship, in partnership with Protagenic Therapeutics Inc, to ZJB.

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Distal extracellular teneurin region (teneurin C-terminal associated peptide; TCAP) possesses independent intracellular calcium regulating actions, in vitro: A potential antagonist of corticotropin-releasing factor (CRF)
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Previous studies indicated that TCAP-1 inhibits CRF action in vivo. Intracerebroventricular (ICV) TCAP-1 administration into rats ablates the CRF-mediated cFos protein expression response in the limbic regions [41] and significantly reduces the CRF-mediated actions on the acoustic startle response (ASR) [2,37], open-field, elevated plus-maze [36,37,47,48] and cocaine-seeking [38–40] models of behaviour [49]. CRF has been implicated an increase of these behaviours via cAMP and Ca2+ mediated intracellular responses [42–44,49–51].
Teneurin C-terminal associated peptides (TCAP) are natural bioactive peptides that possess anxiety-reducing roles in animals, in vivo, and increase cell viability, in vitro. Although these peptides have some primary structural similarity to corticotropin-releasing factor (CRF), they are derived from the distal extracellular region of the teneurin transmembrane protein where they may act as separate soluble peptides after auto-catalytic cleavage from the teneurin protein following interaction with the cognate teneurin receptor, latrophilin (ADGRL), or expressed as a separate mRNA. However, although the signal transduction mechanism of TCAP in neurons has not been established, previous studies indicate an association with the intracellular calcium flux. Therefore, in this study, we have characterized the TCAP-mediated calcium response in hypothalamic cell lines using single-cell calcium methods with pharmacological antagonists to identify potential calcium channels, in vitro. Under normal circumstances, TCAP-1 reduces cytosolic calcium concentrations by uptake into the mitochondria and efflux through the plasma membrane independently of the teneurins. In doing so, TCAP-1 could inhibit the potential ‘stress’ -inducing actions of CRF.
Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse
2018, Cell
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This observation, however, does not explain the functional role of the TEN barrel itself, which in bacterial toxins serves as a chamber to protect the producing cell from being exposed to the toxic cargo and also functions as an auto-proteolysis machinery that cleaves and activates the encapsulated toxin (Busby et al., 2013; Meusch et al., 2014). The possibility that the barrel of TEN species encompasses an active auto-protease machinery is exciting because of the similarity with the presumably cleaved domain with HNH-DNases, pre-pro-hormones, and neuropeptide precursors (Figure 3) and because their mature product, TCAP, is detected in brain lysates and was shown to mediate multiple functions in the brain (Al Chawaf et al., 2007; Erb et al., 2014; Lovejoy et al., 2006). Moreover, such an auto-proteolysis event may release the toxin-like region into the extracellular space and convert TEN into a diffusible ligand that may act during axonal pathfinding.
Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large β barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a β propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the β propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.
Teneurin C-Terminal Associated Peptide (TCAP)-1 and Corticotropin-Releasing Factor (CRF) Interactions in the Modulation of Cocaine-Related Behavior
2017, The Neuroscience of Cocaine: Mechanisms and Treatment
Stress is a key contributor to an elevated risk of cocaine dependence and relapse. The stress-related neuropeptide, corticotropin-releasing factor (CRF), mediates many of the effects of stress on cocaine dependence. The teneurin C-terminal associated peptide-1 (TCAP-1) is a recently discovered neuropeptide that regulates structural plasticity, cellular metabolism, and many physiological and behavioral effects of CRF. In recent animal studies, we examined the ability of synthetic TCAP-1 to modulate CRF-mediated responses induced by prior cocaine experience; these included CRF-induced reinstatement of cocaine seeking and CRF-induced expression of locomotor sensitization to cocaine. Repeated administration of TCAP-1 robustly inhibited cocaine-related behavioral responses to CRF. We discuss possible neuroanatomical and cellular mechanisms for these effects of TCAP-1, and suggest that the brain permeability, potency, and persistency of the effects of TCAP-1 support its potential clinical utility in reducing the adverse effects of CRF in cocaine-dependent individuals.
Expression and actions of corticotropin-releasing factor/diuretic hormone-like peptide (CDLP) and teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: Antagonism of the feeding response
2017, General and Comparative Endocrinology
Citation Excerpt :
Although the exact ancestral relationship between CRF and TCAP is unclear, numerous physiological studies in vertebrates indicate that the two peptides have antagonistic actions. In rats, TCAP-1 inhibits the CRF-mediated acoustic startle response (Tan et al., 2008) as well as CRF-induced cocaine addiction reinstatement (Kupferschmidt et al., 2011; Erb et al., 2014). Moreover, TCAP-1 modulates CRF-induced behavior in the elevated plus-maze and open-field tests in rats (Tan et al., 2008; Al Chawaf et al., 2007).
Teneurin C-terminal associated peptide (TCAP) is a neuropeptide that bears some structural similarity to the corticotropin-releasing factor (CRF) family of peptides. TCAP and CRF are both implicated in the regulation of stress-related behaviors, as established in rodent models. However, in vertebrates, both TCAP and CRF possess three additional paralogous forms making vertebrate models difficult to assess with respect to TCAP-CRF interaction. As a urochordate, this species possesses single homologs of TCAP and of a CRF/Diuretic-like peptide (CDLP) in the genome, thereby establishing Ciona intestinalis as an excellent model organism to examine the interaction of these peptide systems. However, the lack of C. intestinalis synthetic peptides and specific antisera has complicated experimentation. We, therefore, prepared synthetic versions of CDLP and TCAP to prepare specific antisera and to investigate their bioactivity in this species. To analyze stress-related behaviors, a novel behavioral assay was used to characterize different types of contraction-based behaviors, using buccal opening contractions, cloacal opening contractions, lateral contractions, longitudinal contractions and expulsions. Protein and mRNA expression data indicate that the mature versions of both peptides are present in a number of tissues. With respect to behavioral activity, both TCAP- and CDLP-treated animals had distinct contraction profiles under ambient conditions. Moreover, food stimulation tests revealed that whereas CDLP-treated animals displayed a strong expulsion behavior in response to feeding, TCAP-treated animals did not show this effect. These actions are consistent with previous studies done in vertebrates.
Characterization of the teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: A novel peptide system associated with energy metabolism and reproduction
2015, General and Comparative Endocrinology
Citation Excerpt :
However, in vertebrates, TCAP-1, is independently transcribed as a separate gene (Chand et al., 2013a,b) and is taken up by surrounding cells to regulate a number of cell-associated functions (Chand et al., 2012a,b; Ng et al., 2012). Moreover, TCAP-1 has been previously shown to be highly cell protective (Trubiani et al., 2007) and inhibits corticotropin-releasing factor (CRF)-mediated stress associated behaviors (Al Chawaf et al., 2007b; Erb et al., in press; Tan et al., 2008, 2009, 2011a,b; Tan & Lovejoy, 2009; Kupferschmidt et al., 2010; Wang et al., 2005). These studies indicate a fundamental interaction between the CRF and TCAP families of peptides.
The vase tunicate, Ciona intestinalis, is a protochordate and is considered a sister lineage to the chordates. The recent sequencing of its genome has made this species a particularly important model to understand the genetic basis of vertebrate evolution. However, C. intestinalis is also a highly invasive species along the Atlantic coast of North America and other regions of the world which have caused considerable economic stress due to its biofouling actions and, in particular, negative impacts on the mussel- and oyster-based aquaculture industry. Despite this background, little is known about C. intestinalis physiology. The teneurin C-terminal associated peptides (TCAP) are a family of highly conserved peptide hormones found in most metazoans. Moreover, these peptides have been implicated in the inhibition of stress and stimulation of feeding-based metabolism. We have, therefore, identified this peptide using an in silico approach and characterized its immunological expression in tissues using a mouse polyclonal antiserum. These data indicate that its primary structure is more similar to invertebrate TCAPs relative to vertebrate TCAPs. Immunological expression indicates that it is highly expressed in the digestive tract and gonads consistent with findings in vertebrates. Synthetic mouse TCAP-1 administered into the brachial basket significantly increases the incidence of non-stress contractile behaviors. These findings support the hypothesis that TCAP is a bioactive peptide in C. intestinalis. Thus, C. intestinalis and tunicates in general may offer a simple model to investigate peptide interaction while providing information on how to control this invasive species.
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2014, Seminars in Cell and Developmental Biology
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Given the evolutionary history of the Teneurins, this signalling system is thought to have evolved earlier than the CRF family [33,34]. The synthetic peptides (termed Teneurin C-associated peptides or TCAPs) generated from this region have been shown to promote neurite outgrowth [35] and to modulate a number of behaviours relating to stress and anxiety [36–38]. Recent work has demonstrated that TCAP-1 (the TCAP associated with Ten-m1) may be independently transcribed from the rest of the protein [39].
A functionally critical feature of the nervous system is the precision of its connectivity. An emerging molecular mediator of this process is the teneurin/ten-m/odz family of transmembrane proteins. A number of recent studies have provided compelling evidence that teneurins have homophilic adhesive properties which, together with their corresponding expression patterns in interconnected groups of neurons, enables them to promote appropriate patterns of connectivity. Particularly important roles have been demonstrated in the visual, olfactory and motor systems. This review attempts to relate new insights into the complex biology of these molecules to their roles in the establishment of functional neural circuits.

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Short CommunicationRepeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats

Highlights

Abstract

Section snippets

Conflict of interest

Acknowledgements

Brain Res Rev

Brain Res

Peptides

Mol Brain Res

Behav Brain Res

Peptides

Peptides

Neurosci Lett

Behav Brain Res

Gen Comp Endocrinol

Neuroscience

Front Neurosci

Physiol Behav

Short Communication
Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats