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

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 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 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.

A procedure for studying the footshock-induced reinstatement of cocaine seeking in laboratory rats.

The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self-administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re-exposure to drug-associated cues, or exposure to a stressor. Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking. Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA(5). Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA. Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking.

Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala.

We recently reported that central injections of noradrenaline (NA) induce reinstatement of cocaine seeking in rats. Here, we replicate and extend our finding to an additional dose of NA and show that it is associated with the induction of c-fos mRNA expression (a marker of neuronal activation) in functionally relevant brain regions, including the bed nucleus of the stria terminalis and central nucleus of the amygdala.

Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat.

RATIONALE: Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been demonstrated. OBJECTIVES: The objectives of this study were to determine whether CRF and NA systems can interact to influence reinstatement responding and, if so, in what direction the interaction occurs. MATERIALS AND METHODS: Rats were trained to self-administer cocaine (0.23 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished, and tests for reinstatement were conducted following: (1) pretreatment with the CRF receptor antagonist, D: -Phe CRF(12-41) [1 microg, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 microg; Experiment 1); (2) pretreatment with the alpha(2) adrenoceptor agonist, clonidine (40 microg/kg, i.p.), prior to i.c.v. injections of CRF (0.5 microg; Experiment 2); (3) pretreatment with D: -Phe (1, 5 microg, i.c.v.), prior to systemic injections of the alpha(2) adrenoceptor antagonist, yohimbine (1.25 mg/kg; Experiment 3A); or (4) pretreatment with clonidine (40 microg/kg, i.p.) prior to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B). RESULTS: NA reliably induced reinstatement, an effect that was blocked by pretreatment with D: -Phe. In contrast, CRF-induced reinstatement was not attenuated by pretreatment with clonidine. Pretreatment with neither D: -Phe nor clonidine was effective in blocking yohimbine-induced reinstatement. CONCLUSION: Together, the present findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA.

Footshock stress reinstates cocaine seeking in rats after extended post-stress delays.

RATIONALE: Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement. OBJECTIVE: The objectives of the study were to determine for how long footshock remains effective in inducing the reinstatement of cocaine seeking if testing is delayed after termination of the stressor and to determine whether the context in which a post-stress delay is carried out influences the magnitude of reinstatement. MATERIALS AND METHODS: Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. After extinction, tests for reinstatement by intermittent footshock (20 min; 0.8 mA) were conducted after post-stress delays of up to 60 min. Although footshock was always administered in the self-administration (SA) chamber, delays were given either in the SA chamber or home cage (HC). RESULTS: Footshock induced reinstatement after post-stress delays of up to 40 min. No differences in responding during tests for reinstatement were observed between animals in the SA chamber and under HC conditions. CONCLUSION: Within a limited time window, footshock is effective in reinstating cocaine seeking, when testing is delayed after termination of the stressor. Together with previous work from this laboratory, the findings are consistent with the idea that stress can induce the reinstatement of drug seeking by conditioning excitation to the context in which it is administered and that this conditioned excitation can overcome the inhibitory processes maintaining extinction responding, even after a post-stress delay.

A role for corticotropin-releasing factor in the long-term expression of behavioral sensitization to cocaine.

Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.