α1-Noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

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Abstract

In rodents, extended access to cocaine produces an escalation in cocaine self-administration that has face and construct validity for human compulsive drug intake. Here we report that rats with six-hour access (long access, LgA) to cocaine self-administration produced a higher breakpoint for cocaine using a progressive-ratio schedule than rats with one-hour access (short access, ShA), and prazosin1 receptor antagonist) reduced the higher breakpoint for cocaine in LgA rats. Additionally, the number of neurons with α1-adrenergic receptor-like immunoreactivity in the bed nucleus of stria terminalis (BNST) was found to be much lower in LgA rats than in ShA and drug-naive rats. In contrast, UK143042 receptor agonist) and betaxolol1 receptor antagonist) had no effect on cocaine self-administration in either group. The data suggest that activation of the α1-noradrenergic system, perhaps in the BNST, is associated with increased motivation for cocaine in rats with extended access.

Introduction

Cocaine dependence is associated with compulsive use and loss of control over intake (American Psychiatric Association, 2000). In rodents, extended access to cocaine and methamphetamine produced an escalation in self-administration of the drugs (Ahmed and Koob, 1998, Kitamura et al., 2006), which has face validity for compulsive drug intake in humans. Therefore, the investigation of neuropharmacological changes during escalation in cocaine self-administration in rodents may provide key information about the neural mechanisms underlying the development of drug dependence in humans.

Cocaine increases extracellular norepinephrine (NE), dopamine, and serotonin by blocking monoamine reuptake transporters (Reith et al., 1997, Rothman et al., 2001). These findings prompted researchers to investigate the role of monoamines in cocaine self-administration. Focusing on norepinephrine, early studies using a self-administration paradigm found no convincing evidence of the involvement of NE in the acute reinforcing effects of psychostimulants. For example, direct and indirect noradrenergic receptor agonists did not function as positive reinforcers in monkeys or dogs (Risner and Jones, 1976, Wee and Woolverton, 2004, Woolverton, 1987) although the reinforcing effect of clonidine, an α2-adrenergic receptor agonist, has been noted (Davis and Smith, 1977, Woolverton et al., 1982, respectively). Moreover, pretreatment with noradrenergic receptor ligands did not affect amphetamine or cocaine self-administration under a fixed-ratio (FR) schedule in rats or monkeys (Wilson and Schuster, 1974, Woolverton, 1987, Yokel and Wise, 1976, Tella, 1995, Yokel and Wise, 1978). Depleting central nervous system NE did not alter cocaine self-administration under an FR schedule in rats (Roberts et al., 1977).

However, some studies using paradigms other than self-administration seem to support the involvement of NE in the acute rewarding effects of psychostimulants. In conditioned place preference, NE depletion in the medial prefrontal cortex blocked the development of cocaine-associated place preference in mice (Ventura et al., 2007). Alpha1b noradrenergic receptor knockout mice also showed reduced cocaine preference compared to wild type mice under a two-bottle choice paradigm (Drouin et al., 2002). In contrast, dopamine β-hydroxylase knockout mice (NE depletion) showed enhanced sensitivity to cocaine-induced place preference, suggesting the development of compensatory neural responses in knockout mice (Weinshenker et al., 2002). Taken together, the role of noradrenergic activity in the acute reinforcing/rewarding effects of psychostimulants remains speculative.

One possibility is that extended access to cocaine self-administration may alter the noradrenergic system by repeatedly stimulating the system, which may in turn contribute to the development of drug dependence. It was shown that repeated administration of amphetamine produced a sensitized response of NE release in the prefrontal cortex (Salomon et al., 2006). An increased number of norepinephrine transporters in the brain were also found in rhesus monkeys after 100 days of cocaine self-administration compared to 5 days of cocaine self-administration (Macey et al., 2003, Beveridge et al., 2005). Moreover, previous cocaine exposure by repeated passive administration increased a breakpoint for cocaine self-administration on a progressive-ratio (PR) schedule, which was blocked by administration of prazosin in rats (Zhang and Kosten, 2007).

The purpose of the present study was to test the hypothesis that neuroadaptation in the central noradrenergic system has a role in the increased cocaine self-administration in rats with extended access. Our hypothesis was that increased cocaine self-administration under a PR schedule in rats with extended access may be mediated by an altered noradrenergic system. To test this hypothesis, cocaine self-administration in rats with one-hour and six-hour access was tested with pretreatment by prazosin (a selective α1-noradrenergic receptor antagonist; Boyajian and Leslie, 1987), UK14304 (a selective α2-noradrenergic receptor agonist; Andorn et al., 1988, Ernsberger et al., 1997) and betaxolol (a β1-noradrenergic receptor antagonist; Smith and Teitler, 1999). Additionally, the density of α1-noradrenergic receptors in brain regions that are associated with drug dependence (Koob, 2003) was compared between groups.

Section snippets

Experimental procedures

All animal use procedures were approved by The Scripps Research Institute Animal Care and Use Committee and were in accordance with the National Institutes of Health guidelines.

Results

Cocaine self-administration in LgA rats significantly increased over 14 sessions starting in session 2 and 4 compared to session 1, respectively, within a session and during the first hour of each session (Fig. 1). A two-way ANOVA found a significant interaction between access and daily session in escalation of cocaine self-administration within a session as well as during the first hour of each session [session, F(13,325) = 14.74, p < 0.001; first hour, F(13,325) = 5.60, p < 0.001]. Cocaine

Discussion

In agreement with previous studies (Ahmed and Koob, 1998, Ahmed and Koob, 1999), cocaine self-administration increased with 6 h access in LgA rats compared to ShA rats. Additionally, responding for doses of cocaine was higher in LgA than in ShA rats under a PR schedule. An upward shift of the cocaine dose–response function was previously found in LgA rats under an FR and a PR schedule (Ahmed and Koob, 1998, Paterson and Markou, 2003). Additionally, it was reported that LgA rats exhibited

Role of the funding source

National Institute on Drug Abuse grant DA004398 (G.F.K) supported the study; the NIDA had no further role in study design, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

S. Wee performed the self-administration experiment and wrote the first draft of the manuscript. C.D. Maydyam performed immunohistochemistry experiment. S. Wee, C.D. Mandyam and G.F. Koob contributed to the design of the study, analysis of the data and the final manuscript. D.M. Lekic performed part of the self-administration study. All the authors approved the final manuscript.

Conflict of interest

All the authors (S.W., C.D.M., D.M.L., G.F.K.) have no conflict of interest to declare.

Acknowledgement

We gratefully acknowledge the technical assistance of Mike Pham, JoAnn Lee, Stephanie Chan, and Hanan Jammal, who were undergraduate students of the University of California, San Diego, in the self-administration and the immunohistochemistry studies. We also thank Mike Arends for editorial assistance. This is publication number 18632 from The Scripps Research Institute.

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