Catecholaminergic mechanisms of reinforcement: Direct assessment by drug self-administration

doi:10.1016/0024-3205(77)90391-5

Life Sciences

Volume 20, Issue 3, 1 February 1977, Pages 483-492

https://doi.org/10.1016/0024-3205(77)90391-5 Get rights and content

Abstract

Reinforcing qualities in rats were shown by i.v. doses of two dopaminergic agonists, apomorphine and piribedil, and one noradrenergic agonist, clonidine, both in tests for primary reinforcement as seen in self-administration behavior and for conditioned reinforcement. Pretreatment with a dopaminergic blocker (haloperidol) interfered with the reinforcing effectiveness of apomorphine whereas an inhibitor of norepinephrine biosynthesis (U-14, 624) did not. Haloperidol also inhibited piribedil-based reinforcement. Pretreatment with an α-adrenergic blocking agent (phenoxybenzamine) inhibited the reinforcing effect of clonidine. These studies indicate that activation of either central dopaminergic or noradrenergic receptors can result in positive reinforcing effects.

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Citation Excerpt :
Therefore, we conclude that the β1-noradrenergic system is not involved in cocaine self-administration. With respect to the α2-noradrenergic system, clonidine has been shown to have positive reinforcing properties in rats and rhesus monkeys (Davis and Smith, 1977; Woolverton et al., 1982). However, clonidine is a mixed α2-noradrenergic and imidazoline-1 receptor agonist, whereas UK14304 is a selective α2 receptor agonist (Andorn et al., 1988; Ernsberger et al., 1997; Georges et al., 2005; Georges and Aston-Jones, 2003).
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Psychostimulants increase extracellular monoamine concentrations in the CNS. While the contributions of dopamine (DA) and serotonin (5-HT) to the reinforcing effect of psychostimulants have been examined, less is known about the involvement of norepinephrine (NE). In the present study, cocaine, desipramine (DMI) and JZ-III-84 were made available to rhesus monkeys (n = 4) responding under a progressive-ratio (PR) schedule. These compounds vary in their in vitro selectivities for blocking NE uptake relative to DA from high (DMI) to modest (JZ-III-84) to non-selective (cocaine). Additionally, cocaine mixed with DMI in mg/kg dose-ratios of 1:1 to 1:3 was made available for self-administration. NE uptake inhibition by the mixture of cocaine and DMI at a ratio of 1:3 was evaluated in an ex vivo uptake assay. Cocaine (0.01–0.1 mg/(kg injection)) and JZ-III-84 (0.001–0.1 mg/(kg injection)) functioned as positive reinforcers with sigmoidal or biphasic dose–response functions, whereas DMI failed to do so. The addition of DMI to cocaine did not systemically alter self-administration of cocaine. In the ex vivo uptake assay, the addition of DMI to cocaine significantly increased the NE uptake inhibition compared to cocaine. These results support the conclusion that CNS NE is not involved in the reinforcing mechanism of psychostimulants.
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Clonidine HCl is an antihypertensive that is also sometimes used to alleviate symptoms of withdrawal during narcotics detoxification. Recently, there have been reports abuse of clonidine by methadone patients and opioid abusers. The present study evaluated the intravenous self-administration of clonidine in four baboons. Self-injections were available 24 h/day under a fixed-ratio (FR 120 or 160) schedule of injection with a 3-h timeout after each injection. Doses of clonidine (0.0001–0.056 mg/kg per injection) or its vehicle (saline) were substituted for cocaine (0.32 mg/kg) for at least 15 days. Food pellets were available continuously under a concurrent FR 30 schedule of pellet delivery. Clonidine maintained self-injection greater than its saline vehicle in all four baboons. Although self-injection of clonidine increased as a function of dose within each baboon, there were differences between baboons in the range of doses of clonidine that maintained self-injection. Doses of 0.032 or 0.056 mg/kg maintained peak mean levels of clonidine self-injection which ranged from low (3.2 injections/day) to high (>6 injections/day) across baboons. Levels of self-injection were similar to vehicle at 0.01 mg/kg clonidine in two of four baboons. However, in the other two baboons, very low doses of clonidine (0.0001–0.001 mg/kg) maintained low to moderate levels of self-injection. Acute administration of clonidine produced signs of sedation including lip droop, drooling and sitting with eyes closed. At high doses, some toxicity was apparent: Baboons were pale and not responsive. Food intake was generally increased in a dose dependent manner. The present study indicates that clonidine functions as a positive reinforcer.
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Catecholaminergic mechanisms of reinforcement: Direct assessment by drug self-administration

Abstract

Life Sci.

Brain Res.

Physiol. Behav.

Expl. Neurol.

Physiol. Behav.

Brain Res.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Eur. J. Pharmac.

Eur. J. Pharmac.

Physiol. Behav.

Eur. J. Pharmac.

Neuropharmacology

Life Sci.

Br. J. Pharmac.

Br. J. Pharmac.