Research reportRats prefer cocaine over nicotine in a two-lever self-administration choice test
Introduction
The neurobiology of nicotine addiction may be more complex than that of cocaine. Like cocaine, nicotine is thought to produce at least some of its reinforcing effects through activation of mesolimbic dopamine neurons and transient elevation of synaptic dopamine levels [10], [24]. Unlike cocaine, which acts directly on the dopamine transporter to prevent dopamine reuptake [15], [25], nicotine stimulates dopamine release through activation of nicotinic receptors on dopamine neurons in the ventral tegmental area [6], [7], [11], [22]. The complex pharmacology of these receptors may be one reason that the nicotine addiction profile has been difficult to characterize [1].
Reliable intravenous nicotine self-administration has been demonstrated in a number of species, including rats [8], [9], [12], [14], although it is not readily acquired. Food restriction and deprivation will facilitate responding, but they are not necessary for acquisition of nicotine self-administration [13]. Response rates for nicotine are dose-dependent, although compensation for variations in nicotine dose is generally poor [8], [9], [13]. Self-administration response patterns are generally irregular and do not display the well-timed patterning characteristic of cocaine self-administration except at very high doses. Nicotine has been shown to reduce the threshold for electrical self-stimulation [4], but only to levels achieved by weakly reinforcing drugs such as caffeine and pseudoephedrine [3]. The variability of nicotine self-administration patterns and the small decreases nicotine produces in self-stimulation reward thresholds suggest that nicotine is a weaker reinforcer than cocaine. However, the measurement of drug preferences as an index of the relative reward strength of nicotine vs. cocaine or other drugs of abuse has not been performed.
We recently reported the development of a procedure that offers self-administering rats a choice between two, concurrently available intravenous (IV) drug solutions [17]. Cocaine-trained rats exhibited a preference for higher over lower cocaine doses up to an apparent plateau, above which the reinforcing strengths appeared equal. We used this same procedure in nicotine-trained rats to evaluate their preferences for different nicotine doses, and to compare the relative reinforcement strength of nicotine and cocaine.
Section snippets
Animals
Experiments used male albino Sprague–Dawley rats 90–120 days old (250–300 g) at the start of testing. Each animal was housed individually and maintained at 350–400 g throughout the experiments; water was available ad libitum. A 12 h light/dark cycle was maintained with light hours from 07.00 to 19.00 h. All experiments were conducted during the light phase of the light/dark cycle.
Catheter construction
A chronically-indwelling catheter was implanted into the external jugular vein of each animal using a method similar
Nicotine self-administration
All four of the selected nicotine doses (8, 16, 25 and 75 μg) were self-administered by animals in our tests, generating a dose–response curve consistent with previous reports [8], [9], [12]. Mean total self-injections in 3 h at each nicotine dose were as follows: 8 μg — 25.9±4.8; 16 μg — 25.3±4.6; 25 μg — 26.2±3.1; 75 μg — 16.4±1.3. Once acquired, response rates for the baseline nicotine dose, 16 μg/kg/inj, were stable with no apparent variation or drift associated with chronic nicotine
Discussion
The unit dose range for nicotine self-administration in human smokers is estimated to be 10–30 μg/kg based upon the consumption of an average cigarette [2]. The IV self-administration of nicotine doses in this range has been demonstrated to produce nicotine blood levels in rats similar to those achieved by smokers [23]. For the present experiments, we selected nicotine doses in a similar range, 8, 16 and 25 μg/kg/injection, and we also used a higher dose, 75 μg, to test the limits of
Acknowledgements
This work was supported by National Institute on Drug Abuse grants DA05761 (AM), DA05107 (LS), and DA07747 (JB).
References (25)
- et al.
Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats
Eur. Neuropsychopharmacol.
(1999) - et al.
Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen
Behav. Brain Res.
(1998) - et al.
Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons
Brain Res.
(1985) - et al.
Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area
Brain Res.
(1994) - et al.
Rats choose cocaine over dopamine agonists in a two-lever self-administration preference test
Pharmacol. Biochem. Behav.
(2001) - et al.
Chronic and acute tolerance to subjective effects of nicotine
Pharmacol. Biochem. Behav.
(1993) - et al.
The neurobiology of tobacco addiction
Trends Pharmacol. Sci.
(1991) Neural mechanisms underlying nicotine dependence
Addiction
(1994)- et al.
Daily intake of nicotine during cigarette smoking
Clin. Pharmacol. Ther.
(1984) - et al.
Intravenous drug self-administration techniques in animals