Acute Reinforcing and Stimulant-Like Effects of Nicotine
In animals, nicotine lowers brain reward thresholds, similarly to other drugs of abuse (Figure 7.14). Nicotine sustains intravenous self-administration in both animals and humans. In rats, the dose range at which the animal will self-administer nicotine is relatively narrow (Figure 7.15). Animals and humans titrate their intake of nicotine to maintain stable blood nicotine levels.
Probably not surprisingly, nicotine has less efficacy than cocaine as a reinforcer in nondependent animals, reflected by much higher breakpoints for cocaine than nicotine on a progressive-ratio schedule of reinforcement (Figure 7.16). Similarly to its actions in humans, nicotine produces locomotor activation, analgesia, appetite suppression, and improvements in learning and memory in rats.
Figure 7.12 Schematic diagram of the structural organization of the nicotinic acetylcholine receptor (nAChR). The structure of the muscular receptor (left) of the nAChR is well characterized, and much of what we know about the structure of the neuronal receptor (right) is based on studies of the muscular receptor. nAChRs cross the membrane, and the binding of acetylcholine (or nicotine) causes the receptor to change shape and open a channel that allows ions to flow into and out of the cell. The nAChR in adult muscle is made up of the α1, β1, γ, and δ subunits, and there are two different families of nAChRs expressed in neurons. One family is made up of a combination of the α and β subunits (in this subtype, αx = α2–6 and βy = β2–4), whereas the other family can form active receptors made up of only one type of subunit (in this homomeric subtype, αz = α7–9). The five binding sites on the α7 subtype are hypothesized based on a symmetry argument. Because all five subunits of the complex are identical, the structural elements involved in binding ligands (gray triangles) should be identical on each subunit that provides five binding sites. [Taken with permission from Picciotto MR, Zoli M, Changeux JP. Use of knockout mice to determine the molecular basis for the actions of nicotine. Nicotine and Tobacco Research, 1999, 1 (suppl 2): s121–s125.]
Figure 7.14 Mean z-score (standard score) ± SEM changes in intracranial self-stimulation reward thresholds from pre- to post-drug after administration of various doses of nicotine in rats. Saline post-drug minus pre-drug threshold is indicated by a z-score of 0. *p < 0.025, doses of nicotine that significantly lowered threshold. These data show that nicotine, like other drugs of abuse, can facilitate brain stimulation reward. A z-score is a statistical measure (also called a “standard score”), representing a standard distribution around a mean of zero. A +1.96 or −1.96 z-score represents close to two standard deviations away from the mean and is considered a statistically significant difference. [Taken with permission from Huston-Lyons D, Kornetsky C. Effects of nicotine on the threshold for rewarding brain stimulation in rats. Pharmacology Biochemistry and Behavior, 1992, (41), 755–759.]
Figure 7.15 (A) Mean number of nicotine infusions earned during 3 hour sessions of intravenous nicotine self-administration in rats (n = 5–7). The data are expressed as the mean of the second and third days of 3 days of self-administration at each nicotine dose (0, 0.003, 0.01, 0.03, and 0.06 mg/kg/infusion, i.v.). The saline (sal) dose represents the mean of the second and third days after substitution of saline for nicotine. All of the rats were initially trained on 0.03 mg/kg/infusion nicotine. ∗p < 0.05, responding for saline was significantly different from responding for all nicotine doses; #p < 0.05, responding for the 0.03 mg/kg dose was significantly higher than responding for the 0.003 and 0.06 mg/kg doses. (B) Event record of responding for nicotine for each dose tested. These data show that nicotine is reinforcing in rats. Animals without any deprivation will learn to intravenously self-administer nicotine. The function that relates the unit dose per injection with self-administration shows an inverted U-shaped function, similar to other intravenously self-administered drugs in the psychostimulant class, but the function for nicotine has more of an ascending limb and less of a descending limb for such a fixed-ratio 1 schedule of reinforcement compared with cocaine. Notice in the event recordings that the animals “load up” at the beginning of the session, similarly to human cigarette smokers (see Figure 7.7), but then settle down with regular intervals between infusions. [Taken with permission from Watkins SS, Epping-Jordan MP, Koob GF, Markou A. Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacology Biochemistry and Behavior, 1999, (62), 743–751.]
In rats, nicotine produces a stimulant effect that can show either tolerance or sensitization, depending on the nature of exposure to the drug. In nicotine-naive rats, acute nicotine administration decreased exploratory locomotor activity, whereas repeated nicotine administration produced rapid tolerance to this locomotor-depressant effect, followed by an increase in locomotor activity. With repeated intermittent nicotine administration, sensitization to the locomotor-activating effects of nicotine develops (Figure 7.17).
Acute nicotine administration can produce an anxiolytic-like effect in the social interaction test, in which two rats are placed in the same cage and allowed to engage in social contact, but high doses can have an opposite effect. Anxiolytic-like effects have also been observed in the potentiated startle paradigm (skeletomuscular response to an abrupt noise or stimulation) and elevated plus maze, both of which are animal models used to test anxiety-like behavior.
Figure 7.16 The highest fixed-ratio completed by two dogs responding for intravenous infusion of nicotine, cocaine, or saline under a progressive-ratio schedule of reinforcement. Each point represents a single determination at the selected dose and drug. Dog #2968 was tested twice with saline. Notice the logarithmic scale used for the ordinate. These data are one of the only direct comparisons of the relative efficacy of given drugs of abuse measured by progressive-ratio responding. Notice that nicotine under these conditions has much less efficacy as a reinforcer than cocaine. [Taken with permission from Risner ME, Goldberg SR. A comparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. Journal of Pharmacology and Experimental Therapeutics, 1983, (224), 319–326.]
Nicotine can reduce pain in humans, and activation of nicotinic receptors elicits an antinociceptive effect in a variety of nonhuman species in a variety of pain tests. Nicotine may act at the spinal cord level of pain processing, in the brain itself. Supraspinally administered nicotine (in the area of the brain above the spinal cord) is more effective than spinally administered nicotine. Nicotine is hypothesized to reduce pain by interacting with several neurotransmitter systems through the release of norepinephrine, the release of endogenous opioids, and through the suppression of inflammatory actions. Nicotine appears to act through both the α4β2 and α7 subunits of the nAChR to produce analgesia (for further reading, see Benowitz, 2008).
Animal studies of the acute reinforcing effects of nicotine using intravenous self-administration have predominantly focused on nAChR activation in the mesocorticolimbic dopamine system that projects from the ventral tegmental area to the nucleus accumbens and prefrontal cortex (Figure 7.18). The presence of nAChRs throughout the mesocorticolimbic dopamine system suggests that any of the regions that comprise this system could mediate the effects of nicotine, but the ventral tegmental area seems to play a more important role than the nucleus accumbens. Microinjection of nicotine directly into the nucleus accumbens or ventral tegmental area increases extracellular levels of dopamine in the nucleus accumbens (Figure 7.19).
Nicotine-induced dopamine release and the nicotine-induced activation of dopamine neurons depend on the β2 subunit. Knockout mice that lack the β2 subunit will not self-administer nicotine (Figure 7.20), indicating that the β2 subunit is critically involved in nicotine reinforcement.
β2-selective nAChR antagonists also block nicotine self-administration in rats, indicating that nAChR activation is involved in the reinforcing actions of nicotine. The ventral tegmental area has been shown to have nAChRs on cell bodies and dendrites of dopamine neurons. Infusions of the nAChR antagonist dihydro-β-erythroidine directly into the ventral tegmental area but not nucleus accumbens significantly decreased nicotine self-administration in rats. Dihydro-β-erythroidine is relatively selective for the α4 and β2 subunits of the nAChR. Chemical lesions with 6-hydroxydopamine of the nucleus accumbens and systemic administration of selective dopamine D1 and D2 receptor antagonists also decreased nicotine self-administration (Figure 7.21). Direct administration of the nAChR antagonist methyllycaconitine into the ventral tegmental area also attenuated the nicotine-induced lowering of brain reward thresholds. Such data indicate that one of the primary sites of action for the acute positive reinforcing properties of nicotine is the mesocorticolimbic dopamine system, and these pharmacological data suggest that α4 and β2 subunits of the nAChR play important roles in nicotine reinforcement (for further reading, see Fowler et al., 2008).
Figure 7.17 Effect of acute and subchronic injections of nicotine on spontaneous locomotor activity in rats. Rats were habituated to the testing environment for 80 min prior to the injection. (A) For acute treatment, subcutaneous injections of saline (n = 6), 0.1 mg/kg nicotine (n = 6), or 0.4 mg/kg nicotine (n = 8) were given at the point indicated by the arrow (time 0). ∗∗p < 0.01. (B) For chronic treatment, rats were pretreated with daily subcutaneous injections of saline (n = 6), 0.1 mg/kg nicotine (n = 6), or 0.4 mg/kg nicotine (n = 10) for 5 days before the test day. On the test day, the animals were given injections of saline or nicotine (0.1 or 0.4 mg/kg), respectively, at the time indicated by the arrow (time 0). ∗∗p < 0.01. These data show that nicotine, similar to other drugs of abuse, can show locomotor sensitization with repeated administration. Some have argued that this locomotor sensitization has motivational significance for the acquisition and reinstatement of drug-seeking behavior. [Taken with permission from Benwell ME, Balfour DJ. The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. British Journal of Pharmacology, 1992, (105), 849–856.]
Cholinergic neurons from the pedunculopontine tegmental and laterodorsal tegmental nuclei project to dopamine neurons in the substantia nigra and ventral tegmental area and may link important components of the nicotine reward circuit. Myelinated axons in the medial forebrain bundle (an area that supports high rates of electrical self-stimulation behavior) that project to the pedunculopontine nucleus activate cholinergic neurons that in turn activate dopamine neurons in the ventral tegmental area by stimulating both nicotinic and muscarinic receptors. The nicotine-induced stimulation of cholinergic neurons in the pedunculopontine tegmental nucleus increases the release of endogenous acetylcholine, which excites dopamine neurons in the substantia nigra and ventral tegmental area. This nicotine-induced activation can by blocked by the nAChR antagonist mecamylamine. Chemical lesions of the pedunculopontine tegmental nucleus or direct administration of the nAChR antagonist dihydro-β-erythroidine into this region blocked nicotine self-administration. Similarly, lesions of the pedunculopontine tegmental nucleus blocked the rewarding effects of nicotine in a conditioned place preference paradigm.
Nicotine also interacts with opioid peptides. High densities of μ opioid receptors are found in the nucleus accumbens. Systemic nicotine administration increases opioid peptide levels in the nucleus accumbens. Some clinical studies found that the opioid receptor antagonist naltrexone blocked or lessened the reinforcing effects of nicotine, and μ opioid receptor knockout mice did not exhibit reinforcing effects of nicotine in the conditioned place preference paradigm. μ Opioid receptor knockout mice also exhibited a reduction of the analgesic effects of nicotine and a reduction of nicotine withdrawal in dependent mice. These results suggest that endogenous opioids may be involved in the reinforcing effects of nicotine.
Figure 7.18 Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of nicotine. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus accumbens, and amygdala either directly or indirectly via actions on interneurons. Nicotine may also activate opioid peptide release in the nucleus accumbens or amygdala independent of the dopamine system. The blue arrows represent the interactions within the extended amygdala system hypothesized to play a key role in nicotine reinforcement and dependence. AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate-putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area. [Taken with permission from Koob GF, Le Moal M. Neurobiology of Addiction. Academic Press, London, 2006.]
Other neurochemical systems also modulate certain components of nicotine reinforcement, including glutamatergic and γ-aminobutyric acid (GABA) systems, at the cellular level (see below). Regardless of the extent to which each of these systems modulates nicotine reinforcement, they all appear to interact with the midbrain dopamine system, although dopamine-independent reinforcing actions have also been demonstrated using conditioned place preference (for further reading, see Laviolette and van der Kooy, 2004).