Exposure to Commercial Cigarette Smoke Produces Psychomotor Sensitization via Hyperstimulation of Glutamate Response in the Dorsal Striatum

Cigarette smoke is a highly complex mixture of nicotine and non-nicotine constituents. Exposure to cigarette smoke enhances tobacco dependence by potentiating glutamatergic neurotransmission via stimulation of nicotinic acetylcholine receptors (nAChRs). We investigated the effects of nicotine and non-nicotine alkaloids in the cigarette smoke condensates extracted from two commercial cigarette brands in South Korea (KCSC A and KCSC B) on psychomotor behaviors and glutamate levels in the dorsal striatum. Repeated and challenge administration of KCSCs (nicotine content: 0.4 mg/kg, subcutaneous) increased psychomotor behaviors (ambulatory, rearing, and rotational activities) and time spent in psychoactive behavioral states compared to exposure to nicotine (0.4 mg/kg) alone. The increase in psychomotor behaviors lasted longer when exposed to repeated and challenge administration of KCSCs compared to nicotine alone. In parallel with sustained increase in psychomotor behaviors, repeated administration of KCSCs also caused long-lasting glutamate release in the dorsal striatum compared to nicotine alone. KCSC-induced changes in psychomotor behaviors and glutamate levels in the dorsal striatum were found to be strongly correlated. These findings suggest that non-nicotine alkaloids in commercial cigarette smoke synergistically act with nicotine on nAChRs, thereby upregulating glutamatergic response in the dorsal striatum, which contributes to the hypersensitization of psychomotor behaviors.

Amphetamine Maintenance Therapy During Intermittent Cocaine Self-Administration in Rats: Reduction of Addiction-like Behavior is Associated with Attenuation of Psychomotor and Dopamine Sensitization

ABSTRACTBackgroundD-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaine’s potency at the DAT.MethodsMale rats self-administered cocaine intermittently (5 minutes ON, 25 minutes OFF x 10) for 14 sessions, with or without concomitant D-amphetamine (5 mg/kg/day via s.c. osmotic minipump). In Experiment 1, psychomotor sensitization, responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed relapse were assessed. In Experiment 2, rats self-administered cocaine or saline intermittently, with or without D-amphetamine, and the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core was assessed using fast scan cyclic voltammetry ex vivo.ResultsIntA cocaine self-administration produced psychomotor sensitization, strong motivation to take and seek cocaine, and it increased cocaine’s potency at the DAT. The co-administration of D-amphetamine suppressed both the psychomotor sensitization and high motivation for cocaine produced by IntA experience, and also reversed sensitization of cocaine’s actions at the DAT, leaving baseline DAT function unchanged.ConclusionsTreatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

Intermittent access cocaine self-administration produces psychomotor sensitization: effects of withdrawal, sex and cross-sensitization

The psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways – showing sensitization or tolerance – depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) neurotransmission, and therefore, may provide insights into how repeated drug use promotes the development of substance use disorders. Indeed, the most widely used preclinical model of cocaine addiction, which involves Long Access (LgA) self-administration procedures, is reported to produce tolerance to cocaine’s psychomotor activating effects and effects on DA activity. This is cited as evidence in support of the view that in addiction, drug-seeking and-taking is motivated to overcome this DA deficiency and associated anhedonia. In contrast, Intermittent Access (IntA) cocaine self-administration is more effective than LgA in producing addiction-like behavior, but sensitizes DA neurotransmission. There is, however, very little information concerning the effects of IntA experience on the psychomotor activating effects of cocaine. The purpose of the studies reported here, therefore, was to determine whether IntA experience produces psychomotor sensitization with similar characteristics to that produced by the intermittent, noncontingent administration of cocaine. It did. The psychomotor sensitization produced by IntA experience with cocaine: (1) was greater after a long (30 days) vs short (1 day) period of withdrawal; (2) was greater in females than males; and (3) resulted in cross-sensitization to another psychomotor stimulant drug, amphetamine. This pattern of cocaine experience-dependent plasticity favors an incentive-sensitization view of addiction.

Effects of dopamine receptor antagonism and amphetamine-induced psychomotor sensitization on sign- and goal-tracking after extended training

RationaleThe dopamine system is important for incentive salience attribution, where motivational value is assigned to conditioned cues that predict appetitive reinforcers. However, the role of dopamine in this process may change with extended training.ObjectivesWe tested the effects of dopamine D1-like and D2-like receptor antagonism on the expression of sign-tracking and goal-tracking conditioned responses following extended Pavlovian conditioned approach (PCA) training. We also tested if amphetamine-induced psychomotor sensitization accelerates the shift to sign-tracking that is observed with extended training.MethodsIn experiment 1, 24 male Long-Evans rats received 20 PCA sessions in which one lever (CS+, 10 s) predicted 0.2 mL sucrose (10%, w/v) delivery and the other lever (CS–) did not. SCH-23390 (D1-like antagonist) or eticlopride (D2-like antagonist) were administered before non-reinforced behavioural tests at doses of 0, 0.01, and 0.1 mg/kg (s.c.). In experiment 2, rats received vehicle or 2 mg/kg amphetamine (i.p.) for 7 days (n = 12/group). Ten days later, they received 16 PCA training sessions.ResultsBoth doses of SCH-23390 reduced sign- and goal-tracking, but also reduced locomotor behaviour. A low dose of eticlopride (0.01 mg/kg) selectively reduced goal-tracking, without affecting sign-tracking or locomotor behaviour. Amphetamine produced psychomotor sensitization, and this did not affect the acquisition of sign- or goal-tracking.ConclusionsFollowing extended PCA training, dopamine D2-like receptor activity is required for the expression of goal-tracking but not sign-tracking. Psychomotor sensitization to amphetamine did not impact incentive salience attribution; however, more selective manipulations of the dopamine system may be needed.

Wheel-running exercise before and during gestation against acute and sensitized cocaine psychomotor-activation in offspring

While animal research has consistently reported preventive effects of exercise against drug abuse vulnerability, little is known about the influence of the developmental stage during which exercise is displayed on addictive drugs responsiveness. This study aimed to determine whether prenatal exercise could attenuate acute cocaine reactivity and psychomotor sensitization in youth offspring. We used a split-plot factorial design where C57BL/6J females were randomly assigned into sedentary or exercised (wheel-running) conditions before and during gestation, the wheels being removed on gestational day 18. Offspring were weaned, gendered and individually housed on 24-28 days old. At 38-42 days old, they were tested for their acute psychomotor responsiveness to 8 mg/kg cocaine and their initiation of sensitization over 8 additional once-daily administrations, the long-term expression of sensitization occurring 30 days later. Adolescent females born from exercised mothers were much less responsive to the acute psychomotor-stimulating effect of cocaine than those born from sedentary mothers (d = 0.75, p = .02), whereas there was no evidence for such a difference in males (d = 0.34, p = .17). However, we did not find sizeable attenuating effects of prenatal exercise on the initiation and the long-term expression of the psychomotor-activating effect of cocaine, in either sex (Cohen’s ds varying from −0.23 to 0.39). These results suggest that prenatal exercise may induce initial protection against cocaine responsiveness in youth females, a finding that warrants further research.

Evidence for a long-term protection of wheel-running exercise against cocaine psychomotor sensitization in adolescent but not in young adult mice

Rodents housed with a running wheel can exhibit attenuated cocaine seeking and cocaine-induced psychomotor activation. However, the longevity of the exercise anti-drug protection and the influence of the developmental stage during which exercise is displayed received little attention. Here, females and males C57BL/6J mice, aged 28 (adolescents) or 77 (young adults) days were housed with (n=56) or without (n=28) a running wheel. After 3 weeks in these conditions, half of the exercised mice were deprived of their wheel (n=28) whereas the other half and the sedentary mice (no wheel) were kept in their respective environments throughout experimentation. After 3 additional weeks, mice were tested for initiation of psychomotor sensitization to 9 once-daily intraperitoneal injections of 8 mg/kg cocaine (following 2 drug-free test sessions). The expression of sensitization was assessed on a single test session 30 days after the last sensitizing cocaine injection. Continuously exercised mice (wheel throughout experimentation) were less responsive to the initiation and the expression of cocaine effects, regardless of the gender and the developmental period during which exercise was introduced. Wheel-running during adolescence attenuated in later life the initiation and the expression of sensitization in females and only its expression in males. In adult females and males, previously-exercised and sedentary mice exhibited indiscernible levels of initiation and expression of sensitization. Thus, the likelihood of the long-term protection of exercise against cocaine vulnerability may depend not only on the gender but also and especially on the period of life in which exercise took place.