Stimulants Amphetamines and Cigarettes

Acute doses of d-amphetamine and bupropion increase cigarette smoking.
Source
University of Chicago, Department of Psychiatry

RATIONALE:
Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking.

OBJECTIVE:
To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers.

METHODS:
Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period.

RESULTS:
After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked.

CONCLUSION:
Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.

Tobacco, Alcohol and Dopamine

Right after you take that first puff on your cigarette or the first sip of your martini or soda, trillions of potent molecules surge through your blood stream and into your brain. Once there, they set off a cascade of chemical and electrical events, a kind of neurological chain reaction that ricochets around the skull and rearranges the chemical make up of the mind. Given the obvious complexity of these events and the inner workings of the brain in general, it does not seem alarming that even though scientists have spent much time and effort researching this topic they still struggle to make sense of the exact mechanisms of addiction.


Why do certain substances have the power to make us feel so good (at least at first)? Why is it that some people are so easily enticed into the wrath of alcohol, cocaine, nicotine and other addictive substances, while others can, literally, take them or leave them? Many scientists are convinced that the answer may be simpler than any of us has dared imagined. What ties all of these mood-altering drugs together, they say, is a remarkable ability to elevate levels of a common substance in the brain called dopamine? The evidence of a link between dopamine and these highly addictive drugs which are commonly abused in our society has become so well researched that the distinction between substances that are addictive and those that are merely habit-forming has very nearly been swept away.



A GABA cell releases the neurotransmitter GABA. A nearby dopamine cell takes up the GABA in specially shaped GABA receptors (but not nicotine receptors). This tells it to stop releasing dopamine. Then, the enzyme GABA-transaminase destroys the GABA. The dopamine cell receives the GABA signal and stops releasing dopamine. Meanwhile, the dopamine that has already been released docks on a neighbor cell, then re-enters its home cell through a gate. After the dopamine docks on a neighbor cell, it sends a "pleasure signal". When it leaves, the pleasure stops. This happens normally, for example after eating.



Nicotine travels to the brain and finds its way to special receptors on dopamine cells. It starts sending a signal that drowns out the GABA signal. Nicotine's signal tells the dopamine cell to release much more dopamine, causing a large increase in the amount of dopamine available in between cells. The increased dopamine sends a pleasure signal over and over. This feeling -- and the craving to repeat it -- help create addiction.




The History of Addiction to Alcohol and Tobacco

The Liggett Group, smallest of the U.S.'s Big Five cigarette makers, broke ranks in March of this year and finally admitted that not only is tobacco addictive but also that the company has known it all along. While RJR Nabisco and others powerhouses in this field continue to battle in courts, insisting that smokers are not hooked, just exercising free choice, their denials are becoming increasingly skeptical in the face of growing weight of evidence. Over the past year, several scientific groups have made the case that in dopamine-rich areas of the brain, such as the nucleus accumbens (the so-called pleasure center), nicotine behaves remarkably like cocaine. Recently a federal judge ruled that for the first time the Food and Drug Administration has the right to regulate tobacco as a drug and cigarettes as the delivery vehicle.

Nicotine's pharmacokinetic properties have been found also to enhance its abuse potential. Cigarette smoking produces a rapid distribution of nicotine to the brain, with drug levels peaking within 10 seconds of inhalation. This fast delivery of drug assures that the smoker receives instant reinforcement for smoking, this perpetuates the continuation of smoking. The acute effects of nicotine dissipate in a few minutes, making the smoker continue dosing frequently throughout the day in order to maintain the drug's pleasurable effects and prevent the uncomfortable symptoms of withdrawal. What people frequently do not realize is that the cigarette is a very efficient and highly engineered drug-delivery system. By inhaling, the smoker can get nicotine to the brain very rapidly with every puff. A typical smoker will take 10 puffs on a cigarette over a period of 5 minutes in which the cigarette is lit. Thus, a person who smokes about 1-1/2 packs (30 cigarettes) daily, will get 300 "hits" of nicotine to the brain each day. These factors contribute considerably to nicotine's highly addictive nature.

Similar evidence is being found regarding the addictive nature of alcohol as we learn more and more about the physiology of the nature of alcoholism. Alcoholism has long been blamed on the genetics, on what is passed down to you from generation to generation. However, recent research is again pointing at Dopamine being one of the major players. Although alcohol causes relaxation and euphoria when initially consumed, it also acts as a depressant on the central nervous system. Although the research is not conclusive alcohol appears to have a major effect on the hippocampus, which is the part of the brain which is thought to be responsible for learning and memory, emotion, sensory processing, appetite and stress. It has also been suggested through research that people with severe alcoholism may have a gene that affects the function of the D2-Dopamine receptor.



Alcoholics may be divided into two distinct groups. The first of these groups is the Noradrenergic Type in which 80% of alcoholics fit into. Drinking alcohol improves their mood. Biochemically, during the depressive phase low levels of brain nor adrenaline, serotonin and dopamine have been observed. Excessive drinking may results in sedation, sombulance and hangovers. Increased consumption of stimulants such as coffee or nicotine occurs during withdrawal. Some of the symptoms of withdrawal are palpitations, high blood pressure, tremors of the hand, epilepsy and panic attacks. These individuals can be treated with the drugs niacin and tyrosine (dopamine precursor) supplements.

The serotonin Type is the category that remaining 20% of alcoholics fall into. Alcohol causes damage to the prefrontal lobe thus resulting in judgement loss. These individuals find it difficult to recognize their state of inebriation. Alcohol raises brain levels of noradrenaline, serotonin and dopamine, the opposite to the first group. These individuals find alcohol an excellent antidepressant and need to drink to stay normal. Thus reducing alcohol in this group results in decrease in brain neurotransmitter release. In a way they drink themselves sober. Withdrawal in this group can cause hallucinations, distortion of perception, night terrors and vision disturbances such as nystagmus. These individuals can be treated with tryptophan or glutamine supplements.



Studies done on Dopamine, Alcohol and Tobacco

A recent finding further associates dopamine and addiction to alcohol and tobacco. Recently an epilepsy drug was tested in it's effectiveness of treating nicotine (active ingredient in tobacco), cocaine, methamphetamine, heroine and alcohol addiction. The drug, gamma-vinyl GABA (GVG), blocks the release of dopamine in the brain. Blocking its release could reduce the addictive tendencies of drugs that boost brain levels of dopamine, such as tobacco and alcohol. This drug would counteract any pleasurable experiences that may be gained by the increase in dopamine in the brain. GVG, or Vigabatrin (Sabril), is currently available in Canada and the UK to treat epilepsy but is not yet approved for use in the US.
In a subsequent study, rats that were given methamphetamine had a 2,700% increase in release of dopamine in the nucleus accumbens, the region in the middle of the brain that acts as the "reward center." However, GVG inhibited the increase by 61% at the highest dose. Similarly, rats had a 170% increase in dopamine in response to heroin, a reaction that could be inhibited completely by a higher dose of the drug. Alcohol only produced a 140% increase in dopamine suggesting that the effect of dopamine could be completely inhibited by a lower dose of GVG. This finding, reported senior investigator Dr. Stephen Dewey of Brookhaven National Laboratory in Upton, New York, and colleagues, proposes a possible treatment for alcoholism.

However, the researchers admit that although dopamine probably plays a vital role in the reward and reinforcement of behavior associated with addictive substances, other neurotransmitters and factors most likely play an important role as well. Studies have suggested that dopamine release in the nucleus accumbens is important, but is not the only factor in drug involved in these addictions.

Nicotine may not be the only psychoactive component in tobacco smoke. Using positron emission tomography, an advanced neuroimaging technology, Dr. Joanna S. Fowler and her colleagues at Brookhaven National Laboratory in Upton, New York, have produced images showing that smoking decreases the brain levels of an important enzyme that breaks down the neurotransmitter dopamine. The amount of the enzyme, called monoamine oxidase (MAO), is reduced by 30 to 40 percent in the brains of smokers, compared to nonsmokers or former smokers. The reduction in brain MAO levels subsequently results in an increase in the levels of dopamine in the brain. This agrees with the previous studies which suggest that dopamine is important in the addictive properties of tobacco and cigarettes.

Research has shown that although nicotine causes increases in brain dopamine it has no affect on the MAO levels in the brain. This leads to the possibility that another component of cigarettes other than nicotine may be inhibiting MAO. "Whatever is inhibiting MAO could be acting in concert with nicotine to enhance dopamine's activity by preventing its breakdown," is a hypothesis formed Dr. Fowler and her colleagues.

The concept that the smoking-related reduction of MAO activity may synergize with nicotine's stimulation of dopamine levels to produce the diverse behavioral effects of smoking leads to the suggestion that MAO inhibitor drugs may be useful as an additional therapy with people who are attempting to quit smoking, she adds. MAO inhibitor drugs are currently used to treat depression and Parkinson's disease. One such drug, moclobemide, is already being used experimentally to assist persons trying to quit smoking.

It has been reported in the past that tobacco smokers have a much lower risk of developing Alzheimer's disease and Parkinson's disease. The ratio of homovanillic acid in the caudate and putamen was significantly reduced in smokers (p<0.05). Also it was found tht the dopamine levels in the caudate were significantly higher in smokers than in non-smokers. Interestingly, there was no significant change in the number of D1, D2 or D3 receptors in the striatum. These finding suggest that we may have a mechanism to delay basal ganglia pathology. The same study found that there might be a connection between many psychiatric conditions and smoking. The Hippocampal formation showed a higher density of high affinity nicotine binding in smokers compared to non-smokers. It has been suggested that because of these findings smokers may be less susceptible to these diseases. Recently at the University of Cincinnati Medical center researchers found that the cerebral spinal fluid of smokers contains a much lower concentration of HVA (homovanillic acid, a domapine metabolite). This would elevate the levels of dopamine in the brain and thus provide further evidence that dopamine is somehow associated with cigarette addiction.

We now know that dopamine, either directly or indirectly, most likely plays an important role in getting and keeping people addicted to tobacco and alcohol. It is interesting to look at how dopamine effects withdrawal from these substances. Alcohol addiction is believed to be caused by morphine like substances which arise from acetaldehyde and dopamine in the brain. Nicotinic acid (vitamin B3) can help metabolize alcohol and reduce the acetaldehyde levels and thus possibly reduce craving for alcohol. G.A.B.A agonists have also been found to be effective in relieving alcohol intoxication. The nutritional precursor of GABA is glutamine. D-phenylalanine inhibits enkephalinase, thus maintaining the brains endogenous opiate levels and reducing craving.

At Wayne State University as study was performed in which Pregnant Long-Evans dams were intubated with different concentration of alcohol from gestational day 8-20. It was found that the resulting offspring had a significantly decreased number of dopamine binding sites within the dorsal and ventral striatum. This would suggest that prenatal alcohol expose would cause persistent changes within the dopaminergic system. Another study performed at the University of Illinois studied the potential rapid changes in extracellular dopamine during the first 5-10 minutes after ethanol injection. It was found that ethanol significantly increased extracellular dopamine. These results further support that theory that alcohol consumption causes an increase in dopamine secretion in the nucleus accumbens, which activates the reward pathway.

Alcohol is metabolized in two stages by the enzyme alcohol dehydrogenase and by the enzyme aldehyde dehydrogenase; both require niacin as cofactor. In alcoholics the first stage reaction is faster than in normal or control subjects. The second stage reaction involving the conversion of the acetaldehyde (formed from alcohol) to acetate is reduced in alcoholics. The end result is an accumulation of acetaldehyde in tissues particularly in the brain. Recent evidence has shown that 4.5 gms/kg of alcohol was equivalent to 0.3 ml/kg of acetaldehyde in promoting sedation and loss of muscular coordination.

Alcohol inhibits the enzyme delta 6 desaturase which is important in converting linoleic acid to gamma linolenic acid(GLA). Supplementation with GLA has been found to reduce the craving for alcohol. EPA/DHA from fish oils (GLA/EFA) also has beneficial effects.

Alcohol also increases the release of prostaglandin E1 (PGE1) in the brain. PGE1 has been shown to elevate mood and the suggestion has been put that the craving for alcohol is due to a drastic fall in PGE1 in the alcoholic brain. GLA is a precursor of this mood elevating prostaglandin and therefore contributes positively to reducing the alcohol craving. Many alcoholics have food sensitivities particularly to foods from which alcohol has been derived, most commonly to wheat, corn, grapes, yeast or potato. These foods must be eliminated from the diet as they have a tendency to aggravate the withdrawal phase as well as promote drinking.





References

Court JA; et al. Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. MRC Neurochemical Pathology Unit, UK. Neuroscience 1998 Nov; 87(1): 63-78.

Fowler, J.S.; Volkow, N.D.; et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature 379:733-736, 1996.

Geracioti TD Jr.; et al. Low CSF concentration of a dopamine metabolite in tobacco smokers. Department of Psychiatry, University of Cincinnati Medical Center. American Journal of Psychology 1999 Jan 156(1): 130-2

Court JA; et al. Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. MRC Neurochemical Pathology Unit, UK. Neuroscience 1998 Nov; 87(1): 63-78.

Randall S, Hannigan JH; In utero alcohol and postnatal methylphenidate: locomotion and dopamine receptors. Department of Psychology, Wayne State University. Neurotoxical Teratology 1999 Sept-Oct; 21 (5): 587-93.

Rationale: Psychomotor stimulants previously have been found to increase the frequency of cigarette smoking, but it is unclear whether this is due to a non-specific increase in general activity or a specific increase in the reinforcing effects of smoking.

Objectives: To investigate whether d-amphetamine increases the relative reinforcing effects of cigarette smoking.

Methods: Ninety minutes after d-amphetamine (7.5, 15 mg/70 kg) or placebo administration, 13 male and female subjects participated in 3-h sessions during which they could make a maximum of 20 choices between cigarette smoking (two puffs per choice), earning money ($0.25 per choice), or neither. In separate sessions, using the same subjects, the effects of d-amphetamine on the frequency of ad libitum smoking was assessed. Results: During choice sessions, d-amphetamine dose-dependently increased smoking choices from 4.2±0.6 to 5.7±0.6.

During sessions in which subjects smoked ad libitum, d-amphetamine increased number of cigarettes smoked from 2.8±0.4 to 3.8±0.6. Breathe carbon monoxide (CO) levels, a measure of smoke exposure, showed corresponding dose-related increases.

Conclusions: These results are consistent with previous findings that d-amphetamine increases smoking and provide evidence that this effect is due to a drug-produced increase in the relative reinforcing effects of cigarette smoking.