Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
1998-09-24
2003-02-11
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C424S001110, C424S001650, C424S009100
Reexamination Certificate
active
06517812
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to inhibition of psychostimulant-induced or nicotine-induced craving in humans.
The use of psychostimulants, such as cocaine, and of nicotine often leads to repeated use and a profound state of addiction in humans, which is characterized by compulsive drug use and an inability to control use despite significant adverse consequences. Cocaine, for example, is one of the most reinforcing drugs known (Johanson et al., 1989, Pharmacol. Rev. 41:3-52). Progress toward understanding the neural substrates of addiction to cocaine and other addictive drugs has mostly been limited to research with animal models. The use of such animal models, however, has been limited by the inability to correlate observed patterns of brain activation with subjective information about emotional and cognitive responses to drugs, such as euphoria or craving typically experienced after use of addictive drugs.
SUMMARY OF THE INVENTION
It has now been shown that a distinct pattern of brain activation is exhibited by humans during periods of craving induced by a psychostimulant. As determined by functional magnetic resonance imaging (fMRI), psychostimulant-induced craving (e.g., cocaine-induced craving) is strongly correlated with early, but sustained, signal changes (positive or negative) in the nucleus accumbens and in the amygdala. In contrast, as shown below, the cocaine-induced experience of rush is associated with a pattern of brain activation distinct from the pattern exhibited during cocaine-induced craving. As discussed in further detail below, the studies described herein demonstrate that (a) humans have the same extended neural network of reward circuitry as animals, and (b) this circuitry performs both reinforcement reward and incentive reward function (e.g., craving). These observations, along with (1) observations from animal studies, showing that drugs specific for D1 receptors alter reward processes in the brain and (2) observations regarding the distribution of dopamine receptor subtypes in the brain, indicate that agonists and antagonists of the D1-like receptors can be used to inhibit craving of psychostimulants in humans, with or without inhibition of euphoria. In addition, such agonists and antagonists can be used to inhibit craving of the stimulant nicotine, which is associated with intense craving and is predicted to induce patterns of brain activation that parallel those seen with psychostimulants such as cocaine.
Without being bound to any particular theory or mechanism, D1-like agonists (also referred to herein as “D1-like receptor agonists”) are thought to provide some or all of the sensations of rush and high associated with the use of a psychostimulant or nicotine, without leading to significant levels of further drug craving. Although a patient treated with a D1-like agonist may consume an initial quantity of a psychostimulant or nicotine, further craving of the addictive drug will be inhibited, thereby inhibiting binge-like drug consumption. D1-like antagonists are thought to inhibit initial cravings for psychostimulants or nicotine or to reduce the euphoria felt from psychostimulants or nicotine, thereby inhibiting the initiation of binge-like behavior.
Accordingly, the invention features a method for inhibiting a psychostimulant-induced craving in a human, which method entails identifying the human as being psychostimulant-dependent, and administering to the human a D1-like antagonist or D1-like agonist in an amount effective to inhibit craving of the psychostimulant. In various embodiments, the psychostimulant may be cocaine (including crack cocaine) or amphetamine.
In a related method, the invention features a method for inhibiting a nicotine-induced craving in a human, which method entails identifying the human as being nicotine-dependent, and administering to the human a D1-like antagonist or D1-like agonist in an amount effective to inhibit craving of nicotine (e.g., craving of nicotine-containing cigarettes). Typically, in practicing the methods of the invention, the patient (i.e., human) is a compulsive user of the psychostimulant or nicotine. The methods of the invention are particularly useful in inhibiting drug-induced craving, which is the craving experienced after drug use (e.g., within 15 seconds to 120 minutes).
Now that, as shown by the experiments described below, the psychostimulant-induced patterns of brain activation in humans and rodents are known to overlap each other closely, rodents (e.g., rats and mice (including knockout mice, such as knockouts of the D1 receptor or DAT transporter)) can be used as animal model systems for measuring the ability of a test compound to inhibit psychostimulant-induced or nicotine-induced craving in a human. This method of the invention entails administering the test compound to a rodent; administering a psychostimulant or nicotine to the rodent; and measuring an attenuation in the level of brain activation in the rodent subsequent to administration of (a) the test compound and (b) the psychostimulant or nicotine, as compared with the level of brain activation obtained upon (a) administration of the psychostimulant or nicotine to the rodent without (b) administration of the test compound, as a measure of the ability of the test compound to inhibit psychostimulant-induced or nicotine-induced craving in a human. In various embodiments, the psychostimulant can be cocaine (including crack cocaine) or amphetamine. The animal may be drug-naive, or it may be chronically addicted to a psychostimulant or nicotine by virtue of its having been repeatedly treated with the drug previously. Useful animal models of chronic addiction include, without limitation, (a) animals taught to self-administer drugs and (b) condition-place preference paradigms (where the readiness of an animal to go to a place where the animal has previously had the drug is measured). The test compound can be a known D1-like agonist or D1-like antagonist (such as those described herein), or it may be any compound of interest, such as uncharacterized small organic molecules of interest. The test compound typically is administered at a dosage of 0.0001 to 100 mg/kg of the body weight of the rodent. Typically, the test compound is administered to the animal 0 minutes to 2 days (e.g., 15 minutes to 8 hours) prior to administration of the psychostimulant or nicotine to the animal. The test compound can be administered to the animal in a single dose or in repeated doses (e.g., 1, 2, or 5 or more times daily) prior to administration of the psychostimulant or nicotine. The decrease in the level of brain activation can be measured by any of the various methods for measuring brain activations, such as functional MRI (with or without contrast agents such as monocrystalline iron oxide nanocolloid (MION) particles or gadolinium) and laser Doppler-flowmetry, as described above for example.
Examples of suitable D1-like antagonists for use in the methods of the invention include SCH 39166; SCH 23390; A-69024; bulbocapnine; butaclamol HCl, (+)-; fluphenzanine HCl; flupenthixol 2 HCl, cis-(Z)-, fluspirilene; haloperidol; SCH-12679; SKF-83566; thioridazine HCl; thiothixine HCl; trifluoperazine 2HCl; and trifluorperidol HCl. Examples of suitable D1-like agonists include A-86929; 6-chloro-PB HBr, (±)-(SKF 81297); SKF 38393; A-69024, N-allylnorapomorphine HBr, R(−)-; apomorphine HCl, R(−)-; 6-bromo-APB HBr, r(+)-; 6-Chloro-APB HBr,(±)-(SKF-82958); Pergolide methanesulfonate, and SKF 77434. Such agonists or antagonists can be administered to the patient or animal at a dosage of 0.0001 mg/kg to 100 mg/kg of the body weight of the patient or animal, and more typically at a dosage of 0.1 to 1.0 mg/kg of the body weight of the patient or animal. In a typical method of administration, the D1-like antagonist or D1-like agonist is administered to the patient or animal orally, intravenously, or intramuscularly. Typically, an initial dosage of the D1-like antagonist or D1-like agonist will be administered to the p
Breiter Hans C.
Kosofsky Barry E.
Mandeville Joseph B.
Marota John J. A.
Rosen Bruce R.
Fish & Richardson P.C.
Jones Dameron L.
The General Hospital Corporation
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