Tolerance cocaine

Dependence and withdrawal can occur with all of the stimulants. Cocaine is one of the most strongly reinforcing drugs in self-administration paradigms in animals and also has a psychological withdrawal syndrome. A typical pattern of withdrawal includes a ravenous appetite, exhaustion, and mental depression, which may last for several days after the drug is withdrawn. Because tolerance develops quickly, abusers may take large doses, compared with those used medically, for example, as anorexiants. 

A formal diagnosis of substance dependence requires a maladaptive pattern of abuse that leads to clinically significant impairment or distress. More detailed criteria revolve around the development of tolerance, the experience of withdrawal when abstinence is required, the inability to stop using the drug, and continued use over a protracted period of time. The question is whether or not these criteria, clearly applicable to cocaine, heroin, and other drugs, are met by caffeine. 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

Aloyo V., Pazalski P., Kirifides A., Harvey J. Behavioral sensitization, behavioral tolerance, and increased 3II WIN 35,428 binding in rabbit caudate nucleus after repeated injections of cocaine. Pharmacol. Biochem. Behav. 52 335, 1995. 

Cocaine Clinically used as a local anaesthetic during eye surgery recreational use widespread tolerance develops readily highly addictive, especially crack cocaine severe potential problems similar to amphetamine users often become suspicious and paranoid, displaying antisocial and troublesome behaviour patterns. 

In neurochemical terms, amphetamine and cocaine boost monoamine activity. Amphetamine has a threefold mode of action first, it causes dopamine and noradrenaline to leak into the synaptic cleft second, it boosts the amount of transmitter released during an action potential and third, it inhibits the reuptake of neurotransmitter back into presynaptic vesicles. These three modes all result in more neurotransmitter being available at the synapse, thus generating an increase in postsynaptic stimulation. Cocaine exerts a similar overall effect, but mainly by reuptake inhibition. The main neurotransmitters affected are dopamine and noradrenaline, although serotonin is boosted to a lesser extent. These modes of action are outlined in Chapter 3, and the neurochemical rationale for drug tolerance is covered more fully in Chapter 10. The main differences between amphetamine and cocaine are their administration routes (summarised above) and the more rapid onset and shorter duration of action for cocaine. 

Other knockout models that could be used to validate candidate genes include mice that lack monoamine oxidase A (MAO-A), which have demonstrated altered behavior and alcohol tolerance [54]. Transgenic mice in which the dopamine transporter gene has been deleted show striking hyperactivity via enhanced persistence of dopamine which is not altered by cocaine or amphetamine administration [55]. Knockouts of the serotonin IB receptor are also available and are best used as models of vulnerability to drug abuse [56]. 

Tolliver BK et al. Genetic analysis of sensitization and tolerance to cocaine. J Pharmacol Exp Ther 1994 270(3) 1230-1238. 

Upregulation of the cAMP pathway may be a common mechanism by which a number of neuronal cell types respond to chronic opiates and develop tolerance and dependence (see Ch. 56). There is also evidence that similar mechanisms involving alterations in the cAMP second-messenger and protein phosphorylation pathway may mediate aspects of addiction to other types of drugs of abuse, for example, cocaine and alcohol [66],... 

The hydrochloride salt is inhaled or injected. It can be converted to cocaine base (crack or rock) and smoked to achieve almost instant absorption and intense euphoria. Tolerance to the high develops quickly. The high from snorting can last 15 to 30 minutes the high from smoking can last 5 to 10 minutes. 

Coca-cola got its name from the coca leaf extract which it contained (as did a variety of wines) until 1904. Neither tolerance nor physical addiction to cocaine seem to occur, so sniffing it occasionally should be quite safe. 

Addiction is a prominent problem with cocaine use. Cocaine is highly reinforcing to both animals and humans, probably through inhibition of dopamine reuptake in mesolimbic systems and stimulation of brain areas known to subserve behavioral reinforcement (Kiyatkin and Stein 1995 Woolverton and Johnson 1992 Ritz et al. 1987). Although sensitization to the stimulant effects occurs in animals, humans do not sensitize to the euphoric effects of cocaine but develop a tolerance (O Brien 1996). In animals and humans alike, self-administration often follows a binge pattern, consisting of repeated use over a period of hours or days until the supply is used up. 

LSD produces a rapid and complete tolerance, but it is not powerfully reinforcing the way drugs of abuse like cocaine and heroin are. LSD does not produce any known withdrawal syndrome (Abraham et al. 1996). It does not produce positive reinforcement in animal self-administration models. Concurrently in humans, it does not lead to patterns of repeti-... 

Cao YJ, Bhargava HN. (1997). Effects of ibogaine on the development of tolerance to antinociceptive action of mu-, delta-, and kappa-opioid receptor agonists in mice. Brain Res. 752(1-2) 250-4. Cappendijk SL, Dzoijic MR. (1993). Inhibitory effects of ibogaine on cocaine self-administration in rats. EurJ Pharmacol. 241(2-3) 261-65. 

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