Cocaine Bupropion

There are many pieces of evidence that indicate the rapid disappearance of DA following electrical stimulation observed in brain slices is due to uptake. The rate of disappearance of DA is far too quick in comparison to diffusion. Also, when the effect of diffusion through the thin Nation film is removed, no time lag between stimulation and DA uptake is observed in the disappearance as would be expected for diffusion [43]. Additionally, well-studied DA uptake inhibitors including bupropion, cocaine, and nomifensine [46,47], both in vivo and in brain slices, affect the rate of clearance. Lastly, a strain of mice was created that had the gene for DA transporter deleted [48]. In brain slices prepared from these uptake-deficient animals, stimulated DA remained in the extracellular fluid on a time scale consistent with that predicted for diffusion. 

A meta-analysis of placebo-controlled studies by Levin and Lehman (1991) showed that desipramine produced greater cocaine abstinence than placebo. Although a more recent review did not concur (Lima et al. 2001), secondary analyses of studies with imipramine, desipramine, and bupropion suggested that depressed cocaine abusers are more likely to show significant reductions in cocaine abuse than nondepressed cocaine abusers (Margolin et al. 1995 Nunes et al. 1991 Ziedonis and Kosten 1991). Furthermore, recent work with desipramine supported its efficacy in opioid-dependent patients, particularly in combination with contingency management therapies (Kosten et al. 2004 Oliveto et al. 1999). 

Margolin A, Kosten TR, Avants SK, et al A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients. Drug Alcohol Depend 40 125— 131, 1995... 

Isolated seizures that are not epilepsy can be caused by stroke, central nervous system trauma, central nervous system infections, metabolic disturbances (e.g., hyponatremia and hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures I or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsy-chotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Cone EJ (1995) Pharmacokinetics and pharmacodynamics of cocaine, J Anal Toxicol 19 459-78 Cryan JF, Bruijnzeel AW, Skjei KL, Markou A (2003) Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat. Psychopharmacology 168 347-358... 

Dopamine-Stimulating Medications. A variety of drugs that increase the availability of dopamine have been studied in cocaine addicts including L-DOPA, bupropion, amantadine, and methylphenidate. In small uncontrolled trials, these have shown some benefit, but definitive studies have yet to be performed. In addition, some dopamine-stimulating medications (in particular, the stimulants like methylphenidate or the amphetamines) are themselves subject to abuse, though, of note, this is typically not a problem when they are prescribed to patients who do not have a history of substance abuse such as, for example, in the treatment of attention deficit-hyperactivity disorder. 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

AMPHETAMINES BUPROPION 1. t plasma concentrations of these substrates, with risk of toxic effects 2. t risk of seizures. This risk is marked in elderly people, patients with a history of seizures, those with an addiction to opiates/ cocaine/stimulants, and those with diabetes treated with oral hypoglycaemics or insulin 1. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 2. Bupropion is associated with a dose-related risk of seizures. These drugs that lower seizure threshold are individually epileptogenic. They have additive effects when combined 1. Initiate therapy with these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. amphetamines) 2. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis)... 

Some antidepressants, notably mazindol and bupropion (3), inhibit the dopamine transporter (DAT) as well as NET or SERT. The DAT is best known, however, as one of the principal sites of action of the psychostimulant drug cocaine. Mice that are genetically engineered to knock out the expression of the DAT gene are profoundly hyperactive and fail to show any further stimulation of activity in response to cocaine or (-i-)-amphetamine (109). Such animals, nevertheless, will continue to self-administer cocaine (110), suggesting that the rewarding properties of the... 

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