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Author Topic: Cocaine tolerance: behavioral, cardiovascular, neuroendocrine functions in men  (Read 3069 times)

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Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men.

April 1998

Some excerpts follow ...


Cocaine tolerance was assessed by comparing the acute effects of cocaine in drug-abstinent men who reported occasional cocaine use (n = 6) and in men who met DSM-III-R diagnostic criteria for dependence on both cocaine and opiates (n = 6).

Peak plasma cocaine levels were equivalent in the two groups, and pharmacokinetic analyses revealed no significant differences in cocaine levels at any time.

Cocaine induced a significantly greater increase in ACTH in the occasional cocaine users than in the cocaine dependent men (p < .01).

Heart rate and systolic and diastolic blood pressure increases after cocaine were also significantly greater in the occasional cocaine users than in the cocaine-dependent men (p < .05). These neuroendocrine and physiologic differences were paralleled by significantly greater subjective reports of "high" and "euphoria" by the occasional cocaine users (p < .03 to .0001).

These data are consistent with the conclusion that tolerance to cocaine's physiologic, neuroendocrine, and subjective effects may occur as a function of chronic use.

Cocaine and Opiate Interactions

It is also possible that the preexisting condition of dual dependence on both opioids and cocaine contributed to the results observed. There is considerable clinical evidence that cocaine dependence is often associated with concurrent opiate abuse and dependence (Condelli et al 1991; Gastfriend et al. 1993; Kosten et al. 1989, 1987; Schottenfeld et al. 1993).

Moreover, controlled clinical studies report that methadone maintenance may enhance the subjective effects of cocaine in experienced users under some conditions (Foltin et al. 1995; Preston et al. 1996). Although opiate dependence in a drug-free individual (as in the present study) and concurrent maintenance on an opiate (as in the studies by Foltin et al. 1995; Preston et al. 1996) are not equivalent conditions, these clinical data are more consistent with the possibility that opioid exposure may increase, rather than decrease, the acute effects of cocaine.

Preclinical studies often indicate that opiates increase, rather than decrease, the effects of cocaine on some behavioral endpoints. For example, pretreatment with mu receptor selective opioids potentiated cocaine's discriminative stimulus effects in squirrel monkeys (Spealman and Bergman 1992, 1994). Similarly, in rhesus monkeys, pretreatment with the mu opioid agonist fentanyl and morphine increased cocaine's discriminative stimulus effects in some monkeys (Negus et al., in press).

Experimental studies in rodents have demonstrated that opiate administration may induce locomotor sensitization after administration of cocaine or amphetamines (DuMars et al. 1988; Kalivas 1985; Vezina et al. 1989; Vezina and Stewart 1990).

In addition, opiate administration before cocaine administration may facilitate rather than inhibit cocaine-conditioned place preferences (Bilsky et al. 1992) and conditioned reinforcement (Cunningham and Kelley 1992).

One important mechanisms underlying opiate-cocaine cross sensitization may be related to the effects of both drugs on the cyclic adenosine monophosphate AMP system (Cunningham et al. 1997).

Because men who were concurrently dependent upon heroin and cocaine had significantly lower cardiovascular and neuroendocrine responses to intravenous cocaine administration than the occasional cocaine users, opiate-induced sensitization to cocaine effects is unlikely to account for the different responses observed in the current study.

The significant differences in cocaine-induced increments in plasma ACTH levels in occasional cocaine users and cocaine-dependent men were paralleled by statistically significantly greater increments in heart rate and diastolic blood pressure and the perception of “high” and “euphoria” in the occasional cocaine users than in cocaine and opiate-dependent men.

Cocaine and ACTH Interactions

It has been postulated that cocaine-related stimulation of corticotrophin releasing factor (CRF) may be one mechanism underlying the reinforcing properties of cocaine in experimental animals and humans (Borowsky and Kuhn 1991b; Calogero et al. 1989; Levy et al. 1991; Mendelson et al. 1992a, b; Moldow and Fischman 1987; Rivier and Vale 1987; Sarnyai et al. 1992; Teoh et al. 1994; Vescovi et al. 1992).

Several studies that have assessed sensitization and tolerance associated with chronic cocaine administration to rodents did not reveal any significant degree of tolerance for cocaine-induced stimulation of ACTH. Borowsky and Kuhn found no changes in cocaine-stimulation of ACTH after 3 and 7 days of chronic cocaine administration to rats (Borowsky and Kuhn 1991a). Levy et al. (1992) also did not observe any changes in ACTH stimulation after cocaine administration for 14 days.

The differences observed in this study between occasional cocaine users and men with concurrent cocaine and opiate dependence and data obtained with rodents may reflect species differences. However, the cocaine-dependent men who participated in this study reported a very long duration (mean 8.83 years) of heavy cocaine use.

It is possible that chronic cocaine administration for up to 14 days may not be long enough to result in tolerance for cocaine-induced ACTH stimulation in rodents.

There is evidence that synthetic CRF administration has a number of cocaine-like effects, including induction of stereotyped behaviors and increased locomotor activity (Dunn and Berridge 1990). Recent studies have demonstrated that some cocaine-induced changes in the behavior of rodents can be modulated by blockade of corticosterone secretion (Marinelli et al. 1997).

Moreover, adrenalectomy completely eliminated cocaine self-administration in rats (Goeders and Guerin 1996), a finding consistent with the notion that ACTH (and by inference CRF) may be important for cocaine's reinforcing effects. We have previously observed that maintenance on buprenorphine, an opioid mixed agonist-antagonist, suppressed both cocaine-induced euphoria and ACTH secretion in humans (Mendelson et al. 1992a).

Buprenorphine also reduced cocaine self-administration by rhesus monkeys (Mello and Mendelson 1993, 1995; Mello et al. 1989, 1990).

The current observations that cocaine induces greater increments in ACTH secretion and greater behavioral and cardiovascular responses in occasional cocaine users than in men with a past history of cocaine and heroin dependence suggests that there is a relationship between neuroendocrine, cardiovascular, and behavioral tolerance for cocaine in humans.

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I do not condone or support any illegal activities. All information is for theoretical discussion and wonder.
All activities discussed are considered fictional and hypothetical. Information of all discussion has been derived from online research and in the spirit of personal Freedom.


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