Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug

Gillis, Richard A.; Hernandez, Y. M.; Erzouki, Hashim K.; Raczkowski, V. F. C.; Mandal, Aloke K.; Kuhn, Frederick E.; Dretchen, Kenneth L.

doi:10.1016/0376-8716(94)01087-2

Cited by 42 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A further increase in skin temperature points to a post-stimulation increase in heat dissipation. In light of the known vasoconstrictive action of cocaine (Gillis et al 1995;Williams and Wasserberger 2006), it is surprising that acute decrease in skin temperature following its iv administration was quantitatively similar (but more prolonged) to that occurring with natural arousing stimuli. In contrast to the very tight correlation between basal brain and muscle temperatures, such a correlation was much weaker for skin temperature (Fig.…”

Section: Brain Temperature As a Sensitive Index Of Brain Metabolic Acmentioning

confidence: 99%

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

Smirnov

Kiyatkin

2008

Brain Research

View full text Add to dashboard Cite

Marijuana smoking dramatically alters responses to various environmental stimuli. To study this phenomenon, we assessed how delta-9-tetrahydrocannabinol (THC), a primary psychoactive ingredient of marijuana, affects locomotor and brain (nucleus accumbens or NAcc), muscle and skin temperature responses to natural arousing stimuli (one-min tail-pinch and one-min social interaction with another male rat) and iv cocaine (1 mg/kg) in male rats. THC was administered at three widely varying doses (0.5, 2.0 and 8.0 mg/kg, ip), and the drug-induced changes in basal values and responses to stimuli were compared to those occurring following ip vehicle injections (control). Each stimulus in control conditions caused acute locomotor activation, a prolonged increase in brain and muscle temperature (0.6-1.0°C for 20-50 min) and transient decrease in skin temperature (−0.6°C for 1-3 min). While THC at any dose had a tendency to decrease spontaneous locomotion as well as brain and muscle temperatures, true hypothermia and hypoactivity as well as clearly diminished locomotor and temperature responses to all stimuli were only seen following the largest dose. In this case, temperature decreases in the NAcc were stronger than in the muscle, suggesting metabolic brain inhibition as the primary cause of hypoactivity, hypothermia and hyporesponsiveness. While weaker in strength and without associated vasodilatation, this response pattern is mimicked by general anesthetics, questioning to what extent the hypothermic action of THC is specific (i.e., mediated via endogenous cannabinoid receptors) or non-specific, reflecting drug interaction with membrane lipids or other receptors. In contrast, weaker behavioral and temperature effects of THC at lower doses resemble those of diazepam, whose locomotion-and temperature-decreasing effects are evident only in activated conditions, when rats are moving and basal temperatures are elevated. Keywords brain metabolism; brain and body temperature; cannabinoids natural arousing stimuli; intravenous cocaine; vasoconstriction

show abstract

Section: Brain Temperature As a Sensitive Index Of Brain Metabolic Acmentioning

confidence: 99%

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

Smirnov

Kiyatkin

2008

Brain Research

View full text Add to dashboard Cite

show abstract

“…Although a central mechanism was not always confirmed in certain animal models (Gillis et al, 1995), a more recent study in human subjects seemed to support the role of the CNS (Vongpatanasin et al, 1999). The results of this study support the concept of a central component since pretreatment with central administration of hemicholinium-3 blocked the subsequent pressor response to intravenous administration of cocaine.…”

Section: Central Pressor Response To Cocaine 189mentioning

confidence: 48%

“…In fact, agonists at central ␣ 2 -adrenergic receptors such as clonidine and ␣-methyldopa are effective antihypertensive drugs; and levodopa and other dopaminergic antiParkinson agents often produce orthostatic hypotension as a side effect. Also, systemic administration of cocaine has been reported to decrease sympathetic nervous activity (Knuepfer and Branch, 1992;Gillis et al, 1995;Abrahams et al, 1996). Yet, there have been instances when cocaine has been administered directly into the CNS, usually via the cerebrospinal fluid, that the drug elicits an increase in arterial blood pressure.…”

Section: Introductionmentioning

confidence: 99%

“…Whereas cocaine conforms to this classification both in the peripheral and central nervous systems, the role of the CNS in terms of blood pressure alterations has been debated (Knuepfer et al, 1993;Gillis et al, 1995;Bernards, 1996). In fact, agonists at central ␣ 2 -adrenergic receptors such as clonidine and ␣-methyldopa are effective antihypertensive drugs; and levodopa and other dopaminergic antiParkinson agents often produce orthostatic hypotension as a side effect.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Importance of Brainstem Cholinergic Neurons in the Pressor Response to Cocaine

Buccafusco¹,

Davis²,

Shuster³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

After intracisternal injection, 140 nmol (48 g) of cocaine (but not lidocaine or procaine) evoked an increase in mean arterial pressure (MAP) of 41 mm Hg. The increase in MAP began within 1 min after injection and lasted 10 to 15 min. The pressor response to intracisternal injection of cocaine was not mediated through central ␣-adrenergic receptors, but intracisternal pretreatment with D1 or D2 dopamine receptor antagonists shortened the duration of the response. Pretreatment with intracisternal injection of hemicholinium-3 to deplete medullary acetylcholine produced a dose-dependent inhibition of the pressor and tachycardic responses to intracisternal injection of cocaine. Central pretreatment with hemicholinium-3 also inhibited the pressor response to intravenous injection of 0.5 mg/kg cocaine. Atropine pretreatment was only partly effective in blocking the pressor and tachycardic responses to intracisternal injection of cocaine. However, a single intracisternal injection of the nicotinic ganglionic receptor blocker hexamethonium inhibited the pressor response to cocaine administered intracisternally 24 h later, and on each of the following 4 days. The blocking effect of hexamethonium was not mimicked by the ␣7 selective antagonist methyllycaconitine or by the ␣4␤2 subtype-preferring antagonist dihydro-␤-erythroidine. The data suggest that the pressor response to cocaine is mediated by medullary acetylcholine release on to nicotinic receptors of the ganglionic type, enhancing the output of bulbospinal sympathetic premotor neurons. Our results provide new evidence for the prolonged inactivation of relevant central nicotinic receptors by nicotinic receptor antagonists, and suggest that such compounds might be used safely for cocaine overdose, as well as for antiabuse issues without the concern for autonomic side effects.The ability of cocaine to increase systemic blood pressure usually is considered to be commensurate with drug's pharmacological classification as an indirect-acting sympathomimetic amine. Whereas cocaine conforms to this classification both in the peripheral and central nervous systems, the role of the CNS in terms of blood pressure alterations has been debated (Knuepfer et al., 1993;Gillis et al., 1995;Bernards, 1996). In fact, agonists at central ␣ 2 -adrenergic receptors such as clonidine and ␣-methyldopa are effective antihypertensive drugs; and levodopa and other dopaminergic antiParkinson agents often produce orthostatic hypotension as a side effect. Also, systemic administration of cocaine has been reported to decrease sympathetic nervous activity (Knuepfer and Branch, 1992;Gillis et al., 1995;Abrahams et al., 1996). Yet, there have been instances when cocaine has been administered directly into the CNS, usually via the cerebrospinal fluid, that the drug elicits an increase in arterial blood pressure. However, based upon the requirement for relatively high doses to elicit a pressor response via the lateral ventricular route (Knuepfer et al., 1993), it is unlikely that forebrain str...

show abstract

“…[5][6][7][8][9][10] Second, cocaine is known to be a potent inhibitor of norepinephrine reuptake, which constitutes the major mechanism for modulating the activity of the agonist at the postsynaptic receptor. [11][12][13] Third, cocaine has been shown to have direct effects to impair baroreflex functions independently of autonomic effects. 14,15 Finally, cocaine has local anesthetic properties 16 that constitute its most common therapeutic application.…”

mentioning

confidence: 99%

Role of Cardiac Nerves in the Cardiovascular Response to Cocaine in Conscious Dogs

2001

View full text Add to dashboard Cite

Background-Although the cardiovascular toxicity of cocaine is well recognized, considerable controversy remains as to the relative contribution of local norepinephrine reuptake inhibition versus central stimulatory effects of cocaine in eliciting its cardiovascular actions. The purpose of the present study was to determine the role of cardiac nerves in mediating the left ventricular (LV) and coronary hemodynamic responses to cocaine. Methods and Results-We studied the cardiovascular response to acute cocaine administration (1 mg/kg) in 10 intact, conscious dogs and 6 dogs with ventricular denervation (VD). There were no significant differences in baseline hemodynamic parameters or plasma catecholamines between the 2 groups. In response to acute cocaine, LV and coronary hemodynamic responses were enhanced in the VD dogs. The enhanced systemic pressor and heart rate responses in VD dogs suggest that cardiac nerves mitigate the response to cocaine through ventricular mechanoreceptors rather than mediating the responses. Conclusions-These data suggest that peripheral blockade of norepinephrine reuptake is not the principal mechanism of the acute cardiac effects of cocaine. Rather, cardiac nerves modulate the effects of cocaine through baroreflex mechanisms. Thus, individual differences in baroreflex sensitivity may explain the hemodynamic variability observed in response to cocaine. (Circulation. 2001;103:1674-1680.)

show abstract

Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug

Cited by 42 publications

References 23 publications

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

The Importance of Brainstem Cholinergic Neurons in the Pressor Response to Cocaine

Role of Cardiac Nerves in the Cardiovascular Response to Cocaine in Conscious Dogs

Contact Info

Product

Resources

About