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Effects of joint cocaine and ethanol on the brain opioid systems

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posted on 2024-09-02, 18:28 authored by Åsa Rosin

Concurrent abuse of cocaine and alcohol is common among human addicts, where 85% of all cocaine users have also been shown to meet the criteria for alcohol dependence. Concurrent abuse of cocaine and alcohol is associated with a more severe dependence and a more pronounced abstinence than using either drug alone.

The neurobiological basis for the high frequency of concurrent use of cocaine and alcohol is not known, but the drug combination causes an increased and prolonged euphoria as compared to when either drug is taken alone which suggests that the two drugs may interact. Features shared by cocaine and ethanol are their ability to increase dopamine concentrations in the mesolimbic dopamine pathway.

Closely connected to the mesolimbic dopamine system and involved in the effects of cocaine and ethanol is the endogenous opioid system. To investigate possible common mechanisms of concurrent cocaine and ethanol, the effects of separate as well as combined cocaine and ethanol on the endogenous opioid system and on die dopamine system were investigated.

An acute challenge of cocaine and ethanol in combination significantly increased the prodynorphin mRNA expression in the striatum and nucleus accumbens (NAcc), with a potentiated effect in the dorsolateral striatum. On the other hand, the combination of cocaine and ethanol down-regulated kappa-opioid receptor mRNA levels in the striatum, NAcc, ventral tegmental area (VTA) and substantia nigra compacta with an additive effect in NAcc core. In addition, the combination of cocaine and ethanol produced a general decrease of kappa-Opioid receptor protein levels while increasing p-opioid and ORL 1 receptors throughout the brain. No effects on deltareceptors were detected in any of the treatment groups. These results show that initially both cocaine and ethanol affect prodynorphin and kappa-opioid receptor mRNA expression as well as µ-, kappa-opioid and ORL 1 receptor levels.

Chronic ethanol administration and a subacute cocaine treatment significantly down-regulated kappa-opioid receptor mRNA in the VTA and the NAcc separately and in combination, while two days of "binge" cocaine administration did not effect µ- opioid receptor mRNA expression in the NAcc. Further, pretreatment of ethanol caused a potentiated effect of cocaine-induced dopamine release in the NAcc, an effect that may be related to the increased euphoria produced by this drug combination in humans.

The decreased expression of kappa-opioid receptor mRNA levels in the NAcc and VTA after ethanol administration might influence the enhanced effect of cocaine-induced dopamine output in the NAcc after ethanol pre-treatment. This is supported by the data showing that blockade of kappa-opioid receptors by locally applied nor-BNI increased dopamine release in the nucleus accumbens following chronic ethanol administration. Conversely, kappa-opioid receptor stimulation with U50, 488H had less impact on the dopamine release in ethanol pre-treated rats as compared to the control group.

Taken together, these studies show that ethanol potentiates the cocaine-induced dopamine release in the NAcc, in combination with alterations on the dynorphin/kappa- opioid receptor system. Together these alterations might influence the probability of a continued drug intake.

List of scientific papers

I. Rosin A, Lindholm S, Franck J, Georgieva J (1999). Downregulation of kappa opioid receptor mRNA levels by chronic ethanol and repetitive cocaine in rat ventral tegmentum and nucleus accumbens. Neurosci Lett. 275(1): 1-4.
https://doi.org/10.1016/S0304-3940(99)00675-8

II. Rosin A, van der Ploeg I, Georgieva J (2000). Basal and cocaine-induced opioid receptor gene expression in the rat CNS analyzed by competitive reverse transcription PCR. Brain Res. 872(1-2): 102-9.
https://doi.org/10.1016/S0006-8993(00)02481-1

III. Lindholm S, Rosin A, Dahlin I, Georgieva J, Franck J (2001). Ethanol administration potentiates cocaine-induced dopamine levels in the rat nucleus accumbens. Brain Res. 915(2): 176-84.
https://doi.org/10.1016/S0006-8993(01)02847-5

IV. Rosin A, Kitchen I, Georgieva J (2003). Effects of single and dual administration of cocaine and ethanol on opioid and ORL1 receptor expression in rat CNS: an autoradiographic study. Brain Res. 978(1-2): 1-13.
https://doi.org/10.1016/S0006-8993(03)02674-X

V. Rosin A, Hurd Y, Georgieva J (2005). Acute ethanol and cocaine co-administration differentially affects brain prodynorphin and kappa-opioid receptor mRNA expression. [Submitted]

VI. Lindholm S, Rosin A, Dahlin I, Georgieva J, Franck J (2005). Ethanol alters the effect of kappa receptor ligands on dopamine release in the nucleus accumbens. [Submitted]

History

Defence date

2005-11-01

Department

  • Department of Clinical Neuroscience

Publication year

2005

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-441-4

Number of supporting papers

6

Language

  • eng

Original publication date

2005-10-11

Author name in thesis

Rosin, Åsa

Original department name

Department of Clinical Neuroscience

Place of publication

Stockholm

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