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Continuous cocaine administration produces persisting changes in brain neurochemistry and behavior
Source: Brain Research 1991 Jun;552(1):27-35.
Author: Zeigler S, Lipton J, Toga A, Ellison G.
PubMed ID: 1655167
Abstract:
ABSTRACT: Rats were administered either continuous cocaine, daily injections of cocaine, continuous amphetamine, or no drug for 5 days and then given a 30 day drug-free recovery period. When subsequently tested in open field, the daily cocaine injection animals were the most hyperactive whereas the cocaine pellet animals were the most fearful. In vitro autoradiography was then utilized to examine persisting changes in receptor binding for D2 ([3H]spiperone), D1 ([3H]SCH23390), bensodiazepine ([3H]flunitrazepam), 5-HT1 ([3H]5-HT), 5-HT2 ([3H]ketanserin), and muscarinic acetylcholine (ACh) receptors ([3H]QNB:quinuclidinyl benzilate). In the amphetamine pellet animals, there were large increases in [3H]spiperone binding in several dopamine (DA)-rich regions; these were accompanied by conversely decreased [3H]SCH23390 binding. Cocaine pellet animals showed a completely different pattern, with appreciable increases in [3H]flunitrazepam binding in DA-rich areas, cortex, and amygdala but decreased [3H]QNB binding in DA-rich areas, hippocampus, and amygdala. While cocaine injection animals showed elevated D2 ([3H]spierone) binding in caudate and substantia nigra, they had generally smaller changes in most brain regions than the other drug groups. These findings replicate and extend previous reports that continuous drug administration induces long-lasting alterations in brain chemistry, but indicate that continuous cocaine has enduring effects on different neurochemical systems from continuous amphetamine. INTRODUCTION: Chronic abuse of the psychomotor stimulants amphetamine and cocaine can result in profound disturbances of personality and behavior and may, if prolonged, produce a psychotic state resembling paranoid schizophrenia. Cocaine is similar to AMPH in its ability to elicit sympathomimetic effects, increased motor activity and motor stereotypy, and inthe production of a paranoid-like stat with continuous use. This is becoming of increasing concern due to the popularity of freebasing and consequent nearly contiuous use patterns like bingeing. Furthermore, as is the case with AMPH, repeated but spaced intermittent dosage with cocaine results in persistent sensitization to its locomotion and stereotypy-eliciting effects. Although continuous cocaine will produce a behavioral progression similar to that found with AMPH, it appears to be much more potent in producing the late stage hallucinatory like behaviors than is continuous AMPH. METHODS: In order to study the possible neurotoxic effects of cocaine in a manner which approximates the binge pattern of administration which develops in the human abuser, we have employed a subcutaneous slow-release silastic pellet containing cocaine base which allows a fairly steady release rate over several days yet, because the drug is released over a very large surface area, avoids the problems of skin necrosis and lesions at the release site commonly encountered with subcutaneous cocaine injections or minipump administration. Following 5 days of chronic drug administration, a 30 day drug-free period was given, a period considered sufficient to assure that results would demonstrate long-lasting changes unrelated to transient withdrawal effects. The drug-free period was followed by a both a behavioral measure and autoradiographic study of brain using a variety of ligands. Autoradiographic studies seem well suited for initial investigation of long term drug induced changes, as they allow for the sampling of a variety of brain regions and neurotransmitters. A daily cocaine injection group was included in order to test the possibility of different effects from the different drug regimens, as has been demonstrated with AMPH. RESULTS: The greatest changes were clearly in the AMPH pellet animals, which showed a significantly heightened spiperone binding over controls in a number of DA-rich areas. The AMPH animals also displayed increased [3H]spiperone binding in the 2 hippocampal samples, in amygdala, and in cortex. When the animals were tested in the open field 30 days after cessation of drug administration, some of the largest behavioral alterations in the drug-treated groups were observed in the COC-INJ animals, which had received 5 daily injections of cocaine followed by the 30 day recovery period. These animals locomoted and reared the most of all groups when tested alone, and also displayed the most social and exploratory behaviors when tested in pairs. Yet, of all the drug-treated groups, these COC-INJ rats showed the least alterations in brain receptor density across all ligands, being almost indistinguishable from controls. DISCUSSION: Since AMPH and cocaine are both powerful central stimulants which induce a paranoid-like psychosis when administered continuously over prolonged periods and which both increase stimulation at DA receptors in brain, it might have been anticipated that prolonged and continuous administration of either of these two drugs might induce similar long-term alterations in brain chemistry and behavior Yet the present results indicate that this is clearly not the case. The results from autoradiography ligands show that the COC-PLT animals of this experiment evidenced a pattern of long-term alterations which was clearly distinct both from the changes observed in the intermittent cocaine and the continuous AMPH animls and in fact, represents one never previously reported.
Source: Brain Research 1991 Jun;552(1):27-35.
Author: Zeigler S, Lipton J, Toga A, Ellison G.
PubMed ID: 1655167
Abstract:
ABSTRACT: Rats were administered either continuous cocaine, daily injections of cocaine, continuous amphetamine, or no drug for 5 days and then given a 30 day drug-free recovery period. When subsequently tested in open field, the daily cocaine injection animals were the most hyperactive whereas the cocaine pellet animals were the most fearful. In vitro autoradiography was then utilized to examine persisting changes in receptor binding for D2 ([3H]spiperone), D1 ([3H]SCH23390), bensodiazepine ([3H]flunitrazepam), 5-HT1 ([3H]5-HT), 5-HT2 ([3H]ketanserin), and muscarinic acetylcholine (ACh) receptors ([3H]QNB:quinuclidinyl benzilate). In the amphetamine pellet animals, there were large increases in [3H]spiperone binding in several dopamine (DA)-rich regions; these were accompanied by conversely decreased [3H]SCH23390 binding. Cocaine pellet animals showed a completely different pattern, with appreciable increases in [3H]flunitrazepam binding in DA-rich areas, cortex, and amygdala but decreased [3H]QNB binding in DA-rich areas, hippocampus, and amygdala. While cocaine injection animals showed elevated D2 ([3H]spierone) binding in caudate and substantia nigra, they had generally smaller changes in most brain regions than the other drug groups. These findings replicate and extend previous reports that continuous drug administration induces long-lasting alterations in brain chemistry, but indicate that continuous cocaine has enduring effects on different neurochemical systems from continuous amphetamine. INTRODUCTION: Chronic abuse of the psychomotor stimulants amphetamine and cocaine can result in profound disturbances of personality and behavior and may, if prolonged, produce a psychotic state resembling paranoid schizophrenia. Cocaine is similar to AMPH in its ability to elicit sympathomimetic effects, increased motor activity and motor stereotypy, and inthe production of a paranoid-like stat with continuous use. This is becoming of increasing concern due to the popularity of freebasing and consequent nearly contiuous use patterns like bingeing. Furthermore, as is the case with AMPH, repeated but spaced intermittent dosage with cocaine results in persistent sensitization to its locomotion and stereotypy-eliciting effects. Although continuous cocaine will produce a behavioral progression similar to that found with AMPH, it appears to be much more potent in producing the late stage hallucinatory like behaviors than is continuous AMPH. METHODS: In order to study the possible neurotoxic effects of cocaine in a manner which approximates the binge pattern of administration which develops in the human abuser, we have employed a subcutaneous slow-release silastic pellet containing cocaine base which allows a fairly steady release rate over several days yet, because the drug is released over a very large surface area, avoids the problems of skin necrosis and lesions at the release site commonly encountered with subcutaneous cocaine injections or minipump administration. Following 5 days of chronic drug administration, a 30 day drug-free period was given, a period considered sufficient to assure that results would demonstrate long-lasting changes unrelated to transient withdrawal effects. The drug-free period was followed by a both a behavioral measure and autoradiographic study of brain using a variety of ligands. Autoradiographic studies seem well suited for initial investigation of long term drug induced changes, as they allow for the sampling of a variety of brain regions and neurotransmitters. A daily cocaine injection group was included in order to test the possibility of different effects from the different drug regimens, as has been demonstrated with AMPH. RESULTS: The greatest changes were clearly in the AMPH pellet animals, which showed a significantly heightened spiperone binding over controls in a number of DA-rich areas. The AMPH animals also displayed increased [3H]spiperone binding in the 2 hippocampal samples, in amygdala, and in cortex. When the animals were tested in the open field 30 days after cessation of drug administration, some of the largest behavioral alterations in the drug-treated groups were observed in the COC-INJ animals, which had received 5 daily injections of cocaine followed by the 30 day recovery period. These animals locomoted and reared the most of all groups when tested alone, and also displayed the most social and exploratory behaviors when tested in pairs. Yet, of all the drug-treated groups, these COC-INJ rats showed the least alterations in brain receptor density across all ligands, being almost indistinguishable from controls. DISCUSSION: Since AMPH and cocaine are both powerful central stimulants which induce a paranoid-like psychosis when administered continuously over prolonged periods and which both increase stimulation at DA receptors in brain, it might have been anticipated that prolonged and continuous administration of either of these two drugs might induce similar long-term alterations in brain chemistry and behavior Yet the present results indicate that this is clearly not the case. The results from autoradiography ligands show that the COC-PLT animals of this experiment evidenced a pattern of long-term alterations which was clearly distinct both from the changes observed in the intermittent cocaine and the continuous AMPH animls and in fact, represents one never previously reported.