Cocaine’s mode of action has been shown to involve the dopamine receptors. This paper will discuss how cocaine affects dopamine receptors, the mode of addiction, how cocaine affects the frontal brain metabolic activities, as well as the role of excitatory amino acids in cocaine’s mechanism. I will also discuss how cocaine affects another system through its mechanism on the brain—the renin angiotensin system.

Cocaine influences dopamine, norepinephrine and serotonin neurotransmission by inhibiting their reuptake. Pimozide, alpha-flupenthixol, perphenazine and chlorpromazine, all dopamine antagonists, were used to pre-treat rats in an attempt to demonstrate the reinforcing effects of dopamine. Because rats demonstrated a reduced rate of self-administration during extinction as well as after pre-treatment with antagonists, it is conceivable that dopamine receptors are involved in the reinforcing effects of cocaine (Hubner & Moreton, 1991).

Two dopamine receptors, B1 and B2, are believed to be involved in these rewarding effects of cocaine. Rats were trained to self-administer cocaine intravenously on a fixed-ratio (FR) 5 schedule of reinforcement. When these rats were pretreated with SCH23390, a D1 antagonist, and spiperone, a D2 antagonist, their response rates varied. At doses up to l0ug/kg, the rats exhibited an increased response rate; whereas at doses higher than this, the rats showed a decrease in their response rate. A similar decrease in response rate was produced when central dopamine containing neurons were destroyed with the neurotoxin, 6-hydroxy-dopamine (Hubner &Moreton, 1991).

The mode of action of the D1 receptor subtype is on adenylate cyclase. Upon activation, it stimulates activity of adenylate cyclase. Contrasting, to this, the stimulation of the D2 receptor either inhibits or does not have an effect on adenylate cyclase (Hubner & Moreton, 1991).

Progressive ratio schedules have been used to study the effects of different drugs or doses. The progressive ratio schedule is defined as increasing the ratio requirement (the number of responses needed to acquire an injection) following each reinforcement until there is no longer a response. The breaking point is the final ratio and is used to evaluate the efficacy of the reinforcer. Different motivational variables change the value of the breaking point. Increasing the dose of cocaine increases the value of the breaking point. On the other hand, pre-treating animals with spiperone or SCH23390 will decrease the breaking point. Therefore, it can be implied that both D1 and D2 receptors are needed to reinforce the effects of cocaine (Hubner & Moreton, 1991).

Cocaine has been Shown to block the reuptake of norepinephrine (NE) at the adrenergic nerve ending. Consequently, there is an increase in the postsynaptic stimulation of NE receptors and their target cells because of the increased levels at NE in the synapse. Cocaine’s effect on the adrenergic neurons themselves is inhibition (Dackis & Gold. 1987).

It has been reported that gestational exposure to cocaine results in long-term reductions in metabolic activity in the hypothalamus and limbic regions postnatally. There is also a reduced responsiveness to a catecholaminergic challenge, and an increase in the affinity of striatal dopamine D2 receptors. The adult animal who chronically uses cocaine has decreased dopamine levels in the frontal cortex and nucleus accumbens and reduced tyrosine hydroxylase immunoreactivity in the frontal cortex, tegmental area, and caudate nucleus (Rodriguez-Sanchez et.al., 1991).

These decreased dopamine levels could contribute to the addictiveness of cocaine. The definition of addiction is the compulsive use of a drug despite its adverse consequences. In the first few days of its use, dopamine levels are increased, whereas as mentioned above, chronic cocaine use decreases dopamine levels. Therefore, animals will continue to use cocaine to try to restore dopamine levels. This leads to an addiction to cocaine (Nestler, 1992).

In the brain, most types of neurotransmitter receptors present produce most of their physiological responses in target neurons through a complex cascade of intracellular messengers. G-proteins are included in these intracellular messengers. The G-proteins couple the receptors to intracellular effector systems, and the intracellular effector systems themselves. Protein kinases, proteine phosphatases, and phosphoproteins are all second messengers to the intracellular effector systems (Nestler, 1997).

The addiction to a drug develops gradually and progressively responding to the continued use of the drug. It can also persist long after the drug has been withdrawn. For these reasons, it is probable that the regulation of neuronal gene expression is of relevance to addiction. There have been experiments to demonstrate that changes in the activity of cAMP second messenger, G-protein, and protein phosphorylation pathway mediate important aspects of cocaine addiction in many brain regions responsive to drugs (Nestler, 1997).

Chronic use of cocaine has been found to decrease the levels of G--proteins and increase the levels of adenylate cyclase and cAMP dependent protein kinase in the nucleus accumbens (NAc). In other major dopaminergic systems in the brain such as the nigrostriatal system, which consists of dopaminergic neurons in the substantia nigra and their major projection region and the caudate-putamen, cocaine regulation of these intracellular messengers was not observed. Psychotropic drugs that do not have reinforcing properties do not regulate the G-proteins or cAMP system (Nestler, 1992).

Supersensitivity of NAc neurons to the inhibitory actions of D1-dopaminergic agonists, has been shown to be a consequence of chronic cocaine use. The occurrence of this supersensitivity is in the absence of consistent changes in the levels of D1 receptors. This suggests that post-receptor mechanisms are involved. The D1-receptor supersensitivity could be accounted for by the observed increase in adenylate cyclase and cAMP dependent protein kinase, with the decrease in Gi but not Gs (Nestler, 1992).

The mesolimbic dopamine system has also been observed to have a similar change in its levels of the same phosphoproteins. These phosphoproteins are named MCRPPs (morphine- and cocaine-regulated phosphoproteins). "TH" is one of the MCRPPs. Initial studies in vitrio showed an increase in levels of TH phosphorylation in the ventral tegmental area (VTA). This was subsequently shown to be a result of the drug-induced increases in the total amount of the enzymes, but not involving a change in its degree of phosphorylation. Contrasting to this, the chronic use of cocaine showed a decrease in the degree of phosphorylation of TH in the NAc without changing the total amount of the enzyme. Dephosphorylating TH decreases its catalytic activity; therefore the decreased activity in the NAc region can be attributed to this decrease in phosphorylation induced by cocaine. TH within the NAc is located within dopaminergic nerve terminals of axons which are projected from the VTA. Therefore, the enzyme can be regulated by cocaine differentially in cell body and nerve terminal regions of the mesolimbic dopamine system. There is a possibility that the effects of chronic cocaine use on intracellular messenger proteins represent part of the biochemical basis of long-term functional chances in the VTA-NAc pathway that modify the mechanisms of drug reward (Nestler, 1992).

There are certain genetic factors that play a role in drug addiction. Experimentally, there are some breeds of rats who prefer drugs more than others. Based on the data from the experiments, the drug-addicted or genetically drug-preferring state is associated with higher levels of TH and lower levels of neurofilaments in the VTA. There are also lower levels of Gi and GH and higher levels of adenylate cyclase and cAMP-dependent protein kinase in the NAc. The lower levels of the neurofilaments have been shown to be associated with decreased rates of axonal transport and decreased axonal caliber. All of the experiments point to the association of drug addiction to structural alterations responding to chronic exposure to psycho-stimulants. The altered responses the NAc neurons to other synaptic inputs may very well be one of the major changes in the brain that underlie drug addiction and craving (Nestler, 1992).

The disruption of the dopamine system is seen in both cocaine addicts and schizophrenics. Brain glucose metabolism has been shown to be a sensitive indicator of brain function. PET scans were used to measure brain glucose metabolism in cocaine abusers. One to six weeks following cocaine withdrawal, patients were observed to have a decreased brain glucose metabolism in the frontal cortex. Predominantly, the lowered metabolism occurred in the left frontal cortex. The left dorsal medial and left dorsal lateral regions were significantly lower. There was a negative correlation between the years of cocaine use and the metabolism of the dorsal medial cortex. In contrast to this, the brain glucose metabolism levels increased following the immediate withdrawal which was less than one week. There is also a decrease in the amount of cerebral blood flow in the frontal cortex. Chronic cocaine users also showed a higher frequency of cerebral blood flow (CBF) defects in the anterior brain areas as well as the left hemisphere. Chronic schizophrenics also have a fronted glucose hypometabolism. There are some similarities in the clinical presentation of schizophrenics and cocaine addicts. Anergia and anhedonia are symptoms of both. The two also involve the disruption of the dopamine system. When tested three to four months after cocaine withdrawal, the subjects still exhibited a decreased frontal metabolism. This suggests that these changes are long-term actions of cocaine in the human brain. There is not concrete evidence to show if the decreased metabolic activity in the frontal cortex is secondary to the decrease in CBF or whether it relates to cocaine’s direct action on the CNS tissue (Volkow et. al., 1992).

The releasing mechanism of dopamine in the striatum has been shown by experiments to involve excitatory amino acids (EAA). Extensive data also shows that there are numerous glutamatergic projections in the striatum, including afferents from corticostriatal and hippocampal-accumbens. There are synapses between the glutamatergic corticostriatal and dopaminergic nigrostriatal projections as well as common dendrites. It is these neuroanatomical relationships that provide a basis for the interaction between these two systems. Experimentally, anti-convulsant doses were selected for the doses of EAA antagonists. N-methyl-D-aspartate (NMDA) antagonists, both competitive and non-competitive, block the cocaine-induced stereotypy. In contrast to this the non-NMDA EAA antagonist, 6,7--dinitroquinoxaline (DNQH), was not effective. As a result of this experiment, it can be hypothesized that EAA involvement is selective for the NMDA component (Karler & Calder, 1992).

The local anesthetic activity of cocaine that induces convulsions and the dopaminergic effects, can be blocked by NMDA antagonists, CGS 19755 and dextromethorphan. The results from experiments with CGS 19755 and dextromethorphan indicate that doses that increase the NMDLA-convulsive threshold also increase the cocaine-convulsive threshold. Haloperidol in an anti-dopaminergic dose does not have an effect on either the NMDLA- or the cocaine-convulsive threshold. It can be implied from these findings that the convulsant effect of cocaine is not from the dopaminergic system but, rather, from the activation of EAA systems. Stereotypy, locomotor stimulation, and convulsions, all cocaine-caused effects, can be blocked by EAA antagonists. These effects appear to require excitatory receptor activation. Stereotypy and locomotor stimulation are stimulated by the dopaminergic activation of the caudate-putamen and nucleus accumbens, respectively. Glutamate afferents go to both of these structures; the caudate from the cortex, the nucleus accumbens from the hippocampus (Karler and Calder, 1992).

By cocaine’s actions in the brain, it affects many systems throughout the body. It affects renin secretion not by its effects on the cardiovascular system, but rather, by its effects on the brain. Van De Kar et. al. performed an experiment to evaluate whether the decrease in secretion was through peripheral or central mechanisms. They injected cocaine both intracerebro-ventricularly and intraperitoneally. Injections by using both of these methods produced a decrease in renin activity and concentration. The minimal dose to decrease the activity intraperitoneally was 5 mg/kg. whereas intracerebro-ventricularly it was 50 mg/kg. When cocaine was applied to the kidney tissue itself, it showed no marked decrease in renin secretion (Van De Kar et. al., 1992).

To determine whether the effect was from cocaine’s local anesthetic or cardiovascular actions, Van De Kar et. al. compared cocaine and procaine. When cocaine was injected intracerebro-ventricularly, there was a significant increase in blood pressure without having an effect on the heart rate. It also had a decreased plasma renin concentration 15 minutes after the injection. In contrast to this, when procaine was injected intracerebro-ventricularly, there was an increase in both blood pressure and renin secretion. When procaine and cocaine were injected intra-atrially, neither affected the blood pressure significantly. Cocaine reduced the plasma renin concentration while procaine did not have any effect. Cocaine also reduced heart rate whereas procaine did not. The intraperitoneal injection of cocaine and procaine did not significantly alter blood pressure or heart rate. Procaine increased and cocaine decreased renin secretion, but not as much as when injected intracerebro-ventricularly. Therefore, cocaine has a more potent effect when it is injected intracerebro-ventricularly than when it is injected intraperitoneally. It did not exhibit any effect when injected into the kidney itself. The results indicate that cocaine’s actions on renin secretion is not due to its local anesthetic activity because cocaine and procaine produced different results. It is probably due to a mechanism involving the CNS. An increase in blood pressure causes a decrease in renin secretion. However, it is not very likely that the hypertensive effects of cocaine cause the decrease in renin secretion. This is because intra-atrial and intraperitoneal injections decreased plasma renin concentrations without increasing blood pressure. The minimal dose that decreases renin secretion is 5-6 times lower than the minimal dose that significantly increases blood pressure (50ug/kg. versus 300ug/kg. Respectively). Procaine’s effect on blood pressure was to increase it, but it also increased renin secretion. Therefore, not every drug that increases blood pressure will decrease plasma renin concentration. Therefore, cocaine’s actions on renin secretion is through mechanisms involving the CNS and not its actions on the cardiovascular system.

In summary, cocaine affects many systems through its actions on dopamine. D1 and D2 receptors seem to be the primary receptors involved. The addictive properties con be attributed to the decreased levels of dopamine caused by chronic use of cocaine. Excitatory amino acids are also involved in some of the cocaine-induced effects. Frontal glucose metabolism is also affected by the disruption of the dopamine system. Cocaine affects other systems in the body through its mechanisms in the CNS. Renin secretion is one of them. Its level is decreased after exposure to cocaine, not due to its effects on the cardiovascular system, but due to its effects in the CNS.

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