Basis For Dependence

The production of dependence (physical) by the depressant drugs is thought to result from an adaptation of the CNS to the altered environment due to chronic drug use. In the case of the depressant drugs the CNS is believed to establish a new homeostatic state by supersensitivity of the pathways involved, counteracting the drug depression. When the drug is discontinued the depressive effect is removed and dramatic withdrawal symptoms result from this supersensitivity. Since opiates act on specific opiate receptors the withdrawal symptoms are relatively specific, whereas withdrawal from a general depressant such as alcohol produces more marked and generalised symptoms. The supersensitivity has been proposed to result from a number of changes in the depressed pathways that are not mutually exclusive:

(1) Receptor supersensitivity

(2) Unmasking of other neuronal pathways

(3) Synthetic enzyme induction, increasing transmitter levels

(4) Nucleotide changes or coupling to receptor increasing receptor sensitivity

(5) Membrane depolarisation

None of these are mutually exclusive and they may all relate to a common mechanism. Figure 23.2 shows a schematic diagram of how the adaptation of the CNS to a depressant drug can lead to the symptoms of dependence. There is an extensive literature showing that physical withdrawal can be reduced or prevented by drugs acting on related inhibitory systems (e.g. clonidine acting on the G-protein linked a2-adrenoceptor counters the withdrawal from opioid receptor agonists — the mu opioid receptor has very similar effector mechanisms to the a2-receptor). Furthermore, withdrawal can be reduced by a large range of drugs that block excitatory systems such as excitatory amino-acid receptor antagonists, calcium channel blockers, etc.

Most of the work has been based on opioids since it is the easiest system to manipulate as administration of the antagonist, naloxone, precipitates withdrawal. Here, the idea that physical dependence results from opposing changes in the neuronal systems depressed by the drug of dependence is borne out by consideration of the acute effects of an opioid and the withdrawal symptoms. They are mirror images of each other:

Opioid Dependence Digram

Figure 23.2 A schematic diagram illustrating the ways in which the CNS counters the depressant effects of a drug such as alcohol or an opioid and how this leads to the manifestation of physical dependence when there is abstinence from the drug. These excitatory compensations produce symptoms opposite to the acute effects of the drug

Figure 23.2 A schematic diagram illustrating the ways in which the CNS counters the depressant effects of a drug such as alcohol or an opioid and how this leads to the manifestation of physical dependence when there is abstinence from the drug. These excitatory compensations produce symptoms opposite to the acute effects of the drug

Acute effects

Analgesia Depressed reflexes Feeling of warmth Anxiolysis Constipation Drying up of secretions

Symptoms of withdrawal

Spontaneous aches and pains Spontaneous twitches (kick the habit) Feeling of cold (cold turkey) Anxiety and paranoia Diarrhoea

Lacrimation, runny nose, salivation

Although these symptoms last for several days and are not pleasant, they are not that different from a bad cold with influenza yet clearly will be a deterrent to discontinuing the use of a drug. However, a number of people go through withdrawal and yet then go back to the drug. Thus, it is felt that the psychological effects of drugs are critical aspects as are the social issues that interact with continued drug use.

The psychological effects of drugs are poorly understood but involve dopamine systems in the CNS. It is thought that drugs can cause psychological dependence by interactions with dopamine systems that mediate learning so that drug use becomes a learned behaviour. The circuits important in this centre on the nucleus accumbens. The nucleus has inputs from a number of cortical regions and, in turn, projects to the septum, frontal and cingulate cortex and the hypothalamus. The inputs to the accumbens that are thought to be critical for dependence are the dopamine pathways from the ventral tegmental area. Dopamine modulates activity in the nucleus accumbens and these pathways have been implicated in some of the positive symptoms of schizophrenia. In the context of drug dependence of a psychological type, increases in dopamine activity in the VTA are thought to reinforce behaviours occurring at the time. Drug administration becomes associated with environmental cues, such as the paraphenalia associated with the drug and the location where the drug is used. Also the physical and psychological effects of the drug become reinforcing. Thus, electrical stimulation of these areas is rewarding and drug self-administration in animals is reduced by lesions or dopamine receptor antagonists applied to this area. Interestingly, all drugs with psychological dependence liability, despite very different pharmacological actions, produce similar cravings and all increase dopamine activity in the VTA. This is due to release in the case of amphetamine-like drugs and cocaine, via direct depolarisation of the neurons in the case of nicotine. Increased dopamine activity results from disinhibition (of GABA neurons) with alcohol, opioids and cannabinoids although the latter drugs, befitting the mild cravings they produce, only slightly increase activity.

The increased dopamine hypothesis is supported by findings of gene induction in the target areas and the indications that individual differences in dopamine receptors and transporters may underlie impulsive and addictive behaviour in humans. Studies in knock-out mice have, however, provided evidence for complex roles of 5-HT in these processes.

Human data fit well with these ideas since it is very clear that following prolonged drug use the context of the use of the agent has huge importance. Heavily dependent US soldiers in Vietnam during the war, perhaps up to 20% of the troops, were using opium but gave up easily on their return home, where the conditions of war were removed. Many dependent drug users go through physical withdrawal and then re-use the drug when they return to where they took the drug previously, whereas those who move away can do much better in keeping off the drug.

Figure 23.3 Types of drug users and some of the factors that may lead to use of drugs. The triangle represents a simple model whereby three main types of users can be identified—any individual can be at any point on the lines

Continue reading here: Major Problems Of Drug Dependence And Abuse

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