Drug dependence types , causes and mechanism of action

Drug dependence pharmacology

1. drug dependence ( Cellular and molecular mechanism )

2. Drug Dependence Dependence is a compulsive craving that develops as a result of repeated administration of the drug. As per WHO, A state psychic and sometimes also physical , resulting from interaction between a living organism and a drug characterized by behavioural and other changes that includes a compulsion to take the drug on a continuous or periodic basis to avoid its psychic effects and sometimes to avoid the discomfort. Drug abuse : compulsive and excessive use of habit forming drugs or substances, leading to addiction or dependence, serious physiological injury. All dependence producing drugs activates mesolimbic dopaminergic pathway.

3. Types of drug dependence:- 1.Psychic dependence :- A condition in which a drug produces A feeling of satisfaction A Psychic drive that require periodic or continuous administration of the drug. 2.Physical dependence:- Its a state in which A body achieves an adaptive state Causes physical disturbances when the drug is withdrawn. Withdrawal syndrome varies in type and intensity for different classes. 3.Combined dependence :-it involves both psychic and physical dependence terms. An overpowering desire to continue taking the drug in spite of knowing its harmful effects. A tendency to increase the dose. A high tendency to withdrawal syndromes.

4. Withdrawal Syndrome withdrawal of the psychoactive drugs produces distorted homeostasis leading to the development of a withdrawal syndrome.(discontinuation syndrome). It is a set of symptoms of variable degree of severity which occur on cessation or reduction of psychoactive drugs. A withdrawal syndrome is one of the indicators of a dependence syndrome. Example, the alcohol withdrawal syndrome is characterized by tremor, sweating, anxiety, depression, nausea and malaise.

5. Drugs known to cause dependence I . Drugs that cause sever psychic and physical dependence: Opiate or morphine type: Morphine and its congeners Codeine, Dihydromorphinone and Heroin, synthetic morphine substituents like Meperidine. Alcohol barbiturate type: Ethyl alcohol, Barbiturates, Paraldehyde, Benzodiazepines and Meprobamate. Nicotine (tobacco) II. Drugs cause definite psychic but mild or questionable physical dependence: Opiate antagonist type: Nalorphine (morphine antagonist) Amphetamine type : Amphetamine, Methamphetamine and Phenmetrazine. III. Drugs that cause only psychic dependence : Cocaine, LSD, Cannabis and Caffeine.

6. Mesolimbic pathway Mesolimbic pathway ( reward pathway) is a dopaminergic pathway in the brain which connects ventral tegmental area located in the midbrain to the nucleus accumbens. The mesolimbic pathway releases dopamine into the nucleus accumbens and stimulates rewarding system. Abused drugs [alcohol, opiates, Δ 9 tetrahydrocannabinol ( Δ 9 - THC), and psychostimulants, including nicotine] interact with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. In nucleus accumbens, ∆FosB functions as a master control protein in the development of drug addiction. Once it is overexpressed it triggers series of transcription events that ultimately produce an adaptive state.

7. Cannabis (marijuana) Cannabis is one of the oldest known psychoactive plant. It is obtained from the Hemp plants, Cannabis sativa Cannabis indica The active ingredients are present in the resinous exudate of the tops of the female plants. The psychoactive principle of cannabis is known as ∆-9-tetrahydrocannabinol (THC). Cannabinoids are less liable than opiates, nicotine and alcohol to cause dependence having long term psychological effects .

8. Cannabinoid receptor: ∆THC acts on the CB1 (central) and CB2 (immune cells) cannabinoid receptors. Ligands for these receptors proteins include Endocannabinoids (produced naturally in the body by animals) eg. Anandamide, 2- Arachidonoyl glycerol Phytocannabinoids (found in the cannabis species) eg. ∆ THC Synthetic cannabinoids (manufactured artificially) eg. Naphthoylindole, Phenacetylindole.

9. Mechanism of action of cannabinoids CB1R is a G protein-coupled receptor located in the central and peripheral nervous system. Activated by the endocannabinoid neurotransmitters Anandamide and 2- Arachidonoyl glycerol or by THC. CB1R is linked via Gi protein it inhibits adenylate cyclase and voltage operated calcium channels and activates G-protein-sensitive inward-rectifying potassium channels(GIRK) causing hyperpolarization and inhibits neurotransmitter release. CB1R also influences gene expression both directly by activating mitogen-activated protein kinase and indirectly by reducing the activity of protein kinase A as a result of reduced adenylate cyclase activity.

10. Molecular mechanism of cannabinoid dependence : prolong exposure of cannabinoids on several components of the brain neuronal circuits lead to cause dependence via 1)Synaptic plasticity: Neuronal circuits and their elements undergo important adaptation due to addictive drugs by Modulating the number and strength of neuron-neuron connections Synaptic plasticity (the dynamic adjustment of synaptic efficacy occurring in response to environmental or internal stimuli) Endocannabinoids supresses presynaptic glutamate release leading to a depolarization-induced suppression of excitation(DSE) and inhibit presynaptic GABA release leading to depolarization suppression of inhibition (DSI), both effects lasts for 1 minute. THC acts via presynaptic CB1 receptor to inhibit release of glutamate and GABA in the striatum and cause long term form of synaptic plasticity like long term potentiation (LTP) and long term depression(LTD). This effect can last for hours or weeks.

11. 2) Changes in CB1R density and function: CB1R is coupled to G-proteins of the Gi class, which implies its activation and inhibits adenylate cyclase and voltage gated Ca++ channels and activate K+ channel and hinders synaptic transmission. Uncoupling and downregulation of brain CB1R after prolonged THC exposure plays key role in development of cannabinoid addiction and tolerance. Repeated THC exposure reduces coupling efficacy of CB1R to Gi transduction proteins, the receptors gets desensitized .

12. 3) Signalling cascades: The  MAPK/ERK pathway   is a chain of  proteins  in the  cell  that communicates a signal from a  receptor  on the surface of the cell to the  DNA  in the nucleus of the cell. The signal starts when a signalling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division The members of the mitogen-activated protein kinase(MAPK) signalling system, such as MEK1/2, JNK(c-Jun N-terminal kinase)and ERK (extracellular signal regulated kinases) are major modulators of cell functions, including proliferation, differentiation and survival. Cannabinoids increase concentration of MAPK due to which this MAPK/ERK1/2 cascade pathway gets activated which alters gene expression.

13. signs of abuse/dependence Anger or Aggression Decreased Appetite / Weight Loss Irritability Nervousness / Anxiety Restlessness Sleep Difficulties / Strange Dreams

14. Drugs used for treatment: Dronabinol (Acts as an agonist & It reduces symptoms of withdrawal syndrome and reduces use of cannabis) Encaptone (It is used to decrease cannabis cravings) Divalproex Buspirone R ecent pre-clinical studies suggest the potential of FAAH inhibitors such as URB597, endocannabinoid metabolising enzymes