Figure 4.10 Drug Effects on Presynaptic Mechanisms Most drugs affect synaptic transmission Figure 4.10 Drug Effects on Presynaptic Mechanisms Local anesthetics block sodium channels and, therefore, block action potentials. Most drugs affect synaptic transmission. Presynaptic events are affected by drugs that: Affect transmitter synthesis enzymes. Affect transport (e.g. colchicine inhibits microtubule maintenance). Affect storage (e.g. reserpine inhibits catecholamine storage in vesicles) Prevent synaptic transmission (e.g. tetrodotoxin blocks Na+ channels, preventing action potentials). Alter release of neurotransmitter (e.g. amphetamine stimulates release of catecholamines). Neuromodulators affect either transmitter release or receptor response. Caffeine is an exogenous neuromodulator that blocks the effect of adenosine, an endogenous neuromodulator that normally inhibits catecholamine release. Caffeine stimulates catecholamine release, causing arousal. Adenosine is normally released along with the catecholamines and acts on autoreceptors—receptors on the same terminal that released it. Some drugs affect how long transmitters remain in the synapse (transmitter reuptake). They interfere with transporters, specialized proteins that return the transmitter to the presynaptic membrane (e.g., cocaine). Some drugs may also interfere with degradation, or the breakdown of neurotransmitters, causing neurotransmitters to have lasting effects. Cholinesterase inhibitors inhibit the breakdown of ACh at the synapse by the enzyme acetylcholinesterase (AChE), causing prolonged muscle contraction.

Figure 4.11 Drug Effects on Postsynaptic Mechanisms Postsynaptic receptors can be blocked or activated by drugs. Prolonged transmitter-receptor activity can alter behavior in profound ways.

The GABAA Receptor Has Many Different Binding Sites Picrotoxin, an antagonist, occurs naturally in the fruit of the Anamirta cocculus Allopregnanolone Valium Downers GABA Ionophore Several binding sites, that enhance or inhibit GABA’s effects. Benzodiazepines (valium) bind at an orphan receptor–no known endogenous ligand. Allopregnanolone, a steroid, is elevated during stress and is calming. Other neurosteroids (steroids produced in the brain) may act on GABAA sites. Alcohol’s effects are biphasic—an initial stimulant phase followed by a depressant phase. Alcohol activates GABAA receptors and increases inhibitory effects. This contributes to social disinhibition and loss of motor coordination.

Classification of drugs Stimulants - Amphetamines, Caffeine, Nicotine, Cocaine Depressants Analgesics: relieve pain, aspirin or opiates Narcotics: Opiates such as Heroine, Morphine, fentynal Non-narcotics: Aspirin, etc. Sedative Hypnotics: relax, induce sedation Alcohol (ETOH) Anxiolytics: Anti-anxiety agents, Valium Non-Barbiturates: Qualude, Halcion Barbiturates: Phenobarbital or Seconal Anti-Psychotics: Typical: Thorazine or Haldol Atypical: Clozapine Anti-Depressants: MAO Inhibitors: Parnate or Marplan Trycyclics: Tofranil SSRIs: Prozac, Zoloft Neuroactive (Psychogenic) Hallucinogens: LSD, PCP, Ecstasy Marijuana Inhalants – Nitrous Oxide

Drug Effects Amphetamine and methamphetamine: release of dopamine, norepinephrine and epinephrine even in the absence of action potentials Cocaine: increased levels of dopamine because cocaine binds to reuptake mechanism on presynaptic terminal MDMA (Ecstasy): increases in serotonin levels Opiates: such as hydrocodone (e.g., Vicodin), oxycodone (OxyContin, Percocet), bind to opioid receptors Delta (δ), Kappa (κ), Mu (μ) Marijuana or cannabis: cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) bind to Cannabinoid receptors CB1, CB2 Diazepam (Valium): binds to GABA receptors as an agonist SSRI fluoxetine (Prozac): blocks reuptake of serotonin Nicotine: Agonist at the nicotinic acetylcholine receptor

Medical Marijuana Reduces nausea and vomiting from chemotherapy Stimulation of hunger in AIDS patients Lowered intraocular eye pressure (shown to be effective for treating glaucoma) General analgesic effects (pain relief) Anxiety low doses tend to induce anxiolytic-like effects, i.e. reduce anxiety high doses often cause the opposite effect, can increase anxiety CBD in treating refractory childhood epilepsy Synthetic cannabinoids are available as prescription drugs Dronabinol (Marinol) synthetic THC, used to treat nausea and vomiting caused by chemotherapy Nabilone (Cesamet) used as an antiemetic and as an adjunct analgesic

Marijuana and Mental Illness Reefer Madness Increased risk of psychotic symptoms a greater risk in people who used cannabis most frequently (daily use) stronger in those with any predisposition for psychosis Although individuals may start using cannabis because of predisposition for mental illness recent studies show a cause and effect relationship Le Bec PY (2009) Encephale. 35(4):377-85. Ben Amar M (2007) J Psychoactive Drugs. 39(2):131-42.

Addictive Drugs Characteristics of Addictive drugs voluntarily self administered enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens (NAC) stimulate the functioning of brain reward circuitry (producing the “high” that drug users seek functionally these circuits are involved in regulation of hedonic “pleasurable” quality encoding attention reward expectancy incentive motivation

Short-term VS Long-term Effects of Drugs Short term, acute effects Immediate action of drug binding to receptors Cocaine increases dopamine levels which produces stimulation Long term, such as drug tolerance, addiction Neurons change because of drug exposure neuroplasticity to drug and its effects at dendrites, pre & post synapse, receptors changes to anatomy and chemistry neurotoxicity: damage to neurons

Reward Pathway Ventra Tegmental Area (VTA) to Nucleus Accumbens (NA) Release of Dopamine at NA VTA circuits Are inhibited by GABA via local circuits Get input from hypothalamus, frontal cortex NA circuits Excited by Dopamine, Glutamate, Opiates Input from limbic system and frontal cortex Role of mesolimbic dopamine (DA) systems to reward could be from Liking: the hedonic impact of reward Learning: learned predictions about rewarding effects Wanting: the pursuit of rewards by attributing incentive salience to reward-related stimuli supported by a majority of the evidence

Figure 4.21 A Neural Pathway Implicated in Drug Abuse

The Addicted Brain Drugs of abuse increase activity of the reward system Chronic drug use Structural and biochemical changes Decreased pleasure Increased craving Can last for years See figures in Scientific American article

Fig 3.15 Ionotropic - Metabotropic Neurotransmitters affect targets by acting on receptors—protein molecules in the postsynaptic membrane. Ionotropic receptors are fast—open an ion channel when the transmitter molecule binds. Metabotropic receptors are slow—when activated they alter chemical reactions in the cell, such as a G protein system, to open an ion channel. Receptor subtypes—the same neurotransmitter may bind to a variety of subtypes, which trigger different responses Receptors control ion channels in two ways: Ionotropic receptors open when bound by a transmitter (also called a ligand-gated ion channel). Metabotropic receptors recognize the transmitter but instead activate G proteins. G proteins, sometimes open channels or may activate another chemical to affect ion channels. The chemical is known as the second messenger—it amplifies the effects of the G protein and may lead to changes in membrane potential (The first messenger is the neurotransmitter). Neurotransmitters affect targets by acting on receptors—protein molecules in the postsynaptic membrane. Ionotropic receptors are fast—open an ion channel when the transmitter molecule binds. Metabotropic receptors are slow—when activated they alter chemical reactions in the cell, such as a G protein system, to open an ion channel.

Changes to reward pathway Structural Dendritic spines Size of synapses Receptor density Biochemistry CREB Delta Fos B

Other Addictions? Food addiction Sex addiction Gambling addiction Running addiction TV addiction Cell Phone addiction Internet Addiction Addicted To Love