cyclic-gmp and Substance-Related-Disorders

Substance dependence is a chronic relapsing brain disorder associated with adaptational changes in synaptic plasticity and neuronal functions. The high levels of substance consumption and relapse rate suggest more reliable medications are in need to better address the underlying causes of this disease. It has been well established that the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) and their signaling systems play an important role in the molecular mechanisms of substance taking behaviors. On this basis, the phosphodiesterase (PDE) superfamily, which crucially controls cyclic nucleotide levels by catalyzing their hydrolysis, has been proposed as a novel class of therapeutic targets for substance use disorders. This chapter reviews the expression patterns of PDEs in the brain with regard to neural structures underlying the dependent process and highlights available evidence for a modulatory role of PDEs in substance dependence.

Topics: Animals; Brain; Cyclic AMP; Cyclic GMP; Humans; Molecular Targeted Therapy; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Substance-Related Disorders

This review concerns neuropharmacological properties of clonal cells from tumors in the nervous system and muscle, and/or somatic hybrid cells derived from these clonal preparations. These cells grow well under conditions of culture and show neuronal characteristics identical to those seen in normal cells. Observations of these clonal cells contribute to studies on development, differentiation, synaptogenesis and cellular recognition in the nervous system. Analysis of eukaryotic genes also enables investigations on genetic control mechanisms by which highly differentiated neuronal functions are expressed.

Topics: Adenylyl Cyclases; Animals; Cell Line; Cells, Cultured; Clone Cells; Cyclic AMP; Cyclic GMP; Drug Tolerance; Humans; Hybrid Cells; Membrane Potentials; Mice; Nervous System Neoplasms; Neuroblastoma; Rats; Receptors, Adrenergic, alpha; Receptors, Opioid; Substance-Related Disorders; Synapses; Synaptic Transmission

The distribution and functions of certain neurotransmitter substances seem to correlate with clinical, anatomical and physiological evidence about the mediation of normal and abnormal behaviors in man, though much remains to be learned. The biosynthetic and metabolic pathways, receptors and reuptake mechanisms, and relationships to cyclic nucleotides for several major neurotransmitters are characterized, as well as the specific actions of many behavior-modifying drugs employed clinically. Experimental systems, including nerve cells in culture, permit tests of molecular actions inferred from biochemical and neurophysiological analyses in intact brain. This selective review emphasizes advances in neurochemistry which provide a context for current and future research on neurological and psychiatric disorders encountered in clinical practice.

Topics: Affective Symptoms; Behavior; Biogenic Amines; Brain Chemistry; Cyclic AMP; Cyclic GMP; Deficiency Diseases; Humans; Neurochemistry; Neurons; Neurotransmitter Agents; Pain; Peptides; Prostaglandins; Proteins; Receptors, Drug; Schizophrenia; Substance P; Substance-Related Disorders; Synaptic Transmission

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.

Topics: Analgesics, Opioid; Animals; Calcium; Cyclic GMP; Dopamine; gamma-Aminobutyric Acid; In Vitro Techniques; Long-Term Potentiation; Morphine; Neurons; Nitric Oxide; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Substance-Related Disorders; Synapses; Synaptic Transmission; Ventral Tegmental Area

An alteration in serotonin concentration has been found in patients with chronic headache caused by abuse of analgesic substances as well as an up-regulation of 5HT2 platelet receptors, which has been correlated with chronicization of the headache. In a previous study we demonstrated an increase in L-arginine/nitric oxide (NO) pathway activity in platelets from patients affected by migraine with or without aura, particularly during attacks. In the present research we assessed the variations in platelet L-arginine/NO pathway and cyclic guanosine monophosphate (cGMP) levels in 32 patients affected by chronic daily headache (CDH) (8 M, 24 F, age range 34-50 years) both during and between attacks. In these same patients, the platelet aggregation to different collagen concentrations (0.3, 1, 3 micrograms/ml) was determined as well as the intracellular platelet calcium concentration using fluorescence polarization spectrometry. These parameters were compared with those of an age- and sex-matched control group (n = 25; n = 10, n = 15, age range 35-51 years). A reduction found in platelet aggregation response to each collagen concentration used (p < 0.001) was coupled with an increased NO and cGMP production (NO: p < 0.0001; cGMP: p < 0.001). This was accompanied by a significant increase in intracytosolic Ca2+ (p < 0.0001) concentration and a reduced platelet serotonin content compared to those in control individuals (p < 0.0002). Changes in the above platelet parameters were accentuated more in patients with analgesic abuse than in CDH patients with no drug abuse. These findings suggest the occurrence of an activation of cGMP-Ca2+ mediated events in CDH patients with analgesic abuse. This physiologic compensatory mechanism, which intervenes in overcoming the increase in cytosolic Ca2+ levels, is not as efficient at limiting serotonin depletion by platelet dense bodies. A similar depletion in the central serotoninergic pathway can be assumed in the same patients.

Topics: Adult; Analgesics; Blood Platelets; Calcium; Chronic Disease; Collagen; Cyclic GMP; Cytosol; Female; Headache; Humans; Male; Middle Aged; Nitric Oxide; Platelet Aggregation; Recurrence; Serotonin; Substance-Related Disorders

Female Sprague-Dawley rats were maintained on a diet of powdered food containing barbital for 8 weeks before the drug was abruptly withdrawn. Twenty-four hours later both barbital-dependent and control rats were injected intracerebroventricular (i.c.v.) with saline or one of four doses of kainic acid (KA) or in a separate experiment with saline or one of three doses of N-methyl-D-aspartic acid (NMDA) or of quisqualic acid (QA). After 4.5 min, the animals were killed by focused microwave irradiation, and the cerebella were collected. The levels of cyclic guanosine 3',5' monophosphate (cGMP) were markedly elevated in the cerebella of barbital-withdrawn rats when compared to controls. When compared to saline treatment, KA, at all dosages, resulted in a significantly greater elevation of cerebellar cGMP in the barbital-withdrawn rats than was induced by drug withdrawal alone. Only the two higher dosages of KA produced a significant elevation of this parameter in the control rats. Unlike KA, neither QA or NMDA produced any greater elevations of cGMP in barbital withdrawn rats than were induced by drug withdrawal alone. These collective results suggest that there is an increase in the response to KA but not QA or NMDA following the withdrawal of barbital from dependent rats.

Topics: Animals; Aspartic Acid; Barbital; Barbiturates; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Female; Injections, Intraventricular; Kainic Acid; N-Methylaspartate; Neuromuscular Depolarizing Agents; Oxadiazoles; Quisqualic Acid; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

Female Sprague-Dawley rats were maintained on a diet of barbital for 8 weeks, a period of time previously shown to result in tolerance to and dependence on the drug. After completing this course, the barbital was abruptly withdrawn and the selective antagonist of N-methyl-d-aspartate (NMDA), 2-amino-7-phosphonoheptanoic acid (APH), or saline was infused intracerebroventricularly over 48 hr. Control rats which had not received barbital, were similarly infused with either saline or APH. All animals were observed for 12-48 hr following the withdrawal of the barbital; spontaneous convulsions, previously reported to be numerous and severe after withdrawal of the drug, were counted and graded according to severity. Forty-eight hr after withdrawal of barbital, the rats were killed by focussed microwave irradiation and cerebellae were collected for later determination of levels of cGMP. Nine convulsions occurred in 29 rats withdrawn from barbital and infused intracerebroventricularly with APH, this contrasted markedly with 61 convulsions seen in 29 animals withdrawn from the drug and infused with saline. There was a 3-fold elevation of levels of cGMP in the saline-infused, barbital-withdrawn rats when compared to control rats infused with saline. This evaluation was markedly, although not completely, prevented by the intracerebroventricular infusion of APH. These data provide evidence that dicarboxylic amino acid pathways, specifically those acting through NMDA receptors, are involved in seizure activity seen following abrupt abstinence from barbital.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Aspartic Acid; Barbital; Barbiturates; Cerebellum; Cyclic GMP; Female; N-Methylaspartate; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

Studies of tissue culture cells and tissue slices have implicated the nucleotides, cyclic AMP and cyclic GMP, in the mechanism of action of opiates. However, there are little in vivo data to corroborate this hypothesis. We addicted rats to the synthetic opiate, methadone, by providing the drug in their drinking water (dosage 2.1 mg./kg./day). The two cyclic nucleotides were measured in four brain areas which contain a high concentration of opiate receptors: amygdala, neostriatum, periventricular grey, and thalamus. Data were obtained after acute exposure of the drug (1 day), tolerance (35 days), withdrawal (35 days on drug then 1 day off drug), and readjustment (35 days on drug then 21 days off drug). Cyclic GMP levels were low (0.03 pmol./mg. tissue) in the four regions and did not differ significantly during the experiment. Cyclic AMP levels were higher (1-3 pmol./mg.) and fluctuated consistently in the four regions. After acute methadone treatment, there was a reduction in cyclic AMP, which continued at lower levels after tolerance. One day of withdrawal led to increased cAMP, which rose to near control levels. After readjustment, the levels were reduced. These data indicate an involvement of cyclic AMP in the addiction and withdrawal processes in the intact animal.

Topics: Amygdala; Animals; Brain; Cerebral Ventricles; Corpus Striatum; Cyclic AMP; Cyclic GMP; Male; Methadone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Thalamus; Tissue Distribution

Rats exposed to chronic intake of sodium barbital maintained high circulating levels of barbital in blood and brain and exhibited increased sensitivity ot audiogenic convulsions during the withdrawal period. Levels of gamma-aminobutyric acid (GABA), glutamate, guanosine 3',5'-monophosphate (cyclic GMP) and adenosine 3',5'-monophosphate (cyclic AMP) were measured in selected brain regions after sacrifice with high power microwave inactivation. Cyclic GMP during chronic barbital administration was significantly lower than controls in most brain regions, especially the hindbrain. During the withdrawal period cyclic GMP in the cerebellum was significantly increased, while returning at least to control levels in all other regions. GABA throughout the brain tended to be reduced during barbital dependence, while cyclic AMP and glutamate levels remained unchanged in all groups. These results indicate a possible role for cyclic GMP in the mediation of the central nervous system response during barbiturate dependence and withdrawal.

Topics: Acoustic Stimulation; Animals; Barbital; Barbiturates; Brain; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Glutamates; Humans; Male; Rats; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Analgesics, Opioid; Animals; Brain; Caffeine; Cyclic AMP; Cyclic GMP; Drug Tolerance; Humans; Ileum; Models, Biological; Morphine; Neurons; Rats; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders

The effect of ethanol on cyclic nucleotide levels was investigated in male Sprague-Dawley rats. The rats were sacrificed by microwave irradiation, the brains were divided into four areas, and cyclic nucleotides were measured by radioimmunoassays. Administration of a single dose of ethanol per os produced a dose-dependent decrease of adenosine 3':5'-monophosphate (cyclic AMP) in cerebral cortex, cerebellum, pons and medulla oblongata while guanosine 3':5'-monophosphate (cyclic GMP) was decreased in all brain areas. Dependence on ethanol was induced by three daily administrations of ethanol p.o. for 7 days. The last dose of ethanol did not produce any decrease of cyclic AMP levels while the decrease of cyclic GMP levels was still present. During ethanol withdrawal cyclic AMP levels increased in cerebral cortex, pons and medulla oblongata and did not change in cerebellum. Changes of cyclic AMP in subcortex were more complex. Cyclic GMP levels increased during ethanol withdrawal in cerebellum, pons and medulla oblongata and did not change in cerebral cortex and subcortex. These results indicate that changes of cyclic nucleotides might participate in the mechanism of ethanol dependence and withdrawal.

Topics: Animals; Behavior, Animal; Brain Chemistry; Cerebellum; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Ethanol; Humans; Male; Medulla Oblongata; Pons; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Topics: Adrenergic beta-Antagonists; Animals; Cyclic AMP; Cyclic GMP; Cycloheximide; Drug Tolerance; Humans; Mice; Morphine; Naloxone; Phosphodiesterase Inhibitors; Substance Withdrawal Syndrome; Substance-Related Disorders; Theophylline