Eugene A. Kiyatkin

Dopamine mechanisms of cocaine addiction

The ability of cocaine to induce a compulsive addictive behavior is the most astonishing feature of this drug. Attempting to understand the mechanisms underlying cocaines addictive properties, two major questions should be considered: a) why and how organisms interaction with cocaine results in the development of new, drug-seeking and drug-taking behavior and b) why and how cocaine maintains this behavior when the drug is available. Since a large body of neuropharmacological evidence suggest that the mesocorticolimbic dopamine (DA) system has exclusive importance for the development and maintenance of cocaine addictive behavior, and cocaine is known to interfere in activity of this brain system, examination of mesocorticolimbic DA activity during cocaine self-administration behavior may provide some clues for understanding the drugs additive properties and regulation of this maladaptive goal-directed behavior. The aim of this paper is to discuss the literature and own experimental data on cocaines action on the mesocorticolimbic DA system that may be involved in mediating its addictive properties. Based on these data, it is suggested that an inhibiting action of cocaine on reuptake of released DA, although essential, but not sufficient mechanism for the development and maintenance of addictive behavior. It is hypothesized, that coexistence of functionally antagonistic, inhibiting actions of cocaine on the mesolimbic DA release and reuptake of released DA may be responsible for biphasic fluctuations in DA transmission that appear to be a critical component of central oscillatory mechanism which drives and regulates cyclic drug-taking behavior.

Nociceptive Sensitivity/Behavioral Reactivity Regulation in Rats During Aversive States of Different Nature: Its Mediation by Opioid Peptides

To study the regulation of nociceptive sensitivity/behavioral reactivity in animals during aversive states of different nature, the changes of vocalization thresholds and tail-withdrawal latencies were investigated in rats in free behavior, during restraint stress, after acute trauma to an extremity and under intraperitoneal acetic acid administration. To understand opioid peptide involvement in mediation of the changes obtained, this analysis was also done during opiate receptor blockade by naloxone. The data on the modification of vocalization and movement reactivity as well as on the changes of suprarenal weight and gastric ulceration, produced in normal and naloxone-treated rats by innoxious stressogenic, noxious somatic and visceral stimulation are discussed in relation with: 1. the peculiarities of sensitivity and responsivity of animals to external stimuli in aversive environment; 2. the role of these changes in maintenance of an animals adaptive activity produced by environmental threat and their mediation by endogenous opioids; 3. the functional significance of the activation of endogenous opioidergic neurotransmission in organization, realization and modification of an animals adaptive activity, directed on behavioral escape from aversive environment as well as on satisfaction of actual biological and zoosocial needs, in regulation of precise conformity among homeostasis, behavior and variable environment.

Morphine-induced modification of the functional properties of ventral tegmental area neurons in conscious rat.

To elucidate the functional role of mesolimbocortical dopamine(DA)-containing and other mediator-specific neurons in mediation of different pharmacological effects of opiates, morphine (6 mg/kg, SC)-induced modification of spontaneous discharges of different types VTA-units and their changes during polymodal activating and aversive stimulation and spontaneous movement were studied in conscious, restrained rats. In presumed DA-containing neurons (D-type) prolonged increase of discharge rate, regularization of their pattern and decrease of firing changes during all types of external stimulation and spontaneous or stimulus-induced movement activity were found. This decrease of unit firing changes was connected with significant rising of atypical, compared with control conditions, firing inhibitions. Changes of presumed acetylcholine(ACh)-containing neurons (A-B type) properties were defined as prolonged and pronounced decrease of firing rate, intensification of bursting pattern and decrease of discharge changes during all types of stimulation used and animal movements. This decrease of discharge changes was associated with significant lowering of activations-typical for these units in control conscious animals and rising of firing inhibitions. In presumed ACh- or GABA-containing interneurons of C-type a significant decrease of firing rate, increase of activations and decrease of firing inhibitions, typical for these units in control conscious rats were found. The modifications of different VTA-unit functional properties are discussed in view of main pharmacological effects of opiates (sedation, analgesia, positive reinforcement, movement activation).

Neurobiological Background of Pain and Analgesia: The Attempt at Revaluation According to Position of the Organism's Adaptive Activity

The most adequate and successful way to understand the essence of any complex psychophysiological phenomenon, including pain, is obviously the study of its origin, its genesis, i.e., its biological background. Based on critical analysis of recent literature and our own electrophysiological, biochemical and pharmacological data we tried to overcome the difficulties and contradictions derived from the traditional reflex approach and analytical orientation in understanding the experimental investigation of pain-related problems and to determine the neurobiological background of pain and analgesia through the notion of the organisms adaptive activity. Interrelations between the notion of pain and other biological and psychological ideas, the place and functional significance of pain and endogenous analgesic mechanisms in the organization, maintenance and regulation of the organisms adaptive activity, characterization of the involvement of endogenous opioid peptides and monoamines in central processes associated with pain and analgesia, the essence and mechanisms of pain-depressing activity of the opiates are the main stages in our neurobiological consideration of the phenomenon of pain and its natural and pharmacological regulation.

Dopaminergic Involvement in Nociceptive Sensitivity/Behavioral Reactivity Regulation During Aversive States of Different Nature in the Rat

To investigate the involvement of dopamine (DA) in nociceptive sensitivity-behavioral reactivity regulation in animals during aversive states of different nature, the influence of pharmacologically-induced decrease and increase of DA neurotransmission on vocalization and movement reactivity were studied in rats in free behavior, during restraint stress, after acute trauma of an extremity and under intraperitoneal acetic acid administration. The influence of longterm increase (apomorphine in a high dose) and decrease (haloperidol, apomorphine in a low dose) on suprarenals weight and gastric ulceration in animals exposed by polymodal aversive stimulation was also studied. The data obtained are discussed in relation with; 1. DA involvement in regulation of nociceptive sensitivity and behavioral reactivity in aversive environment; 2. the role of DA and endogenous opioid peptides in endogenous analgesic mechanisms; 3. the functional significance of cerebral DA in organization and realization of various types of an organisms adaptive activity produced by different environmental and homeostatic variables; and 4. the interaction of DA and endogenous opioid peptides in mediation of this activity.

Morphine: Some Puzzles of Well-Known Substance

The study of morphines influence on vocalization and movement, nociceptive reactivity in rats in free behavior, during trauma of an extremity, intraperitoneal acetic acid administration and two-hour restraint allow us to reveal specific analgesic actions of this substance in doses comparable to that used for pain relief in man. This action consisted in the almost disappearance of trauma-induced hyperalgesia or a significant reduction of visceral stimulation-induced hypalgesia without any significant changes in movement reactivity depression typical to these states. Moreover, analysis or morphines influence on movement reactivity depression in free behaving rats of different groups or parts of one group previously housed in different aversive conditions allow to understand the reasons of variability in the action of opiates and the significance of previous living conditions in determination of their effects. Furthermore, the enhancement of morphines action on movement reactivity 3-4 hours after a single naloxone administration was observed, which indicates the possibility of artificial regulation of opiate effects by direct action on opiate receptors by naloxone. Subchronic naloxone administration (0.5 mg/kg, 3 times per day for 3 days) led to substantial and longterm enhancement of morphines depressive effect on movement reactivity (20 and 105 hours after the last naloxone use) and to decrease in movement reactivity depression typical to restraint stress.

Activation-induced changes in evoked and slow brain potentials: Effects of cocaine in awake rabbit

To study the interrelations between event-related potentials and brain activation, evoked responses to visual stimulation registered from occipital cortex and hippocampal CA1 region were investigated in awake animals administered cocaine (2 mg/kg, SC) or saline. Administration of COCA resulted in longterm significant changes in heart and breathing rates and spontaneous EEG (desynchronization in the occipital cortex and slow rhythmic theta activity in the hippocampus), inhibition of animal responses to noxious electroshock stimuli and modification in different amplitudes of evoked responses (mainly in the cortex, the enhancement of negativity and bidirectional changes in late slow phase). Principally identical but more or less changes were observed in response to administration of saline. Obtained results are discussed in respect to their interrelations with the general activation organisms response and the modification of brain metabolism induced by cocaine in restrained rabbits.

Long-Term Changes of Striatal D-2 Receptors in Rats Chronically Exposed to Morphine Under Aversive Life Conditions

Chronic morphine treatment has been shown to cause the development of hyperreactivity of the dopamine system detected as the increased behavioral and biochemical responses to the action of specific dopamine agonists. Furthermore, inverted changes in animal behavioral reactivity to the stimulation of presynaptic, proposed D-2 receptors by apomorphine in a low dose was found in our previous study when morphine was chronically used in animals under conditions of restraint. To estimate the nature and proposed receptor mechanisms of changes found in behavioral reactivity due to chronic morphine administration in aversive life conditions at the level of highly sensitive D-2 receptors, the density and affinity of [3H] spiroperidol binding sites was studied in these animals two weeks after the last opiate administration. Increased density and affinity of D-2 receptors probably indicating their hypersensitivity was found in animals chronically exposed to two-hour restraint stress, while a significant decrease in density accompanied by increase in affinity of these receptors was typical to rats chronically exposed to morphine under conditions of restraint. The data are discussed in aspects of quantitative and qualitative changes in D-2 receptors, and their proposed mechanisms and functional significance in the mediation of modified organisms functional state due to chronic opiate administration in different environmental conditions.

Activation-induced changes in evoked and slow brain potentials: Effect of cocaine in rabbits previously subchronically treated by cocaine

To study the type of adaptive modification (tolerance vs. sensitization) in different organisms indices following intermittent cocaine (COC) administrations, acute COC (2 mg/kg, SC)-induced changes in heart and breathing rate, response to increasing noxious stimulation, spontaneous EEG and event-related evoked and slow brain potentials (ERP) registered from the occipital cortex and hippocampal CA1 region were investigated in naive rabbits and one subchronically treated with COC (6 injections at a same dose). Tolerance developed for bradycardia, depression of noxious responsiveness, cortical desynchronization and increase of main components of cortical ERP, typical to acute COC, while the changes in breathing and hippocampal ERP were stable. These changes as well as a significant increase due to COC administrations of the basal values of an animals noxious responsiveness and increase in relative changes in main component of cortical ERP (N205) are considered as a consequence of adaptive changes in neurophysiological/neurochemical substrate accepting COC action and mediating phenomena tolerance-sensitization and dependence typical to the drug.