Biomedical subjects

Eugene A Kiyatkin

Publications and source records attributed to Eugene A Kiyatkin.

At least 19 recordsLinked to original sources

PubMed2006

The role of peripheral and central sodium channels in mediating brain temperature fluctuations induced by intravenous cocaine.

While cocaine's interaction with the dopamine (DA) transporter and subsequent increase in DA transmission are usually considered key factors responsible for its locomotor stimulatory and reinforcing properties, many centrally mediated physiological and psychoemotional effects of cocaine are resistant to DA receptor blockade, suggesting the importance of other non-DA mechanisms. To explore the role of cocaine's interaction with Na+ channels, rats were used to compare locomotor stimulatory and temperature (NAcc, temporal muscle and skin) effects of repeated iv injections of cocaine (1 mg/kg) with those induced by procaine (PRO 5 mg/kg), a short-acting local anesthetic with negligible effect on the DA transporter, and cocaine methiodide (COC-MET 1.31 mg/kg), a quaternary cocaine derivative that is unable to cross the blood-brain barrier. While PRO, unlike cocaine, did not induce locomotor activation, it mimicked cocaine in its ability to increase brain temperature following the initial injection and to induce biphasic, down-up fluctuations following repeated injections. This similarity suggests that both these effects of cocaine may be driven by its action on Na+ channels, a common action of both drugs. While COC-MET also did not affect locomotor activity, it shared with cocaine and PRO their ability to increase brain temperature but failed to induce temperature decreases after repeated injections. These findings point toward activation of peripheral Na+ channels as the primary mechanism of rapid excitatory effects of cocaine and inhibition of centrally located Na+ channels as the primary mechanism for transient inhibitory effects of cocaine. DA receptor blockade (SCH23390+eticlopride) fully eliminated locomotor stimulatory and temperature-increasing effects of cocaine, but its temperature-decreasing effects remained intact. Surprisingly, DA receptor blockade also altered the temperature fluctuations caused by PRO and COC-MET, suggesting that some of the central effects triggered via Na+ channels are in fact DA-dependent. Finally, repeated administration of PRO to animals that had previous cocaine experience led to conditioned locomotion and potentiated temperature-increasing effects of this drug. It appears, therefore, that, in addition to the central effects of cocaine mediated via interaction with the DA transporter and potentiation of DA uptake, interaction with peripheral and central Na+ channels is important for the initial physiological and, perhaps, affective effects of cocaine, likely contributing to the unique abuse potential of this drug.

Anesthetics, Local↗

PubMed2006

Stability of substantia nigra pars reticulata neuronal discharge rates during dopamine receptor blockade and its possible mechanisms.

It is hypothesized that substantia nigra pars reticulata neurons become overactive during a deficit of dopamine transmission. In this study, we examined how acute dopamine receptor blockade (SCH23390 and eticlopride) affects impulse activity of substantia nigra pars reticulata neurons and their response to iontophoretic gamma-amino-n-butyric acid in awake, unrestrained rats. No changes in discharge rate were found during complete dopamine receptor blockade, but these neurons showed a diminished response to gamma-amino-n-butyric acid, suggesting gamma-amino-n-butyric acid receptor hyposensitivity. This may result from tonic increase in gamma-amino-n-butyric acid input from the striatum and globus pallidus, which are activated during dopamine receptor blockade. As substantia nigra pars reticulata neurons are autoactive and resistant to tonic increases in gamma-amino-n-butyric acid input, changes in their responsiveness to phasic gamma-amino-n-butyric acid inputs, not tonic increase discharge rate, may underlie movement disturbance following dopamine deficit.

Action Potentials↗

PubMed2006

General anesthesia as a factor affecting impulse activity and neuronal responses to putative neurotransmitters.

Although it is evident that general anesthesia should affect impulse activity and neurochemical responses of central neurons, there are limited studies in which these parameters were compared in both awake and anesthetized animal preparations. We used single-unit recording coupled with iontophoresis to examine impulse activity and responses of substantia nigra pars reticulata (SNr) neurons to GABA, glutamate (GLU), and dopamine (DA) in rats in awake, unrestrained conditions and during chloral hydrate anesthesia. SNr neurons in both conditions had similar organization of impulse flow, but during anesthesia, they have lower mean rates and discharge variability than in awake conditions. In individual units, discharge rate in awake, quietly resting rats was almost three-fold more variable than during anesthesia. These cells in both conditions were highly sensitive to iontophoretic GABA, but the response was stronger during anesthesia. In contrast to virtually no responses to GLU in awake conditions, most SNr neurons during anesthesia were excited by GLU; the response occurred preferentially in slow-firing units, which were atypical of awake conditions. Consistent with no postsynaptic DA receptors on SNr neurons, iontophoretic DA was ineffective in altering discharge rates in awake conditions, but often induced weak excitations during anesthesia. Although SNr neurons are autoactive, generating discharges without any excitatory input (i.e., in vitro), their impulse activity and responses to natural neurochemical inputs are strongly affected by general anesthesia. Some alterations appear to be specific to the general anesthetic used, while others probably reflect changes in the activity of afferent inputs, brain metabolism and neurotransmitter uptake that are typical to any type of general anesthesia. Therefore, an awake, freely moving animal preparation appears to be advantageous for studying impulse activity and neurochemical interactions at single-neuron level during physiologically relevant conditions.

Action Potentials↗

PubMed2006

The role of peripheral Na(+) channels in triggering the central excitatory effects of intravenous cocaine.

While alterations in dopamine (DA) uptake appear to be a critical mechanism underlying locomotor and reinforcing effects of cocaine (COC), many centrally mediated physiological and affective effects of this drug are resistant to DA receptor blockade and are expressed more quickly following an intravenous (i.v.) injection than expected based on the dynamics of drug concentration in the brain. Because COC is also a potent local anesthetic, its rapid action on Na+ channels may be responsible for triggering these effects. We monitored temperatures in the nucleus accumbens, temporal muscle and skin together with conventional locomotion during a single i.v. injection of COC (1 mg/kg), procaine (PRO, 5 mg/kg; equipotential anesthetic dose), a short-acting local anesthetic drug that, like COC, interacts with Na+ channels, and cocaine methiodide (COC-MET, 1.31 mg/kg, equimolar dose), a quaternary COC derivative that is unable to cross the blood-brain barrier. In this way, we explored not only the importance of Na+ channels in general, but also the importance of central vs. peripheral Na+ channels specifically. COC induced locomotor activation, temperature increase in the brain and muscle, and a biphasic temperature fluctuation in skin. Though PRO did not induce locomotor activation, it mimicked, to a greater degree, the temperature effects of COC. Therefore, Na+ channels appear to be a key substrate for COC-induced temperature fluctuations in the brain and periphery. Similar to PRO, COC-MET had minimal effects on locomotion, but mimicked COC in its ability to increase brain and muscle temperature, and induce transient skin hypothermia. It appears therefore that COC's interaction with peripherally located Na+ channels triggers its central excitatory effects manifested by brain temperature increase, thereby playing a major role in drug sensing and possibly contributing to COC reinforcement.

Anesthetics, Local↗

PubMed2006

Dopamine action in the substantia nigra pars reticulata: iontophoretic studies in awake, unrestrained rats.

Dopamine (DA) neurons located in the substantia nigra pars compacta release DA not only via axonal terminals, affecting neurotransmission within the striatum, but also via dendrites, some of which densely protrude into the substantia nigra pars reticulata (SNr). Although the interaction of dendritically released DA with somatodendritic autoreceptors regulates DA cell activity, released DA may also affect SNr neurons. These cells, however, lack postsynaptic DA receptors, making it unclear how locally released DA modulates their activity. Although previous work in brain slices suggests that DA might modulate the activity of GABA inputs, thus affecting SNr neurons indirectly, it remains unclear how increased or decreased DA release might affect these cells exposed to normal afferent inputs. To explore this issue, we examined the effects of iontophoretic DA and amphetamine on SNr neurons in awake, unrestrained rats. DA had no consistent effects on SNr cells but amphetamine, known to induce DA release, dose-dependently inhibited most of them. This effect was blocked by SCH23390, a selective D1 receptor blocker, which itself strongly increased neuronal discharge rate. As GABA input is a major factor regulating the activity of SNr neurons, our data suggest that dendritically released DA, by interacting with D1 receptors on striato-nigral and pallido-nigral afferents, is able to decrease this input, thus releasing SNr neurons from tonic, GABA-mediated inhibition. Surprisingly, a full DA receptor blockade (SCH23390 + eticlopride) did not result in the expected increase in SNr discharge rate, suggesting that other mechanisms are responsible for behavioral abnormalities following acute disruption of DA transmission.

Action Potentials↗

PubMed2005

Brain hyperthermia as physiological and pathological phenomena.

Although brain metabolism consumes high amounts of energy and is accompanied by intense heat production, brain temperature is usually considered a stable, tightly "regulated" homeostatic parameter. Current research, however, revealed relatively large and rapid brain temperature fluctuations (3-4 degrees C) in animals during various normal, physiological, and behavioral activities at stable ambient temperatures. This review discusses these data and demonstrates that physiological brain hyperthermia has an intra-brain origin, resulting from enhanced neural metabolism and increased intra-brain heat production. Therefore, brain temperature is an important physiological parameter that both reflects alterations in metabolic neural activity and affects various neural functions. This work also shows that brain hyperthermia may be induced by various drugs of abuse that cause metabolic brain activation and impair heat dissipation. While individual drugs (i.e., heroin, cocaine, methamphetamine, MDMA) have specific, dose-dependent effects on brain and body temperatures, these effects are strongly modulated by an individual's activity state and environmental conditions, and change dramatically during the development of drug self-administration. Thus, brain thermorecording may provide new information on the central effects of various addictive drugs, drug-activity-environment interactions in mediating drugs' adverse effects, and alterations in metabolic neural activity associated with the development of drug-seeking and drug-taking behavior. While ambient temperatures and impairment of heat dissipation may also affect brain temperature, these environmental conditions strongly potentiate thermal effects of psychomotor stimulant drugs, resulting in pathological brain overheating. Since hyperthermia exacerbates drug-induced toxicity and is destructive to neural cells and brain functions, use of these drugs under activated conditions that restrict heat loss may pose a significant health risk, resulting in both acute life-threatening complications and chronic destructive CNS changes.

Adrenergic Uptake Inhibitors↗

PubMed2005

Brain temperature change and movement activation induced by intravenous cocaine delivered at various injection speeds in rats.

RATIONALE: Speed of intravenous (i.v.) injection presumably affects the rewarding effects of cocaine in humans. Work with animals has shown alterations in the behavioral and neurochemical effects of cocaine based on delivery speed. OBJECTIVES: We studied the effects of cocaine (1 mg/kg) as both a single i.v. injection and a series of five repeated injections (8-min intervals) delivered at different speeds (4, 16, and 64 s) on brain, muscle, and skin temperatures, and locomotion in awake, unrestrained rats. Since cocaine has a distinctive action on temperature, any enhancement of cocaine's properties by injection speed should readily be seen. RESULTS: When given as a single injection, cocaine increased brain temperature and locomotion, but transiently decreased skin and muscle temperatures; these effects were augmented by a high injection speed. Regardless of injection speed, however, changes in brain temperature and locomotion were strongly correlated with basal brain temperatures; higher temperatures were associated with less change after cocaine injection. When given as a series of five injections, cocaine increased brain temperature and locomotion. Although skin temperature initially decreased, it increased after successive cocaine injections. With each successive cocaine injection in the series, measures of temperature and movement parameters increased to a plateau and brain temperature change became biphasic. CONCLUSIONS: While confirming the results of others that rapid injection speed enhances cocaine-induced locomotor activation, our study suggests that delivery rate also affects the basic physiological actions of cocaine.

Animals↗

PubMed2005

Brain and body temperature homeostasis during sodium pentobarbital anesthesia with and without body warming in rats.

High-speed, multi-site thermorecording offers the ability to follow the dynamics of heat production and flow in an organism. This approach was used to study brain-body temperature homeostasis during the development of general anesthesia induced by sodium pentobarbital (50 mg/kg, ip) in rats. Animals were chronically implanted with thermocouple probes in two brain areas, the abdominal cavity, and subcutaneously, and temperatures were measured during anesthesia both with and without (control) body warming. In control conditions, temperature in all sites rapidly and strongly decreased (from 36-37 degrees C to 32-33 degrees C, or 3.5-4.5 degrees C below baselines). Relative to body core, brain hypothermia was greater (by 0.3-0.4 degrees C) and skin hypothermia was less (by approximately 0.7 degrees C). If the body was kept warm with a heating pad, brain hypothermia was three-fold weaker ( approximately 1.2 degrees C), but the brain-body difference was significantly augmented (-0.6 degrees C). These results suggest that pentobarbital-induced inhibition of brain metabolic activity is a major factor behind brain hypothermia and global body hypothermia during general anesthesia. These data also indicate that body warming is unable to fully compensate for anesthesia-induced brain hypothermia and enhances the negative brain-body temperature differentials typical of anesthesia. Since temperature strongly affects various underlying parameters of neuronal activity, these findings are important for electrophysiological studies performed in anesthetized animal preparations.

Analysis of Variance↗

PubMed2005

Dopamine-dependent and dopamine-independent actions of cocaine as revealed by brain thermorecording in freely moving rats.

Brain temperature fluctuates biphasically in response to repeated, intravenous (i.v.) cocaine injections, perhaps reflecting cocaine's inhibiting effect on both dopamine (DA) transporters and Na+ channels. By using a DA receptor blockade, one could separate these actions and determine the role of DA-dependent and DA-independent mechanisms in mediating this temperature fluctuation. Rats were chronically implanted with thermocouple probes in the brain, a non-locomotor head muscle and subcutaneously. Temperature fluctuations associated with ten repeated i.v. cocaine injections (1 mg/kg with 8-min inter-injection intervals) were examined after a combined, systemic administration of selective D1-like and D2-like receptor blockers (SCH-23390 and eticlopride) at doses that effectively inhibit DA transmission. In contrast to the initial temperature increases and subsequent biphasic fluctuations (decreases followed by increases) seen with repeated cocaine injections in saline-treated control, brain and muscle temperatures during DA receptor blockade decreased with each repeated cocaine injection. DA receptor blockade had no effects on skin temperature, which tonically decreased and biphasically fluctuated (decreases followed by increases) during repeated cocaine injections in both conditions. DA receptor blockade by itself slightly increased brain and muscle temperatures, with no evident effect on skin temperature. DA antagonists also strongly decreased spontaneous movement activity and completely blocked the locomotor activation normally induced by repeated cocaine injections. Although our data confirm that cocaine's inhibitory action on presynaptic DA uptake is essential for its ability to induce metabolic and behavioral activation, they also suggest that the physiological effects of this drug cannot be explained through this system alone. The continued hypothermic effect of cocaine points to its action on other central systems (particularly blockade of Na+ channels) that may be important for the development of cocaine abuse and adverse effects of this drug.

Animals↗

PubMed2004

Modulation of physiological brain hyperthermia by environmental temperature and impaired blood outflow in rats.

To study the role of ambient temperature and brain blood outflow in modulating physiological brain hyperthermia, temperatures in two brain structures (nucleus accumbens or NAcc and hippocampus or Hippo) and a non-locomotor head muscle (musculus temporalis) were monitored in rats exposed to three arousing stimuli (placement in the cage or environmental change, 3-min social interaction with a female rat, 3-min innocuous tail-pinch) under three conditions (intact animals at 23 degrees C or control, intact animals at 29 degrees C, animals with chronically occluded jugular veins at 23 degrees C). While each stimulus in each condition induced hyperthermia, with more rapid and stronger changes in brain structures than muscle, there were significant differences between conditions. At 29 degrees C, animal placement in the cage resulted in stronger temperature increase and larger brain-muscle differentials, while basal temperatures in Hippo and muscle (but not in NAcc) were higher than control. At 29 degrees C, hyperthermia during social interaction was smaller but more prolonged, while the response to tail-pinch was similar to that seen at normal environmental temperatures. Animals with chronically occluded jugular veins had similar basal temperatures but showed much weaker hyperthermia than intact animals during each stimulus presentation; temperature increases in brain structures, however, were much stronger than in the muscle. Our data suggest that the brain is able to decrease neural activation induced by environmental challenges under conditions of impaired blood outflow and restricted heat dissipation to the external environment.

Analysis of Variance↗

PubMed2004

GABA, not glutamate, controls the activity of substantia nigra reticulata neurons in awake, unrestrained rats.

Substantia nigra pars reticulata (SNr) receives both GABAergic and glutamatergic (GLU) inputs that are believed to act together to regulate neuronal activity in this structure. To examine the role of these inputs, single-unit recording was coupled with iontophoresis of GLU and GABA in rats under two conditions: awake, unrestrained and under chloral hydrate anesthesia. Although GABA potently inhibited SNr cells in both conditions, freely moving rats showed lower sensitivity than anesthetized animals. Likewise, GLU effectively induced excitations in most SNr neurons in anesthetized animals but was much less effective in awake, unrestrained animals in terms of both the number of sensitive cells and the magnitude of GLU-induced excitation. These findings, along with consistent excitations induced by bicuculline in awake, unrestrained rats, suggest that modulation of GABA inhibitory input, not the opposing actions of GLU and GABA, is the primary factor that regulates the activity state of SNr neurons.

Action Potentials↗

PubMed2004

Brain temperature fluctuations during passive vs. active cocaine administration: clues for understanding the pharmacological determination of drug-taking behavior.

While it is generally assumed that cocaine self-administration (SA) is determined and maintained by the pharmacological actions of cocaine in the brain, it is also a drug-motivated and drug-reinforced goal-directed behavior, which is determined by concurrent learning and behavioral performance. To dissociate the contributions of pharmacological and behavioral factors to cocaine SA, it is important to compare cocaine SA with its pharmacological copy, passive intravenous (iv) cocaine administration. This approach was employed in the present study with respect to brain temperatures, a dynamic parameter that reflects metabolic neural activity and shows consistent fluctuations during cocaine SA. Passive cocaine injections performed with the same dose/pattern as SA induced brain temperature fluctuations similar in many ways to those in behaving animals. The initial passive drug administration of a session elevated brain temperature, while subsequent repeated injections were associated with biphasic temperature fluctuations that maintained at a relatively stable plateau. Although the magnitude of these fluctuations was twofold smaller than in behaving animals, passive animals had the same pattern; brain temperatures transiently decreased after cocaine injection, then increased, and were inhibited again by the next cocaine infusion. In contrast to self-administering animals, rats exposed to passive cocaine injections had significantly lower basal temperatures and never showed gradual temperature increases preceding the initial injection. Striking differences in brain temperature dynamics seen in the beginning of a session suggest that during the development of drug-taking behavior the initial cocaine-induced neural activation becomes transformed into behavior-related "anticipatory" neural activation (motivational arousal) that fuels drug seeking and results in the initial drug intake. While this activation is triggered by drug-related cues and enhanced by the initial cocaine intake, subsequent highly cyclical cocaine intakes appear to be primarily pharmacologically determined.

Animals↗

PubMed2004

Brain hyperthermia and temperature fluctuations during sexual interaction in female rats.

Since the metabolic activity of neural cells is accompanied by heat release, brain temperature monitoring provides insight into behavior-associated changes in neural activity. In the present study, local temperatures were continuously recorded in several brain structures (nucleus accumbens, medial-preoptic hypothalamus and hippocampus) and a non-locomotor head muscle (musculus temporalis) in a receptive female rat during sexually arousing stimulation and subsequent copulatory behavior with an experienced male. Placement of the male into a neighboring compartment increased the female's temperature (approximately 0.8 degrees C) and additional, transient increases (approximately 0.2 degrees C) occurred when the rats were allowed to see and smell each other through a transparent barrier. Temperatures gradually increased further as the male repeatedly mounted and achieved intromissions, peaked 2-3 min after male's ejaculation (0.2-0.4 degrees C), and abruptly dropped until the male initiated a new copulatory cycle. Similar biphasic fluctuations accompanied subsequent copulatory cycles. Although both arousal-related temperature increases and biphasic fluctuations associated with copulatory cycles were evident in each recording location, brain sites showed consistently faster and stronger increases than the muscle, suggesting metabolic brain activation as the primary source of brain temperature fluctuations and a force behind associated changes in brain temperature. Robust brain hyperthermia and the generally similar pattern of phasic temperature fluctuations associated with individual events of sexual interaction found in males and females suggest widespread neural activation (motivational arousal) as a driving force underlying this cooperative motivated behavior in animals of both sexes. Females, however, showed different temperature changes in association with the initial (first mount or intromission) and final (ejaculation) events of each copulatory cycle, suggesting sex-specific differences in neural activity associated with the initiation and regulation of sexual behavior.

Animals↗

PubMed2004

State-dependent action of cocaine on brain temperature and movement activity: implications for movement sensitization.

Because neural activity is highly energy consuming and heat producing, brain temperature offers a reliable, real-time measure of an animal's activity state and its changes induced by environmental and drug challenges. Therefore, it allows evaluation of the activity state of an animal preceding drug administration and its relation to subsequent drug-induced neural effects. This approach was used to explore the state dependency of cocaine's effects. Brain and body temperatures, as well as locomotion were measured simultaneously in rats during repeated, daily administration of cocaine (15 mg/kg i.p., daily for 5 days) under different experimental conditions. The drug was administered via (a). a chronically implanted catheter in quiet resting conditions, (b). an injection made under quiet rest or (c). an injection under activated conditions associated with placement in the cage. Although brain temperature and movement increased after cocaine administration in each condition, cocaine's action (evaluated as cocaine-saline difference for both parameters) was situational. Catheter-administered cocaine induced the strongest movement activation and robust, monophasic temperature increase, which remained relatively stable following each subsequent drug infusion. Cocaine injected during quiet and, especially, activated conditions, induced a weaker locomotor activation, while the temperature response (evaluated as drug-saline difference) had a biphasic pattern. Cocaine initially inhibited the temperature increases seen in saline-treated animals (0-20 min) and then induced a more prolonged hyperthermia, which was about twofold weaker than that seen after catheter-administered drug. Although movement activation gradually increased following repeated treatment in activated conditions, the magnitude of this sensitized motor response barely reached the levels induced by the initial cocaine administration via catheter. These data suggest that both the acute effects of cocaine in the brain and their change following repeated drug administration are dependent upon the ongoing neural activity state of the animal. Cocaine's interaction with this activity state is a crucial factor determining the behavioral effects of this drug, including state-dependent motor sensitization.

Animals↗

PubMed2004

Brain hyperthermia induced by MDMA (ecstasy): modulation by environmental conditions.

Drugs of abuse, such as 3,4-methylenedioxymethamphetamine (MDMA), often have more powerful effects during states of increased activation and under specific environmental conditions. Because hyperthermia is a major complication of MDMA use and a factor potentiating neurotoxicity, we examined the effects of this drug (9 mg/kg, sc; approximately one-fifth of the known LD(50) in rats) on brain [nucleus accumbens (Nacc) and hippocampus (Hippo)] and muscle (musculus temporalis) temperatures in male rats under conditions that either model human drug use (social interaction with female, warm temperature) or restrict heat dissipation from the brain (chronic occlusion of jugular veins). Under quiet resting conditions at 23 degrees C, MDMA induced a moderate but prolonged hyperthermia. Both NAcc and Hippo showed more rapid and stronger temperature increases than muscle, suggesting metabolic neural activation as a primary cause of brain hyperthermia. During social interaction with a female, brain hyperthermia induced by MDMA was significantly potentiated (+89%). Brain hyperthermia induced by MDMA was also strongly potentiated (+188%) in animals with chronically occluded jugular veins, suggesting impaired cerebral outflow enhances intrabrain heat accumulation. At 29 degrees C, MDMA pushed temperatures in the brain to its biological limits (>41 degrees C; +268%), resulting in fatalities in most (83%) tested animals. Therefore, by inducing metabolic brain activation and restricting heat dissipation, MDMA use under 'party' conditions may be much more dangerous than under standard laboratory conditions.

Animals↗

PubMed2004

Brain hyperthermia during physiological and pathological conditions: causes, mechanisms, and functional implications.

Although brain metabolism consumes high amounts of energy and is accompanied by intense heat production, brain temperature is usually considered a stable, tightly regulated homeostatic parameter. Current animal research, however, has shown that different forms of functional neural activation are accompanied by relatively large brain hyperthermia (2-3 degrees C), which has an intra-brain origin; cerebral circulation plays a crucial role in dissipating this potentially dangerous metabolic heat from brain tissue. Brain hyperthermia, therefore, reflects enhanced brain metabolism and is a normal physiological phenomenon that can be enhanced by interaction with common elements of an organism's environment. There are, however, instances when brain hyperthermia becomes pathological. Both exposure to extreme environmental heat and intense physical activity in a hot, humid environment restrict heat dissipation from the brain and may push brain temperatures to the limits of physiological functions, resulting in acute life-threatening complications and destructive effects on neural cells and functions of the brain as a whole. Brain hyperthermia may also result from metabolic activation induced by various addictive drugs, such as heroin, cocaine, and meth-amphetamine (METH). In contrast to heroin and cocaine, whose stimulatory effects on brain metabolism invert with increases in dose, METH increases brain metabolism dose-dependently and diminishes heat dissipation because of peripheral vasoconstriction. The thermogenic effects of this drug, moreover, are enhanced during physiological activation, resulting in pathological brain hyperthermia. Since brain hyperthermia exacerbates drug-induced toxicity and is destructive to neural cells, uncontrollable use of amphetamine-like drugs under conditions restricting heat dissipation from the brain may result both in acute life-threatening complications and clinically latent but dangerous morphological and functional brain destruction.

Animals↗

PubMed2003

Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction.

Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) temperatures were continuously monitored. METH produced dose-dependent hyperthermia, with brain structures (especially the NAcc) showing a more rapid and pronounced temperature increase than the muscle. At the highest dose, brain and body temperatures increased 3.5-4.0 degrees C above basal levels and remained elevated for 3-5 hr. Stressful and other high-activity situations such as interaction with a conspecific female are also known to induce a significant hyperthermic response in the rat. A combination of social interaction and METH administration was tested for additive effects. Male rats were exposed daily to a conspecific female for a total of 120 min, and METH was injected at the same doses 30 min after the initial contact with the female. An initial hyperthermic response ( approximately 1.5 degrees C) to social interaction was followed by a large and prolonged hyperthermic response (3.5-5.0 degrees C, 5-7 hr at 9 mg/kg) to METH, which was again stronger in brain structures (especially in the NAcc) than in the muscle. Although the combined effect of the hyperthermic events was not additive, METH administration during social interaction produced stronger and longer-lasting increases in brain and body temperature than that induced by drug alone, heating the brain in some animals near its biological limit (>41 degrees C).

Amphetamine-Related Disorders↗

PubMed2003

Naloxone depresses cocaine self-administration and delays its initiation on the following day.

While dopamine mechanisms play a crucial role in cocaine-taking behavior, the contribution of endogenous opioid systems is less clear. We assessed the effects of opioid receptor blockade by naloxone (1 mg/kg, s.c.) on the daily performance and subsequent initiation of cocaine self-administration in trained rats. Naloxone decreased self-administration rate by approximately half, with the effect varying from complete blockade to no change. On the day following naloxone treatment, the latencies from the drug availability cue to the first self-administration were consistently longer than before naloxone treatment. Measurement of brain temperature and behavioral observations suggested a lower than normal level of motivational arousal as a factor for slow initiation of cocaine-taking behavior. After the first drug infusion, however, performance was uniformly normal. These data suggest endogenous opioid systems play a role in cocaine-taking behavior and indicate a residual inhibitory consequence of naloxone treatment on the initiation of this behavior.

Animals↗