In regard to D-amphetamines therapeutic use and abuse. I've been prescribed 30-45mg of d-amp daily for over 6 months for morbid inattentive ad/hd or high functioning autism, they're unclear as to which one it really is. In recent months i've felt my thought patterns become quite rigid, analytical and logical compared to my once day-dreamy, unrealistic, bored self. These changes are clearly the result of dexedrine use and i belive permanent.
I happen to also be a mod on the largest AD/HD forum on the net so any information i receive will eventually make it to possibly hundreds of people. Please dont dumb it down, im well enough versed in neurochemistry to understand most research papers on pubmed, my vocabulary is simply limited.
Full Version: Please tell me about Neuroplasticity
QUOTE(Dbc @ Apr 04, 2007, 12:41 PM) 
In regard to D-amphetamines therapeutic use and abuse. I've been prescribed 30-45mg of d-amp daily for over 6 months for morbid inattentive ad/hd or high functioning autism, they're unclear as to which one it really is. In recent months i've felt my thought patterns become quite rigid, analytical and logical compared to my once day-dreamy, unrealistic, bored self. These changes are clearly the result of dexedrine use and i belive permanent.
I happen to also be a mod on the largest AD/HD forum on the net so any information i receive will eventually make it to possibly hundreds of people. Please dont dumb it down, im well enough versed in neurochemistry to understand most research papers on pubmed, my vocabulary is simply limited.
Most of my understanding of amphetamine plasticity is in regards to drug dependence and sensitisation, if you are interested, I will write on it. I don't know if that's what you're looking at, but it might be a start.
Please do, thank you.
Also, incase someone was going to bring up the often quoted study D.A.R.E uses to claim amphetamines cause brain cell death in DA transporters. It was found the study was only on IV methamphetamine users and drug agencies were simply misrepresenting its findings.
Also, incase someone was going to bring up the often quoted study D.A.R.E uses to claim amphetamines cause brain cell death in DA transporters. It was found the study was only on IV methamphetamine users and drug agencies were simply misrepresenting its findings.
Ok
Sensitisation
Sensitisation refers to the effect of an increase in response with repeated administration. In reference to amphetamines, it was probably first noted by the behaviouralists who found increased locomotor activity and stereotypy with repeated administration of dopamine modulators (dexamphetamine, methamphetamine, cocaine etc). The primary system underlying this psychomotor sensitisation has been elucidated as the mesolimbic dopamine system. Although most other drugs of drugs of abuse eg opiates, ethanol, PCP can also cause psychomotor sensitisation and it has been noted that there is cross-sensitisation between different types of drugs.
The mechanism for this may be D1 receptor tolerance which produces sensitisation of D2 effects. D1 receptors activate Gs while D2 receptors activate Gi. Gs stimulates cAMP while Gi inhibits cAMP. But I've also read that it could possibly go the other way, D2 tolerance providing D1 sensitisation and that maybe both become sensitised. Further downstream pathways are involved incorporating DARPP-32, CART, IP3, PKA, PP-1 etc. My biochemistry isn’t up to scratch for these and may actually paint a clearer picture if you can wade through the acronyms, see http://www.aapsj.org/view.asp?art=aapsj070235.
It has been suggested by Robinson & Berridge (1993) that this sensitisation underlies drug dependence and renders these brain systems sensitised to drugs and drug related stimuli. They further suggest that the system that is sensitised is the ‘wanting’ (incentive salience as they call it) part which becomes separated from the pleasurable part. I found in their 2000 paper a section that is probably of most interest to you...
The second line of evidence that the neural
substrate sensitized by drugs of abuse is involved
in mediating drug reward comes from studies on
the neurobiology of sensitization. There is not
space here to review this large literature, but
suf. ce it to say there is now considerable evidence
that behavioral sensitization is associated
with neuroadaptations in dopamine/accumbens
systems.3,34,36,121 –124 This is important because it
is well established that these neural systems play
an important role in mediating the rewarding
effects of drugs and other incentives.15,125,126
Thus, if sensitization-related neuroadaptations
are found in this mesocorticolimbic circuitry this
is strong evidence that at least one neural system
known to be critical for mediating drug reward
undergoes “neural sensitization”.
Both pre- and post-synaptic neuroplastic
adaptations have been described in the dopamine/
accumbens system of sensitized animals.
An example of a presynaptic adaptation is a
persistent increase in the ability of a variety of
drugs to increase the over ow of dopamine in
the nucleus accumbens and striatum of sensitized
animals, in vitro and in vivo.3,34,46,79–81,121,122
Examples of postsynaptic adaptations include an
increase in the sensitivity of dopamine D1 receptors78,123
and a decrease in the sensitivity of
glutamate receptors127 in the nucleus accumbens
of sensitized animals (see Wolf124 for a review of
the role of excitatory amino acids in sensitization).
More recently it has been reported that
both amphetamine and cocaine sensitization are
also accompanied by persistent structural
modi. cations in the morphology of output neurons
in both the nucleus accumbens and prefrontal
cortex.128,129 Repeated treatment with
amphetamine or cocaine increases the length of
dendrites on medium spiny neurons in the nucleus
accumbens and on pyramidal neurons in
the prefrontal cortex. This is accompanied by an
increase in spine density on the distal dendrites
of these cells. On medium spiny neurons there is
an especially large increase in the number of
branched spines; that is, spines with multiple
heads. These structural data suggest that sensitization
may involve more than a simple up- or
downregulation of biochemical processes, but it
may involve changes in patterns of synaptic connectivity
in brain reward systems, changes that
may be similar to those seen in other neural
systems in association with other forms of experience-
dependent plasticity.128,129 These observations
are consistent with increasing evidence
implicating neurotrophic factors in sensitization.
130–13
ROBINSON, T.E. & BERRIDGE, K.C. (2000). The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction, 95, 91-117.
Sensitisation
Sensitisation refers to the effect of an increase in response with repeated administration. In reference to amphetamines, it was probably first noted by the behaviouralists who found increased locomotor activity and stereotypy with repeated administration of dopamine modulators (dexamphetamine, methamphetamine, cocaine etc). The primary system underlying this psychomotor sensitisation has been elucidated as the mesolimbic dopamine system. Although most other drugs of drugs of abuse eg opiates, ethanol, PCP can also cause psychomotor sensitisation and it has been noted that there is cross-sensitisation between different types of drugs.
The mechanism for this may be D1 receptor tolerance which produces sensitisation of D2 effects. D1 receptors activate Gs while D2 receptors activate Gi. Gs stimulates cAMP while Gi inhibits cAMP. But I've also read that it could possibly go the other way, D2 tolerance providing D1 sensitisation and that maybe both become sensitised. Further downstream pathways are involved incorporating DARPP-32, CART, IP3, PKA, PP-1 etc. My biochemistry isn’t up to scratch for these and may actually paint a clearer picture if you can wade through the acronyms, see http://www.aapsj.org/view.asp?art=aapsj070235.
It has been suggested by Robinson & Berridge (1993) that this sensitisation underlies drug dependence and renders these brain systems sensitised to drugs and drug related stimuli. They further suggest that the system that is sensitised is the ‘wanting’ (incentive salience as they call it) part which becomes separated from the pleasurable part. I found in their 2000 paper a section that is probably of most interest to you...
QUOTE
The second line of evidence that the neural
substrate sensitized by drugs of abuse is involved
in mediating drug reward comes from studies on
the neurobiology of sensitization. There is not
space here to review this large literature, but
suf. ce it to say there is now considerable evidence
that behavioral sensitization is associated
with neuroadaptations in dopamine/accumbens
systems.3,34,36,121 –124 This is important because it
is well established that these neural systems play
an important role in mediating the rewarding
effects of drugs and other incentives.15,125,126
Thus, if sensitization-related neuroadaptations
are found in this mesocorticolimbic circuitry this
is strong evidence that at least one neural system
known to be critical for mediating drug reward
undergoes “neural sensitization”.
Both pre- and post-synaptic neuroplastic
adaptations have been described in the dopamine/
accumbens system of sensitized animals.
An example of a presynaptic adaptation is a
persistent increase in the ability of a variety of
drugs to increase the over ow of dopamine in
the nucleus accumbens and striatum of sensitized
animals, in vitro and in vivo.3,34,46,79–81,121,122
Examples of postsynaptic adaptations include an
increase in the sensitivity of dopamine D1 receptors78,123
and a decrease in the sensitivity of
glutamate receptors127 in the nucleus accumbens
of sensitized animals (see Wolf124 for a review of
the role of excitatory amino acids in sensitization).
More recently it has been reported that
both amphetamine and cocaine sensitization are
also accompanied by persistent structural
modi. cations in the morphology of output neurons
in both the nucleus accumbens and prefrontal
cortex.128,129 Repeated treatment with
amphetamine or cocaine increases the length of
dendrites on medium spiny neurons in the nucleus
accumbens and on pyramidal neurons in
the prefrontal cortex. This is accompanied by an
increase in spine density on the distal dendrites
of these cells. On medium spiny neurons there is
an especially large increase in the number of
branched spines; that is, spines with multiple
heads. These structural data suggest that sensitization
may involve more than a simple up- or
downregulation of biochemical processes, but it
may involve changes in patterns of synaptic connectivity
in brain reward systems, changes that
may be similar to those seen in other neural
systems in association with other forms of experience-
dependent plasticity.128,129 These observations
are consistent with increasing evidence
implicating neurotrophic factors in sensitization.
130–13
ROBINSON, T.E. & BERRIDGE, K.C. (2000). The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction, 95, 91-117.
This is a "lo-fi" version of our main content. To view the full version with more information, formatting and images, please click here.